DEQ-CFW_00079568

RFCMVED
.KS
PIECE
FOUNDED 7EE7
June 21, 2017
Via Federal Express and Email
Secretary Michael S. Regan
Department. of Environmental Quality
217 West Jones Street
Ralei h, Forth Carolina 27603
Tie: GenX in the Cape Fear River
Addendum to First Set o1' e,quest:s -for DEQ Action
Dear SecretaryRegan:
no Ni3wr" ELm STREET
GREE'NssoP,O, NC 2?4m
T 33E,373,8850
We are environmental counsel for the gape Fear Public [.Utility Authority ("CFPUA"), We
write with rearto the, ft
-fllowing additional toxicological. studies we have found regarding the
GenXr compounds released by Chernoarrs into the Cape Fears River:
• :Melissa Gomis, Froi.n emission source to human tissues- mociel�rt��.�lre �to��.��o t�}..1���m .._.._ ..
• Zha:nyurr Wang, Fluorinated alternatives . to lon,z,, ch.airch.a i. fir �gr��l � l„��r har�� � Iic acids
rlarcA H arr sulfani ; acids ...(P ''�s.'); and their1�q� (2013)
• Gornis &. Wang, ��....Lncdpltp assessment of the... �hysieoehetrrrral_1�roveitres and
environmental ent�al late of emenjng an( oyKI..13�� ar� r� �c�l� �Iaroroal �.1 substance �21
• M.:Beekrrraan. Evaluation of the substances used in the, Gen '�'eolrrrola���< �5�. � � €��rs,
....... .
National Institute fir Public health, 1`he Netherlands (201 ).
Each is enclosed herevvitlr..
We expect the N. C. Department of Environmental Quality (`SI7EQ") or the N.C.
Department of Health and I-TU ran Services ("DIIl S") has already considered these studies, but
CF'PUA wanted to nmke certain. We would appreciate DEQ advising CFPUA of'the studies upon
which DIIIIS is relying to establish the level of acceptable risk in. the £'.ape. Fear River a:oniplex,
E.. tee. ,cC}.1
Brooks, PieciN, NIC'Lenfjon. Hmnnphrev 8� Lwcnard, t_.L.P.
Attc: r c-.vs and Cc3unsel1cws ai Law
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cc: M« B12 Lane
Enclosures
Sincerely,
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DEQ CFW-0 OO795 O

DEQ-CFW 00079571

Ervimn-meFt 1 t n adunal 6c< M02142-246
Fluorinated . alternatives to long -chain perfluoroalkyl carboxylic acids
(PFCAs), perfluoroalkane s l oniacids (PF s) and their
potential precursors
Zharkyun Wan a, lan M COUSit3S b, Martin cheringer a'*,Konrad ungerbOhlei" a
frirtimte for e'henaiorl and sioengbxr -tat; rarr:.ttrictt, i Yaii an Easels-S. sa id, cfi-8033 zuddz SwilzerksM
Depwrrnef F (n.i ). SrVCk11O4n Unl". rsit ' SE..I"Xi'91 Stoe"k tilts, $tNl dcn
A B "T I C L E 1 td F 0
A B S T R A C T
.,_..................................................................................
Attid histitry,
_........_ ...�....�..,...................................... ... ........ ---...-------
Since 2000 there has be n an on -going industrial transition to replace long -chain perfluoroalkyl carboxylic adds
Peceiwed 30 May 2013
(PFCAs), perffuoroalkate sulfonlc adds (i'FSAs) and their preLumrs. To mate, in-foun, ation on these replacements
Accept l 27 August 2013
indudin',e', their 8:hemi al identities, however, has not been published or ina4. e easiiy a£'cessible to the.public, ham -
Available airline 26 era:i:okr 2013
13£'rin; risk aSSeSSrnerit and management nfrhese chemicals, llei'e we i'£?Vier.v 9i1fi7rriaatii7ra on fluorinated altcrna-
.fCe.................. a
tna'rds:t...----------...............,,........................................
tives in the public domain. We ldendf'y over 20 fluorinated substances that are applied in (i) 0uoropuls ricer
nxiluar r ai d alkyl subs=ces
manufacture, [if] surface treatment uftexule, leather and carpets, � Fii) Surface treatment of food contact t nnterials,
p i3`lt3irxin<ii:Ftil [;3ibCt;€ybc add.5
list) Inetdl plating, [VJ f fe-rl b1.'inl� foams, and Jvi] other C47FA merdal and consumer prnL'I3:icts,W- summarize a.`ur-
P lsin£ nated'Wfoxtic adds
:rent knowledge on their environmental releases, persistence, and exposure of biota and humans. Based oil the
Mu)rinated alternatives
ation available, it is unclear whether fluorinated alternatives are said'' for bemoans and the environ-
menL We idora.* three Major data daps that iaxnrst be Tilled to perform ineauiagful risk assessments and recorn -
nneud generation of the missing data through cooperation among all stakeholders (Industry, regulators, academic
scientists and the public),
0 2013 Elsevier Ltd, rill rights reserved.
1. introduction
Since 2000 iong-chairs perffuorualkyl carboxylic acids [PFCAs,
C F2,,+ rCf1t31-1, n �- 1)9 perfluoroalkane sulfonic acids j.PFSA.s„
C,,F2e, .;. TSQ.;I­1, n =? 61 and their potential precursors (3lirk et al.,
2011), have attracted attention as global contaminants. Lung -
chain l'FCAs and PFSAs are problematic because they are highly
persistent (Friimel and ICnepper, 2010; 'arsons et al., 2008),
bioaccumulative (Concer er al., 2008) and have been detected ubiqui-
tously in the ablotic environment (Rayne and Forest, 2009), biota
(Giesy et al., 2001), fond items (Clarke and. Smith, 2011) and hurnans
(Vestergren and. Cousins, 2000). As a result perffuorooctane sulfdnrate
(PFOS) and related substances based on sulfonyl fiuo-
ride (RJSF) were listed under .Annex B (restriction of production and
use' of the Stockholm Convention in 2009, In 2012 Cr i—Cr4 PI`C er s'
were identified as vi'vB chemicals (very persistent and very
bioaccunnilative;, end were included in the Candidate List of Sub-
stances of Very fth Concern under the European chemicals regulation,
REACH (kC'H& 2013a), In 2013, also perfluorooc-tanoic acid (PFOA) and
ammonium perfluorooctinoate (APFf1) were listed in the Candidate &.1st
of Substances of Very High Concern ECl1A. (2013a),
" Corresponding an3 h;>r. "€'e L: [phone]C162.
F-niaii ar".dress: a«nsrhe nge Ecf c hz.ib (m, Sclredngax).
d 1E 12€ ,5 - Srx i -tint utter 2J 26r3 Elsevier Ltd. rill rights xeserraed,
Driven. by concerns about their undesired impacts on humans and
the enviroruuent, there. has been a trend among global producers to re-
place. long-ciiain PFCAs, IiMM and their ,potential precursors with their
shorter -chain homologues (Ritter, 2010) or other gepes of (rion;fluod-
nated chemicals (LINEP, 2012) (these replacements are referred to as
irttrrriative-i in the following). These industry initiatives began in 20 al
when 3M announced a global phase. -out of its product, based on Ce,
Ca and CIO chemistry and replaced them with products based on C4
ciienaistryr such as perflunrobutane sulfonic acid (PFf3S) (3M, 2000',
Ritter, 2010). In 2006, eight major producers of PFCAs„ tluoropolymers
and fluorotelorner substances joined the US EPA 201.0J1 S PrOA Ste.I '-
ardship Program (US EPA, 2006) to work towards the elimination of
long -chain PFCAs and their potential precursors by 2015,
In this study we address the quesdon: are the fluorinated alterna-
tives to long -chain per- and polyfluoroaDWI products safe for humans
and the environment? Recent experience with replacernents of other
chemicais has shown a "lackAe' problem, i.e. one chemical from a
group of structurally similar chemicals was removed from the market
and replaced by other chemicals from the same group, but the basic
problem was not really solved (Goldstein et al., 2013; Strernpel et. al.,
]013). For example, polychlorinated bfphenyls (PCl3s) were replaced
by short -chain chlorinated paraffins, which are currently being eva.blat-
ed under the Stockholm Convention,
To answer this question, information regarding alternatives (includ-
ing, chemical structures, physicochemical propertles, (bio)degradability,
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L Wang et at 1 Emiroraraeat rraterraarorrri 60 (2013) .242--248
bk3accum lotion potentiA, (Leo)toxicity, production and releases, and
environmental and human exposure) is needed. However, due to can-
cerns of business confidentiality„ most of the information required to as-
sess the safety of alternatives has not been published or made easily
accessible. to the public This lack of data makes it unclear whether alter-
natives have been fully tested before they are commercialized, It also
irihibin, scientists and civil society organizations, as an essential supple-
mf:nt to regulators and industry, from proactively minimizing the rides
associated a<vitb alternatives by conducting monitoring activities and re-
search into the environmental fate and potential adverse e•fTe•cts of alter-
nat-ives (Goldstein et al., 2013).
Hero, we review information on fluorinated alterative,, in the public
domain in two respects. (i) to identifsy which c.bernic.als are (possibly)
applied in various industry branches or consumer products; and (h) to
summarize current knowledge on their environrne•otal releases, persis-
tence, and exposure of biota and humans. With the inforarration provid-
ed, we airy to gave an overview of the ran -going transitions to fluorinated
alternatives and of the potential environmental and human exposure
to these chemicals. Due. to :spare limitations, we do not address potential
adverse effects of these chemicals. Related information, however, can be
found it the following references: Asalri (2006), Borg and Hakamson
(2.012), ECHA (201.3b):. E: SA (2010, 2011 a, 2611b)„ Gordon (2011),
Hagenaacs et al. (201.1), Lau et al. (2007), lclurgcard et al. (2010), and
Wang et al. (202a), in addition, it should be noted that several types
of troy fiarcorinaf: ;f substances are also available as alternatives (e,g„
dendrimers, silc)xancs anti silicone polymers) (Paulsen et al., 2005;
tlNEP, 2012), but may not perform as well as fluorinated substances,
particularly in situat ens where extremely low surface tension and;
or durable rail- :anti water -repellence is needed (Mott, 201.1). For
inform idon or uomfluodnated alternatives, we recommend readers
to consult other studies that specifically address these: substances
l_Ilaszewska et al.„ 2012; Wang et al., 201_3b).
2. Production and use of fluorinated alternatives
Hare, we summarize the publicly accessible information on the
production and use of fluorinated alternatives in €lafiereut industrial
branches (for examples, see Fig. 1.). tuber fluorinated alternatives
might also be on the market, their identities, however, couldd not he
identmed,
2,1. Fluoropolyme r rnoual)'arture
Historically, almost all producers applied ammonium or sodi-
um perfluorooctauoate (APFO and NaPFO) as processing aids
in the (emulsion) polymerization of polytetrafluomethylene (PTP6),
perfluorinated ethylene -propylene copolymer (FEP), perluoroalkoxy
polymer (PEA) and certain fluoroelastcomers; and applied ammoni-
um perfluorononanuate. (APFN) in the emulsion polymerization of
polsyvlr;ylidene fluoride oride (PVDF) (Frevedouros et al., 20€)6), However,
during the recent. transition, most of the producers have developed their
town alternatives. Known commerdafized fluorinated alternatives are
functioralized perfluorcopolyethers (PFPEs), including (D .fisDONAr from
31v1jflymeon(CT-.,DCF2(.'F,a£:•FzOC1HFCT,,CC)f)....NW', CAS No. 95 45-44--
f) (Gordon, 2011); (il) Cz-mX from DuPont (CF3CF2CF2GCF(C )COO
NM;', CAS No. 620..37-80-:3) (DuPont, 2010); (iii) cyclic or polymeric
furcticonaGzed PFPEes from Solvay for its irfF"E and PVDF manufacture
,Mmcluonni et it, 20101 Pieri et xis 2011, Spada and Kent, 2011;
(e•g.< a complex process rraixture, C;,FGCIC)-[CF,CF(CFa} 1133 (C (Cla)C3ffa-
CF2CC1OH, n -= 1-4, in — 0--2, with a molecular weight in the range of
500 to 650 Da has been registered at the European .Food Safety Authority
(EFSA), CAS No. 329238-24-6 (F.FSA, 2010)), (iv), C2Ps0C2F40CP2C€ 0--
1` H'(CAS No. 908020-52-0) from Asabi (E.FS& 2011 a); and (v) another
functionallzed PFPE from Chenguang In China. (its structure and CAS No,
remains unrevealed) ,.X4e et A, 2010, 2011). In. Europe, GenX has been
M
registered under REACH with a production volume of 10-100 tonnes
per year (Et HA, 2.013b).
In addition, some producers„ such as Daikin (1v„ai, 2011), may have.,
used ammonium perlluorobexanoate (APFHx) as polymerizadon. pro-
cessing, aids (supported by higher levels of perflncorohexanoic acid
(Alllxc,l) in comparison to other PFCA lrsarualu ues detected in water
samples from a f9uoropolymer manufacturing site in France (Dancby
ea A, 2012)1, Finally, a Chinese producer may use 6.2 fluorotelomer car-
bmWiic acid (6:2 FICA, QFr2Cl12CC3t7pl, CAS No. 531126-12,:,) as an, alter-
native processing aid replacing perfluomoctanoic acid (PRM) (Xta et al.,
2011). No -information is available on the processing aids currently used
by other fluoropolymer manufacturers.
2.2. Staface trearmert of textile, leaOf er and carpets
Side -chain fluorinated polymers, which comprise non -fluorinated
carbon backbones and side -chains containing a mixture of 62 14.2
fluorotelt3mee moiedes (Cjj,-e-,t:,H4--, a 6._14) or moieties de-
rived from POSE, were. widely used ire surface treatment products to irn-
part water- anti oil -resistance to textfle, leather and carpets (Buck et al.,
2011), A current ov.nd is to use shorter -chain homologues to replace
long -chain flurotelrarrrer- or POSF-based derivatives on side -chains
Ritter, 2010). Since 2003, 3M .has commercialized a series of surface
treatment products such as Scotchguard PM-3622 (CABS No. 949581-
65-1), PM-490 CAS No. 940891.99.6) and PM-530 (CAS No. 923298-
12-81� containing C4 (C.J 60,— side -chain fluorinated polyrnecr de-
rived from perfluorobutane sulfbnyl fluoride (Pl3SF) (Penner, 2006).
Muorotelonier inanufacturers have developed products based on highly
purified fluorotelomer raw materials (mostly 6.2, see exanoples coal the
OECD Portal on Perfluoranated Chemicals (OKE), 2013)), including
copolymers derived front 52 fluorotelome:a:s and organusiloxane
(Llnidyne TG--5521 developed by Daikiu and Dow -Corning (DoIA,
Corning. 2007)), Miteni has commercialized polyfluoroalkyl alcohols
(31 and 5:1 Fl Hs. C F2,, . ,Ci-120H, as = 3, 5, CAS % 375-01-9 and
423-46-1) that can be used as building blocks for side -chain fluorinated
polymers (Miteni, 2012) and Solvay has applied IaFPEs such as
Eluorolini€V as alternatives to side -chain fluorinated polymers for textile
surface treatment (Solvay, 2011).
Some producers in China and Italy have initiated the production of
perfluurube sane s€atforryl fluoride (Pl IxSF, f'c e:sS0:,!1:;-based derivatives
as alternatives in su face. treatment products (China MEP, 2012; Miteni,
2012), but these car degrade into perflu.orobexane sulfonate (F 1-1xS) in
the environmeiu (D'coma et al., 2dlN3, Martin et al„ 2006) and are thus
considered as long -chain PFSA precursors (fuck et at., 2011), In China,
it is estimated that in the: nest. 5-l0 years production of surface treat-
ment products containing a�HxSF- or iTSF-derivatives vdil ready more
than 1000 tonnes per year (Huang et al,, 2010).
23. Surface contactmaterials
After Al ceased its production of PCtSF-based side -chairs fluorinated
polymers (e.g., CAS No. 92265.81-1) and phosphate diesters (SAmp?Ap,
e.g., PC 1S07, 0 N o. 30381-98-7) that were used in food contact materials
(AI, 2000), there is no evidence that P6SF-based derivatives are used as
alternatives. Fluorotdoraer manufacturers have developed products
based on 6°2 flan€3rratelcoaraers tr replace their earlier products [both side -
chain fluorinated poly tiers and phosphate daesters (diPA,Ps;[ that were.
based on lorage.r-cla sin ierorotelrrraer derivatives (loi et al., 2013). For ex-
ample, since.2008, seven 6:2 flucorotelomer-based side -chain fluorinated
polymers have been. registered in the inventory of Effective Food Contact
Substance (Ft ) Notifications of the United States Food and Drug Admiu-
kstratiun; they are CAS,No. 1:345817-52-8 byAsahi„ CAS No, 1012783 i0-
8,11:58951-85-9, and 12€.af3450- 09-0 by Dail m and CAS No,1071022-25-
7, 357624--1.5-8, and W71022-26-8 by Dut'ont (US FDA' 2013a). In
addition, products based on P1=PEs such as SolveraID front. Solvay (chemi-
cal structures are Rely sirlailar to HD 0)(OH)PC1--(Ct.12CI-120),"Cl'12CFN-
DEQ-CFW 00079574

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24 - War.; et al.1 Emdronmem h?temmioa ial 60 QUO) ) 2 42--248
Fluoropolymer manufacture Metal plating
ADONA (CAS No. 966446-44-9)
Fe Fz
G C C C00-
F�! Fa HF
GenX (CAS No. 62037-80-3)
F2.
FaC C C C--, F C00—
Fa I
CF3
Asahi°s product (CAS No, 908020-53-0)
Fe F2
F CSC,.,n.,tt„,C00-
F- Fa
olvay's product (CA No 339336.24_6)
C Fa Fa
F�
F2
Fire fighting foams nd miscellaneous
Fi(6t)4-PF (CAS No. 25626-09-4)
zH�
Fe Fa
C Cat to
N
FaC C 50}y
F. CzBt HF,
6.2 FT C, (CAS No, 27619-97-2)
Fa F, Fa Ha
Fa ' C ,10
C, ,01-- .0 N, C 6C
Fx Fa Ala a
F-53 AS No. 754999- 4-7)
F,z Fx Fa Fa
F2 Fx Fa
F-538 (CAS No. 73606619-6)
Fz Fa Fa Fz
C€FzC � C C C
Fx Fa Fa
---------- --------------------------------------------
Fa c� 0 Fa F2 F2�
Ric CF. C
C� C C FAO �� C C NH
Fa Fa H Fz Fx F2, Fa
€ €,
F\ CsHs " aC€
a Fa Fa Hx HHa �
Fa yC N-1C1-",--«,r.,,.^."�GI--,C,, � N-10� t4 �` C � aH "wC%C00 " Ha
Fa Fz Ha H, Ha OChta
r a .1. Examples of tlaarinatvd altexarad'tiTF, idea d€,xedl s'xa di[rere<et nclwrV' braachas.
t0B 1 xj�-(O�t:Fz€ t,j -i CFy�1 (OGi CH2,)a-CP CW(O,(OH) (Trier a1„ and F-53F were used in 2009 in they metal Plating industry (both deco-
2011), have been used as alternatives (Soh% 2011). rative and hard metal plating) in China (Huang et aL. 20101).
2.4. etal (chrortaium) plradng
Historically, salts of PFOS have been used as wetting agents and
rnist-suppressfng agents in decorative pla ing and non -decorative
hard plating, Recent technology development using chr€arnitam-111 m-
stxmd of chromium. -VI has made PMS use in decorative chrome plating
obsolete. Chromium-111, havvever, cannot be used for hard chrome
plating* OJNEP, 2012), In Europe, salts of 6:2 tluorotelorner sulfonk:
acid (6:2 FFS& Cj13Ql-1450-1H) are applied as alternatives to PFt1S,
however, They can only partly be applied in decorative plating due to
slightly higher surface tension compared to PrOS (UNEP, 012). In
addition, OI Et),$-FF6S (CAS No. 25628-011-4) i.s registered for metal
plating under REACH with a production volunud of t.--10 tonnes per
annarrn (KWI, 2013b), Also, a German producer reported. a produc-
tion of 20-50 tonnes of PF35-based (C4F9SO2N', CH;)CH:zCHzC].*l'(C1)OH
(CAS No. 120945-47-3) iu 2003, which is used as defoamer in
tine electroplating industry; (0ECD. 20051. In China, several producers
have used F-53 (salts of CJF 30CF2C-2SO.1H, CM' No. 7 492 r-54-7)
and F-53B (Cl-Cjj20CFzCF2SO_zK, CAS No. 73606-70-6), likely derived
trrrtn fluorotelomer raw materials, since the late 1970s (Huarsq et al.,
MO; 'UND , 20121). It is estimated that about 20-30 tonnes of F-53
25, Fire -fighting foan-.s
In the past, various PFCA-, PHA-, and fluorotelomer-based derivatives
were added (i) as film fortners in aqueous film forming foams (AFFFs)
and film forming fluoroproteins (FI''FPs), HP as fuel repellents in
fluoroprotefn foams (PPS), and (iii) as (earn stabilizers in FFFPs and
alcohol -resistant aqueous film -forming foams (> -ems) (Backe et aL,
20413; ltleiner and jhod 2t1; 9; Place and Hell, 20112). In 2002 3lv4, which
was the only producer, ceased its global procluctiun of POISF-based.
AtFFs (Place and Pieltd, 2012); and thereafter has developed a fire sup-
pression agent based on a gaseous fluorinated ketone (CF3CF2C(0)
(CF3)z. CAS No. 756-13-9] (UNU, 2012). Also, AFFFs based on pure
6.2 fluorotelomers are under development to replace the early genera -
dons that are leased on a armature. of predommanfly 6:2 and 8:2
floorotelomers (IGid n, 2€112; .Fidirarr area jho, 2009). For example,
DuPont commerriahmd ForafacT 1157 that is based on 6.2
fluorotelomer sulfonainide alkylbetaine [63 2 FTAB, C61`1_$CjiIS012..
NHCs1-1cN a (Cl-l3)2CH2C6dt1-(Hagenaars et al., 261.1„ toe or ah,
2012: Pabon area Corp=:aa, , f021) and ForafacV 1183 that is based
on 6:2 fluorotelomer sulfonamide aminoxWe (Cr,Fa Cy1•I1,S02NH
CiHsN(0)(CI-13)2,CASN'o.90475-32-7j (ansenetal.,2003),Inaddi-
tion, a Chinese institute has developed an AFFF formulation based
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Z Wang €t a4 3 a r ti am er C Frt¢era3rado aai 60 (2013) 242_248
can a PFBS desivadve: [CJ9S02N1-1(CH,),Idll- (CH3)2 I (Yang et a1.,
21]09: 2bao, ?012), its rorrarnercialization, however, is unclear.
2.6. Miscellaneous
In addition to those mentioned above, we have idendfled the: fol-
lowing floor•inaated alternatives and blear potential rases: (i)The po--
tassiu.tn salt of PFBS (CAS No, 29420-49-3) is marketed as a fiarrae
retardant for p€alycarbonate resins; 30-5€I tonnes of it were pro-
duced in 203 in Germany (Hubei l-Iengxin, 201.3; Nfitearf, 2M2.;
f.itstrloislai, 2013; OECD, 2005, Wuhan Clreraaieal, 20131). 00 The
imide salt of PFBS HCAS02i2NH, CAS No, 39847-39-71 is marketed
as a surfactant, acid catalyst, and as a raw material for ionic liquids
(Mitsubishi, 2013), (W) A PFIIxA-d€:rivative (CF3(C.F2),CONH(CH,)3
Si(ClCHl )3, CAS No. 1543$f1-34-4) is marketed as a surface treatment
for glasses, natural stones, metals, wood, rellulose, cotton, leather and
ceramics (Miteni, 2012). (iv) In Europe, Dow Corning registered a copol-
ymer comprising 6.2 fluorote:lomers ;and siloxane (CJ13C'FI2CH2
Si(GCI-13)3, CAS No. 85857-16-5) under REACH, its intended use is
unknown (Eai& 201.3h). (v) Nanodlm spray products based on
polysiloxanes with. 6.2 flrrerrertc:lcaaraers in (some no the side -chains are
marketed for coatings of nonahsorbing floor rtfaterials (Norgaard et al„
2010). (vi) In the US DuPont produced CI`t;---: CE-- CF :€ CF3 ,CtGCE2
S xF (CAS No. 16090-14-5,f in an amount larger than 11A tonnes in
2011 (tl5 FPA, 2 312 ), wlrie h is like);l used as a uu leas/ fc<r a ropol /nor
used in polymer electrolyte fuel cells (Ue-matsu ct al., 2006). (vii) In the
US )DuPont produced f7jOCP(CFa)C0F (CAS No, 2927-83-5) in an
amount laa•,ger than I1A tonnes in 2011 (US EPA, 2612), and its u;e
remains unknown,
3. FindronmenW and Tatr.man exposure to fluorinated ahernativres
11. Erwironment€rl releases
.Similarly W APFt1 and APFN, fluorinated alternatives applied as poly-
rnerization processing aids may,/ enter the environment at manufactur-
ing sites where: they art: produced and used to produce fluoropolymers
as well as during use and disposal of fluoropeolytner resins. For example,
.'1DONA was monitored between June 2008 and November 2€ 09 in the
River Ala (Gertrrany) downstream of wastewater effluent discharges
from 3M�Dyneon`s factory and was detected in all samples (range
from 0.32 to 6.2 W/1 (Bal,11.1, 2010a)). In addition, AIIONA is emitted to
air through exhaust gases and there deposited to the ground nearby
31v1/Uyneon's factory, The average deposition rate of ADONA to surfaces
soil near the plant between December 2009 and May 2010 is estimated
at 684 ngi(mz d) (Ba1AJ, 2010b). GenX has also been detected in raver
water downstream of effluent dfsrharges from the DuPont factory in
North Carolina (USA) (Sttynar e:t al„ 2012). The discharge of PF1IrcA
from a fluompolyrmer manufacturing Plant in Franke to the �ceir ing
river is estimated at 10 t/yr (Dauchy et al., 2012),
To date, there is no Information can releases during use and disposal of
fluoropolymer resins that contain.. fluorinated alternatives; but residual
levels of Some fluorinated alternatives in fhaompolynwr resins are report-
ed, The residual levels of ADO.NA in. the finial wintered fluorupulymer ma-
terials and an umintered fluoropolyrner rnfcropowder are <0.02 mg/kg
and 33 mg,,kg, respectively (FICA, 20116); and Genx residuals in
fluoropoly mer resins are: below 0.2 mgAg !,DuPont, 201f1).
For other fluorinated alternatives, no information regarding releases is
available. However, elevated levels of 1111E and/or periluorobutanoic acid
(PfBA, an impurity in PBSr-based derivatives) in water samples from the
river Rhine watershed (Iam: e et al„ 7667; MdUer• et al., 2010), Gem3an.
coast (Ahrens et ai-, 2t1111a), Tokyo flay ;japan) (Ahrens et al., 2010b)
and Northwest Pacific Crean (Cai e r al 2012) indicate an increasing use
and release of PBSF-based derivatives and other potential precursors.
32, Persistence
5
Extensive studies have suggested that 6:2 fluorotelomer-based (Lee
rat al„ 2010; Liu et al„ 2€110a, 201 Bb; Mop et al„ 0I2-, Wang et al., 011,
and PBSF-based alter-
natives (&mskfn et any 2012, 2013; D'eon et al., 200C; ;Mart€n ee al.,
2006; [ileameea e€ al., 2009) can € ndergo similar degradation processes
(reaction with OH radicals, ph€ wly5is or biodegradation, etc,; as their
higher homologues and be transformed into corresponding sbort-
c:lrain PFCtU and/or PFSAs (such as PFBS, Pi 3A or Pn-IxA) in the environ-
ment or biota. Similarly to 6.2 lluorotelomers, 3:1 and 5:1 FT43I1s can
undergo reaction with OH radicals and foram short.-e:laaiar PFC:A hon o-
logues in air (Hurley et al., 2€ C9-; Sulbaek or al., 20;06)o 1"hese short -
chain PFCA5 and PFSAs are as persistent in the environment as their
long -chain homologues.
For PFPE--based alternatives, infhrfnation can degrad;abdity, is scarcer
and soften incomplete. Available: information shows that A>• 6NA is not
readily biodegradable (,Gordon, 2i111), but starts to decompose: ther-
mally at 125 "C with roaupleti.on Pat.1'I5 'C, leading to formation of vol-
atile substances (details on de. radatfnn products were not provided.)
(EFSA, 2€a11b). No hydrolysis and biodegradability ofGenX was ob-
served in testis according to the. OECD test guidelines 111 (tested at
pal -- 4, 7, 9 at 5O 'Q and 30113(tested for up to 2E days), respectively
(ECIIA, 2t1131a) In addition, an atmospheric degradation study of non-
faanctionahzed PFFIF-based product, Galdeffl, HT 6 (consisting of
mainly €: -j(.T(CF3)CF2OCF,0CF3withsmalleramountsofCF_€OCF(CF3)
CF2.O F20(.F,t3t Ra and longer -chain analogs) indicates drat drese PFPEs
degrade slowly in air vvith a lifetime greater than 46 years (through
reaction with C:1 and OH radicals) and 300 years i;through ph.otolysis),
respectively (;'`oup et A- 20061,
.3.3. Exlacorore of )Jain and hurnons
'The hivaaccumulation potential, in terms of serum elimination half-
life, of PI A. PFBS, PFHxA, PPIIxS, PFOA and FEiM in humans ;arid in am-
rnaals has been well studied (see Table 1.). In general, I'MA, PFIIS and
PEEix& which caar be used as alternatives to their higher homologues
in some cases or occur as undesired byproducts of, degradation products
of PBSP. or 6.2 fluorotelomet-based alternatives, heave: shorter half-lives
in humans and biota than their hanger -chain homologues (Ilor;; and
Halianssuu, 2012; hvai. 2€111, Wilbolm et al., 20W). In contrast, PFHXS
has similar or even longer serum half-lives than PFOS in all tested am-
mai5 ( except female rats) and in humans, which retakes PFHxS inappro-
priate as an alternative: to Prt1S. For otherfluorinated alternatives, only
two industry studies of Germ; in rats and mice were found.'reported to
the European Chemicals Agency (E'.CHA)) (ECIIA. 2013b); and the data
reported are only sufficient to calculate are approximate: range of the
serum elimination half-life: of Gent'. ire. rat- and mice, see'l'able I.
Regarding the absolute exposure levels, as recent study on the tem..
poral trends of PF&s and PPSAs in serum from/ prirniparous women in
Sweden between 1996 and 2t110 observed a marked increase of PFBS
and PPIIxS over tiaras ((_ll mn e.° at., 2012). Similar observations of an in-
creasing PFIixS exposure trend after 2006 in the: US have also been re-
ported by Date e:t al. (2t111). For either fluorinated alternatives, no
temporal trend data are. available.
4. Major data gaps and future perspective
There is som.cx publicly ,acce:ssible information on fluorinated
alternatives; it is, however, still heterogeneous among industrial
branches and not sufficient for conducting realistic ride assessments,
There are three major data gaps; (i) the identity of marry alternatives
remains unknown, particularly in those industry branches or regions
that are less strictly regulated, whereas e.g. in Europe (EESA, 2013)
and the US (IDS FDA, 211133_)) food contact material producers are:
obliged to submit spe�c:if c. safety data, (il) for alternatives that have
DEQ-CFW 00079578

DEQ-CFW 00079579

246 Z. (AJnnR nt nL i Ernn vnrnent 1rrer 3odonnl 60 f20131,2422 247
Table I.
Serum e.liminatinn half --lives ni PFBS,
PFHxS, HOS, PFBA, iIFH A, PFOA, cert,y andAl.JONA in fnale' (M) and female (P) rats, mice, ;'61t7I3I eys and humans. in Some crises, ftllf-IA[e 25 £3;t3F'e'ssed
3n the fnrnx of
;'3S3kf3Sf7{'Yi3: ropart ±
Standard €1@A'Ir]tii7Xysvh3]e Ifi other cases when
tlye standard dev'ta, €rE3 9S less t17an t
5% of tl3e ai3'€Ett3rF£-3t]is t37eatl {b331y tl3e arid7?nt`Fic
rnearx iS prnvidnd.
NoFes, on shakes on rats, mine and monkeys
provide informadon oil (losing n3etb0d
(icing€e o;'al d(35e Or shigle 3ntravenom,
(IAI) dose) and dosage tin ppmmg bw), Notes on
studies on humains
Pro"ride Sampte
nurobei5 (n) €bf hE3n3am involved. " " meam no data available,
�......... ...................
PFAAs
Rats
..
Mite
................
..... ......... _... -----------..--------
Monkeys
Hta"nans
------- ----•
t3;2
4elrey
..u..
ilr2 "'lutes t3/", Notes;
it;e Iti€?ter tl.4
.. --- ----- ..................................
Notes Et:.2 Notes.... tF,z
Notes
PPOS (F)
4 h
W1
B h tint)''
............. ..............
- - 87 t 42 h
�..�
€V"" B - 2 h €v` 46 d
..........
PR35 (M)
5 h
30 ppoi
5 h 30 ppm - -
9.5 27 It
10 ppra 15 :A. 10 ppm 24 ±'; d
n = `I'':'
5 It
i F#3x5 F)
2 ti.
IV'
- - 25 d oral
27 d lira) 87 27 d
IV` - - 1219 :-:
n =
O.6 y3'
Mix-S (M)
29 d
10 Pprn
- - 31 d I PPm
28 d 20 i3PEn 141
10 Ppm - - 8.2 .=: 51 yr
n = 24.: -3z
30 d
PR)s (F)
62 d
ofal`
71 d Oral, 38 d oral'
30 d 03'al" 110 €l
Iv, _ _ a 9 :;:. 1 yr
n =
PPOS, (h3)
38 d
2 ppm
41 d 15 plan 43 d 1 Ppm
.36 it 20 pprn 132 d
2 ppm - _. 5A 3.7 yr
33 = 24""
PM- A (F)
I h
iv
2 b OraF 3.4 Draf,
3 h Otal' 41 h
IV, - _ 87 .m 31 h
a = 2"
PMA (RBI)
6 h
30 ppin
0 h 30 ppfn 1 3 - 5 h 10 PPrn
16 :3: 30 Ppm 4€i h
10 ppm .. - &9 3.5 b
n :::: 7 3 is
7 €3
PkY- Mx F)
€3.:1 h
W`
12 h 1'v' <:72 €3 Gac:37e
- - 2A h
IV
MixA, (M)
I h
In print
2,4 h 15 ppm -, 72 h 5() PPm
_ '93 h
10 pptri _ _ c28 d
n = 831',
PPY71't (P)
2 b
€v"
17 d nor r3aPar3ett"
- _ 3s . 7 d
€v' ` -- - :3.:3 y3'
37
PFOA (M)
6 d
20 ppm
- - 19 d
;?I I0 d
10 Ppn3 - - 3.8 :3: L7 yr
n = 2,V3
PFOA (all)
_
_
_
_ _ _
_ _ 3.26 yr
n :::: 138,
PFOA (all)
_
_
_ _ _ _
_
_ _ _ 2.3 yr
n = 2EX),
1'iOA (all)
_
PMA (al I)
_
_
_ _ _
_
_ _ _ 8.5 yr
3x =
Gen3S: (F)
'12 11
oral''
- - } 12 h, <7 d Oral''
Gent (M)
'12 11
30 Ppn7
> 12 13, •, 7 d 3 ppm
ADONA (M)
44It
Sr. oral1e
_ _ _
_ _ _ 23 : 11 d
a 3ss.,;
.;
------------------------------------------------------------------
\.:Ez...r.,.....,.
",...,
� w. .. �._:,:..
.- .. .. ,-7oe�;rsiut6c-¢r�trs,3srs�ni3lc;_fiurapaep3erli3uww'aarev-Pztaonzi3vexPo.>�tti�
the'_ st:b8m3;.•es sad'hz li.
dE in sentm wires ; i . "'neae "MA e: fM13s on fm-ni Pi Opte �xho WUQ, ezPErs;ed to FFf31. =inty hirough high'y crnwliam'-'d dtinkinM XWer,
been identified, information on their potential impacts on humans
and the environment is insufficient (e.g„ knowledge on degradibill-
ty, bioaccumulatioal potential and (eco)toxic:ity of i'FPE's is largely
)missing,); (aft) for all fluorinated alternatives, that actual volumes
that are produced, used and emitted remain imkamwno
Furthermore, even those fluorinated alternatives that are considered
safe because of low acute toxicity and bi.oaccuinulation according to
current regulations may still pose rash's in the future, For example,
short --chain PFCaA and F.FSA homologues such as PFH.xA and l'Fllg
are as persistent in the enviromnent as the long -chain homologues.
Thus, the current increasing llobal production and use of these
chemicals and their potential precursors will lead to increasing
widespread environmer;tal and llurnan e.Isposure that will last for
the foreseeable future, ff, in the future, risks associated with .short -
chain homologues are discovered and regulatory action needed, it
is important to be aware drat it will take decades for global environ-
mental levels of these short -chain homologues to respond) to arty
emission reductions.
In order to prevent a "lock -far" problern in the field of fluorinated
alternatives, nuich effclrt is nerAed, Above all, communication among
stakeholders (manufacturers of fluorinated materials, industrial Users
of these materials, regulators, scientist's and the public) needs to he im..
proved arld intensiflett, A transparent knowledge exchange among
stakeholders would enable, (i) developing accurate analytical techniques
for alternatives that can be used fclr further laboratory testing and field
Monitoring of these chemicals (e.g.PRIES (ltito€ rt o,2all?));(ii)devel-
oping more sophisticated stltdy designs and data analysis for eriviron­
mental faw, toxicity and hioacrunluladon studies to facilitate up. -to --
date regulatory ry decisioris; ;and (iii) developing a new industrial ecology
where ille latest scientific fanlin *s can be readily implemented in the
product design phase to develop materials with similar function, but
with nefdigible hazardous properties.
a dmowledgatlerlt
Funding by the Swiss Federal Office for the Fnvirrinment (%(?IN) is
gratefully acknowledged.
lLefererroes
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Teinaval pathway. Chemos ece 2012;67;5):527-34 i3}t=S;L'ax.3}r{Lo.fv rl z ...................... ....
3 fllheln l €. }Dergniasin 5, €1te3ke FH. C)cc3x£renl:e of perffunxinated compounds `EEGs) in
dnrldug water Of o t"s Rhine-VvesEpimlia, Getraliny ar3£l new approach to assess
drn"king neater e onlan3%nation by shorter -chained C4-€:7 PFC:s, tot 1 Hyg Environ
Heatth2C013;21;3(:3}.274:32. :r::r%tlx{€ui.nd;%IO.L01 t`.4 ehrOz3.OS. Od.
Wuhan t'hemical, Wuhan E henxit;a€ mdus'y Rese.radi f3 seisL'ie %.0 l,i£I. Produrts, in
'l.'lilF7�'•!r�''.F� p.; 3`V,S' i� n'F`.14'I3diinsCC'ai33; nevt;.t3}3; ; };bE.Z:Si'>ir�i€€'is; lxDi£FE€,':irinl fi.a°£'.3?�CFF� €,E'.£t.
lFtxu€?P.£33.€z£Z:Yi{'-k r..F-3s;,;a:::Scmibtatega�;RCatenars€ti--c:"z'zs3U�3'i0fe11
56ffa:ifl 3e<Ff :f.3 £: }:irF3r m `3flt:,,3Ft 7 8 i , [accessed April 4,2013],
Me X, Be R, Ii j, Chen B. Favadng FiOA a e3'E3afivcS t C1 if335k Fy'; f.<{`:£33'FK seE3i'<"EIY¢ K `C e:nUi-
3'£33xFi3rFn�Y€ pri3l:E;£:Ziti¢3 r3?,ponSfoili iin E,-131dt'�i}. 7t<3. CH,3 -aese Nat}};real i:4t'ork t3Op
Onand appnka,l:o,n ft€ fF3n£:6ndal iI:{F3nr1£^ an{: OCO-ne rnatc-
iia_s. 2fl10,
?fie X. Qo €, Bai R, 2)iang ;' Yang X, Patent: Peraridi : fluompoly'-)ter and its Use in emul-
sion palyxneriz ati3D:P of €Ixi£min-c it an311sg n3onomen CIS 201 @;T1207880 A-i z US I'atent
33flice, 2011,
Xu Y, Zh ao tA, Ij N l.d W, Su X Han 7-A r4ael fluor }'F sue: fa ar{t: sltnt€3 s)s ,rt ap..
1 ::ca}:ion :3'F £e3'FP'sD.€Fli333. €St{€y3i3:'3 zat€an t f prrflanrnal€"'i uleriarryiatL'•s.:'a€n't Ow lnd
Yang B, Chen R, Xing
H,Xfan.(.Irerpuurubu7vi-ba-Cd;-I aX, e<aedsurfk 33:'se'i;a€31r#3s;:3
F£:Ea l is Cb ni Sin 2009;25(12)Q4J--:2, fin Chinese].
k'uung CI, 41ahu 5 5F Atranspbcr}c pe3tkro3ivated. atilt pr :vir ur : rliemis3y, occurrence,
add imparts. Rev Emiron Contam 1exicnl 201C;2t1t3:1..k939 I E `i&- { .orife
Young J, tinrzey 1f3, V`Jai3ingtoa Tl, S,3abury Sri Atmuspberlc lifetime and global
awanning potential of a perdluorapatyether. Friviron Sd Tech 2COD6;40(7):2242--0.
02I>'es"MN7a.
ba:X, js lx>D€.37F.a3id;€ i_F ,ta.Fsn fcan ant+ bingag�cnt)Hebei Acadid
2012;20(3;:SS 0.[in Chinese, ISS'i:lfl01-9:3831.
Zhaa IA Fn€soEn fTM Y' olstenholrne 6V 4 Sun H, Wang N, Buck RC. 6:2 t•IUaratelamer ak:o-.
hulbiatrasisfa33nad ca3inanae.EoNcrivers£ fin3>rtsystenyCheniosphere201a;90 2):
2a3-R.h#p:;;C dai.nrw• . GiO;j. 1'{e:3'{n:#3:F :e1£l`<1,€1,03:r.
DEQ-CFW 00079584

DEQ-CFW 00079585

DEQ-CFW 00079586

DEQ-CFW 00079587

National Institute for Public Health
and the Environment
Minispy ofHealth, Welfare and Sport
14 M1 W MM, , MORM-11
RZ-10,111110101AILTA101M UQ 11, 11#1 MR1#1
It Of
RIVM Letter report 2016-0174
M. Beekman et al.
DEQ-CFW-00079588

RIVM Letter report 2016-0174
(D RIVM 2016
Parts of this publication may be reproduced, provided acknowledgement
is given to: National Institute for Public Health and the Environment,
along with the title and year of publication.
M. Beekman (author), RIVM
P. Zweers(author), RIVM
A. Muller (author), RIVM
W. de Vries (author), RIVM
P. Janssen (author), RIVM
M. Zeilmaker (author), RIVM
Contact:
M. Beekman
VSPICH
martijn.beekman@rivm,n1
This investigation has been per -formed by order and for the account of
Ministry of Infrastructure and Environment, within the framework of
National Policy on Chemicals (M/260027116)
This is a publication of:
National Institute for Public Health
and the Environment
P.O. Box 1 1 3720 BA Bilthoven
The Netherlands
www.rivm.ni/en
Page 2 of 92
DEQ-CFW-00079589

RIVM Letter report 2015- 01, 74
Synapsis
Evaluation of substances used in the GenX technology by
emours, Dordrecht
Since 2012, Chemours (Dordrecht) Is using the CenX technology to
produce plastics (fluorcpolymers)o In this technology, the substances
FP.D-9024 FRD-903 and E1 replace the controversial PFOA substances.
o health risk is expected for people living in the vicinity of the pient
due to the emissions of these substances.
This is the finding of the RIVM. Commissioned by the Ministry of
Infrastructure and the Environment (Ie€ M), it is investigated to what
extent the three substances are harmful to people living rear the
factory. For this, the scientific literature and the information in the
European chemicals legislation REACH are examined on the p€-topertles of
the listed substances. In addition, based on both the maximum
authorised quantity and the recorded emission data that Chemsours has
provided, it is calculated to what extent they are released.
FPD-903 is used to manufacture FIND-902. E1 Is formed during the
manufacturing process. FIND--903 and E.I. are emitted to the air. like
PFOA, FpD-903, FRD-902 and El are pe€fluorinated hydrocarbons and
poorly degradable in the environment. Also, FPD-902 and FIND-903 are
causing similar harmful effects as PFOA (such as carcinogenic and
effects on the liver). These substances are, however, less harmful to
reproduction than PFOA, reproductio€, toxicity is the reason to regard
PFOA as substance of very high concern. In contrast to PFOA, FgD-903
and FPD-903 seam not to bioaccumulate in humans.
A safe limit valve for the general population is derived based on aworst-
case scenario. The concentration FPD-903 in air stays below this limit
value. For E1, information is missing to derive a limit value. Based on
the limited available information, this substance is probably less harmful
than PFOA.
Keywords. Gen , PFOA alternative, POT assessment, risk assessment,
REACH
DEQ-CFW 00079590

RIVM Letter report 2016-01:4
Page 4 of 92
DEQ-CFW 00079591

iUV. € Leiter repot 2016-0174
Publiekssamenvatting
Beoordeling vary de stoffen die door hemour (Dordrecht) bij de
Binds 2012 geb€ uikt fabrikant Chaemours (Dordrecht) de CenX-
technologie om plastics (fl€ orpcolymerern) to rnaken. Bij deze technologie
zijn de o r nstreden PFO-verbindirngen vervarngen door de stoffen FRRD-
902 en FRD-903 en El. Naar verwachting vormt de uitstoot van deze
stoffen door de fabriek vie de lucht geen rislco voor de gezondheid yarn
ornwonenden.
Dit blijkt ult onderzoek van het RIVM. In opdracht van het ministerie van
Infrastructuur era Milieu (IernM ) is onderzocht in hoeverre day Brie stoffen
schadelljk zlj€n voor € mwonendaern van de fabriek.o Hiervoor is In de
wetens€.happalijk:e literahjur• en de infermatie in de Europese
stoffern etgeving REACH o nderzocht wat bekernd is over de
elgenschappen van de gernoernde stoffen. Daernaast is rip basis Caen
z€ wel de maxi€nnaal verge nde h oeveelheid els de emissiegegeuens die
Chemours hneeft verstrekt, bereke€nd in Welke mate ze zijn vrljgekomene
FRD--909 wordt gebruikt orn FR.D-902 to rnaeken. E1 ontsteat tljdens het
productieproceso FRD-900 en El worden via de f'abrieksschoorsteen naar
de lucht uitgestoten. Net als PFOA zlj€n a geperfluorideerde
k€ d aterstoffen FRD-902 en FRD-90E en E1 slewht afbreekbsar in het
rnnille€ . Cck veroorzaken FRD-903 en FRD-902 vergelljkbare schadeli,jke
effectern als PFO A (z€nals ka€nkerverwekkend en effecten sip de lever).
Deze stoffen zijn orrel minder schsdeli,jk voor de voortpienting dan PFDAp.
bij FFOA is dit aspect juist de redern ornn deze stcf als zeer zorgwekkend
to belch ouwen. In tegenstelling tot PFDA lijken FRD-903 ern FRD-902
zich niet In de mens rip to Doper€.
Vo or FRD-902 ern FRD -902 h eeft het RIVM eern velllge grerns aerde veer
de slgernene bevolklnsg efgeleid asp basis van eern worst -case scenario.
De concentretie FRD-903 in lucht bUjfl: ender doze grenswaarde.. Voor El
ontbreekt inforrnatie orn eern grerns a,arde to kunnen bepelen, Op basis
van de beperkt beschlkbare lnferrnatle wordt vererndersteld det doze stef
wearschijnlijk minder schadelljk is dan PFCA.
Kern oorden: Gen , PFOA alterrnatlef, P0T beeordeling,
risicobeoordehng, REACH
Rage 5 of 92
DEQ-CFW 00079592

RIB M Letter report 2016-0174
Page 6 of 92
DEQ-CFW 00079593

RI.VM Leer rep, t 2016-01.74
Contents
5amenvatt;irrg —
Introduction — 15
General information — 17
2.1 Description CenX technoio0y -- 17
2.2 Substance identity and status of FRD-902 -- 17
2.3 Substance identity and .status of FpD-90 ® 19
2A Substance identity and status of El --- 21
5T properties — 15
3..1 Persistence FIND-902 --- 25
3.2 Bio ccurnulation FIND-902 — 25
3.3 Toxicity FPD-902 .... 2E
3A Conclusion on Pi3T/vPvi3 stags for FRD-902 — 25
M Persistence, bloaccumuiation and toxicity FRD--903 — 27
3.0 Persistence El — 27
3.7 Sloacc€ mulation El — 27
300 Toxicity El — 27
3.9 Conclusion on PBT/vPvB status for E1 ..__ 27
4 Human health properties — 2
4.1 Human health hazards FRD-902 -- 29
4.2 Conclusion on CMR and STCT RE properties FIND-902 -- 32
4.3 Comparison FRD-902 and APFO -- 32
4A Human health hazards FPD-903 -- 34
4.5 Human health hazards E1 -- 34
405 Conclusion on CMR and STCT RE properties E1 — 35
4.7 Derivation of a general population exposure limit fever- FPD-902 - 35
4.7.1 Approach -- 35
40702 Toxicity studies — 35
4�7.3 Selection of the most appropriate paint of departure 3E
43.4 Inhalation exposure limit — 37
4a8 Derivation of a general population exposure limit for FR.D-903 --- 39
4.9 Derivation of a general population exposure limit for E1 — 40
5 Indicative concentrations around the Chemours plant roue to
E -903 and El emission ® 41
Annex 10 Human health toxicity D-90 — 53
Page 7 of 9-
DEQ-CFW 00079594

}€IVM Letter report 2016-0174
Annex 2. Human health toxicity El — 87
Annex 3. Calculated air concentrations FRD-903 based on the
permitted emissions (in rig/ ,3)
Page 6 of 92
DEQ-CFW 00079595

RIVM Later mport 201.6-01,74
i"T"tenvattian
In dit rapport worden de perfluorVerbiradingen (FRD-903, FRD-90 erg
El) ge&alueerda Deze verbirldingera worded gebruikt of ontstaen bij de
CenX technologle voor het makers van flu orpolyrneren. bij Chernougrs in
Dordrecht. 01j deze technolragle wordt Been gebruaik gerrtaakt: van de
ornstredera PFOA-verbiradingen die eerder werdera toegepest. Hierbij
warden de volgerade vreger€ beeratga word:
L Wat is bekend over de PBT-1 elgenschappera van FRD-903, FRD-
902 erg Ell
, Wat is bekend over de everatuele CMR2 era STCT RE3
elgergschappera (met name lever- ear raiertoxiciteit) van FRD-903,
FIT-902 era El?
g, Wat is bekend over de emissie van FRD-903 era El bij Chernours
in Dordrecht?
4o Wet is er to zeggen over de €gezondheidseffecten (rasa en in de
toek€ mst) voor de omwonenderr als gevoig van blootstelling ears
FRD--903 en El.'s
Aaraageziera alle beschikbare t€ xiciteitsstudies zijn uritgevoerd met het
ammo aiura tout (FRD-902) era niet met het zuauar (FRD-903), is de
beoordelirag very FRD-903 in dit rapport gebeseerd sap de gegevens van
FRD-902. Het is gerechtvaardigd € m de gegevens gars FRD-902 t:e
gebruikerl voor FRD-903 omdet de effecter in het lichaam bij belde
stoffera veroorza kt warden door het anion (2,3,3,-tetreflu oro-2_
(heptafluor€apropoxy)proparacrete)a
Bij de eerste vraag c€arrclurdeert het RtrVM dat het niet is uitgeslot:en dat
de Berg de CenX technologie gerelateerde stoffera (FRD-903, FRD-902 era
El) voldoen Berg de PBT of vPvB4 criteria. Alle drie de stoffen zijn
perfiuorverbindiragen en hierverg kerg warden gesteld dat ze arrijwel zeker
zeer slecht in het milleu w Orden efgebroken. Aerageziera FRD--900 era
FRD-902 smeller derg PFOA het licheerra vedatera, wordt ver Brecht dat
beide stoffen eery geriragere bio ccuamualatie vertonerae Er kerg echter gees
definitieve concluasie warden getrokken omd t data over de
elimira tiesrrelheld bij de rrleras ontbreken. Voor de stof El is er
sargvold€aerade iraf€arrraatie crag eery conclusie to trekkers over de mogelijke
bioeccumullatiea Aerggezien El geen hydrof€ele groep bevat, is de
Verwachting dat de ellmiraatle wars El, treger is en daarmee eery hogere
poterat:le voor bioacc€amurlatie heeft ulen PFOA. Aerg de ergdere kergt wordt:
El wearschijnlijk weer gemakkelijk uitgeademd. FRD-903 erg FRD-902
zijn racer Verwachting minder gev aerlijk: dera PFOA, rraear rack hiervoor
ku nnera gees dednitieve c€ ncluasies ten eeraziera vera het T criteriurm
order getrokken. El voldraet waarschijnlijk niet n het T criterivam van
de PBT analyse,
Pemisa:ant; Moaccurnulat ve and Tcodc
z Careinogenk, rnuragenac or tnxfc for the reprodocrian
spar.lfic target Organ toxirfay a€a:er repeated exposure
a Vary Persi$tent and very Bb oaccoranlarbve
Page 9 of 92
DEQ-CFW 00079596

RTVM LE: t:T rcq)ort 016 -01.74
Eij de I: ecio€ deli ncg van de CMR erg STOT ICE eig€:nschappe€ , w rdt
geconClcrdeerd dat FRD-900 e€-€ FRD-902 geclassibceerd z€ udera ra oeten
worder€ als k<arakerverwekkerad categorie 7 (mogelijk kar€kerverwekkerad
voor de € ens). Verder laten de beschikbare StUdles zien dat belle
stoffera niet rnutage€ n zijn.. De beperkte reprodc€ctie-toxische €:ffecten
die rgevonder€ w order€, leiden normabl gesproken niet teat eery classificatie
cap dit onderdeei, Dit is in tegensteliirwg teat PFO A, welke geclassificeerd is
als schadelijk voor de voortplar€tlrag (categorle J.E). Ten slotte is het
lastig om de toxiciteit voor crganen (zoals lever era rwier) to beoordelera
ramdat de tester€ die bij rr€€.€izerw zijn gedaar€, zijn taiigevoerd bij
doseringera lager darn de voorges€rhrevert doserirwgera in de guidance
docc€ra ent€ n. Dit kart eery irwdicatle zijn dat classidcatie als 9TOT RE
categode 7 noodzakelijk isa De effec:ten die bij de rat zijn wxwraargehclrr€erw,
zijn €nargiraaal erg everweer€s moeilijk to beoordeler€ vanwege de grate
stappera in de doseriragsniveaus die zljra geharwteerdr De effecterw cap de
lever zijn bij FFD-907 en PFOA waargerwornen bij ongeveer vergelljkbare
doseringerae
De beschikbare irwforrrratle over de toxiciteit van E1 is beperkt, rr€aar de
ir€forrr€atie die beschlkbaar is, wijst cap een lage tat zeer lace toxiciteit.
Deze concic€sie w ordt ondersteorad door ir€for€natie over de toxiciteit van
wrergelijkbare wrerbirwdirwger€. Wel diem opgernerkt to w orderw dat alle
beschikbare studies erwkel zijn critgevoerd met mannetjes proefdierera err
slechts van beperkte blootstelliragsduur warer€. De beschikbare in vitro
en in vivo mutag€araiteitsdata, geccarrablraeerd €-net de data ware
vergelijkbare wlerbindingen, tonen aan dat het onw aarschijniijk is dat E1
€ utageen is. Verder later de beschikbare gegevens zien dat het
waarscMjnlijk niet nodig is om E1 to classificeren voor acute toxiciteit en
voor ETOT RE door inademing, De be€ ordeling van El voor classidcatie
cap andere eincip€anten, waaronder carclnogeniteit, reproductletoxiciteit
era ETOT RE door orale blootstelling, is niet mogelijk cap basis van de nu
beschikbare informatie.
Voor F .D-903 en F D-902 w ordt in dlt rapport reke€ping Iwoudend met
een worst -case aanpak - een chronische inhalatieblootstellingslimiet wean
73 ng/ � af9eleid, HierNj is een extra veillgheidsra€arge gehanteerd
vanwege de onzekerheld over de mogeHjke bioaccurw-atflatle van deze
stoffem De. jaargerniddeide concentraties van FRD-903 in de lucht zijn
berekend cap basis wean de maacirnaal wrergunde hoeveelheden, Deze
berekening laat zien dat de concentratle FRD-903 in lucht 70 ng/ � is
bij de dichtstbijzijnde bewoonde gebieden (de dijk aan de € verkant van
de rimer) err lagere concentraties verder van de fabrlek. De berekening
cap basis van de gerapporteerde ernissies in 2014, kornt ult cap 15 ng/m3
voor de dichtstbijzljnde bew oonde gebieden. filet vergelijken wear€ deze
berekende concentraties met de afgelelde grens aar-de van 73 ng/M3
leidt teat de concl€asie dat cap basis vary de beschikbare inforrrrabe er geen
gezondheicisrlsico voor de o€nwonenden van de Che€nours fabriek door
blootsteliing aan FIND-903 to verwachten is.
De infor€natie over de toxiciteit van E1 is beperkt. De gegevens over de
toxiciteit van E1 zijn onvoldoende orn een i€ Matleblootstellingsiimiet
voor E1 of to lelden, De jcaarcgemiddeide concentraties van E1 in de lucht
zijn berek€ nd cap basis van de maxirrraal vergunde hoeveelheden. Deze
be,rekening laat zien dad: de concentratie El in lucht 40 ng/€n� is bij de
€ age 10 of 92
DEQ-CFW 00079597

RIVM Letter report 2016-0174
dichtstbijzijnde bewoonde gebieden (de dijk aan de overkant van de
rivier) en lagere concentraties verder van de fabnek. De berekening op
basis van de gerapporteerde emissies in 2014 karat uit op 20 n g/M3
voor de dichtstbljzljnde bewoonde gebieden. Vanwege de ontbrekende
informatie over de toxicitelt van El, kan er geen conclusle warden
getrokken over eery mogelijk gezondheldsrisico voor de omwonenden
van de Chemours fabriek door blootstelling aan El.
Page 11 of 92
DEQ-CFW-00079598

RIVM Letter report 2016-01.74
Page 12 of 92
DEQ-CFW-00079599

R1VM Letter report 201d- 3 € 74
Summary
In this report., the CenX related perfluorinated substances (FRD-903,
FRD-902 and EI) are evaluated, These substances are used or are
formed during the production of fluoropoly mers by Chen- ours
(Dordrecht) applying the GenX technology. In this technology, the
controversial PFDA substances are replaced. The following questions are
addressed in the evaluatlom
1. What is known about the PBT5_properfies of FP.D-903, FRD--90
and El?
2. What is known ,about the possible CMR6-properties and STOT RE-
propertles7 (especially the toxicity to kidney and liver) of FPD-
90 r FRD-902 and El?
3, What is mown about the emission of FRD-903 and E1 by
Chem€ ors (Dordrecht)?
. What are the possible health effects (now and in the future) for
people living in the vicinity of the Chemours Dordrecht plant due
to exposure to FPD-903 and El?
For FIT-903 the evaluation is based on read across from FRD-902, since
all available toxicological studies were performed with the ammonium
salt (FRD-902), Dead -across of the toxicological properties of the
ammonium salt to the acid (FRD-909) is considered justifwd for
systemic effects as after dissolution and dissociation of the acid and the
salt the absorption in the intestinal tract and the lungs and distribution
over the body of the anion (2,3r9,3-tetrafluoro--(heptafluoropropoxy)-
propaanoate) will be the same.
As to the first question above, it is concluded that RIVM cannot exclude
that the GenX related substances meet the PBT/vPvW criteria, All
evaluated substances (FR.D-90 , FPD-9€ 2 and E.I.) are perfluorinated
compounds and can be regarded as certainly very persistent, Since F .D-
900 and FPD-902 are more rapidly ellminated than, PF€ A, it is expected
that both substances bioaccumulate to a lesser degree than PFOA does,
However, it is not possible to reach a conclusion on the human
bioaccumulation potential in absence of data on the human clearance
time, For the substance El, insufficient information is available to draw
a conclusion about the bioaccumulation potential. Since El contains no
hydrophilic group, the human clearance time of the substance and the
bioaccurr elation potential are expected to be higher than for PFOA,
although E1 has the potential to be excreted via exhalation, FR.D-903
and FRD-902 are considered less hazardous compared to PFDAo
However, no definitive conclusion can be reached whether they meet the
T criteria. Et will most likely not meet the T criteria.
For the C.MP and STOT RE properties, it is concluded that classification
as carcinogenic category 2 (suspected human carcinogen) is justified for
Persistent, t ianrrurnaaant:€ c snag T*Yk:
a a zrrinogenic, rnu€:agenlc or toxic For the reprodurtinn
spedfic'i'amet organ-r'nxii it:g, R:ar:?a>.ate'i Exposure
s Very Persistent and vea i Bioaccurnulat've
Feye 13 et' 92
DEQ-CFW 00079600

RIVM Le'fter reeaert 2016-01.74
FRD-903 and lyRD-902. The available studies show that: both substances
are not mut:agenic. On reproductive toxicity the Ilmited effects observed
in presence of maternal toxicity do not normally result in classification,
whereas PFOA is classified as toxic for the reproduction (category 19)a
The requirement of STOT RE E (like liver and kidney) is difficult to
assess due to dose levels tested in rice clearly below the guidance
values, which may be taken as an indication that STOT RE 2 Is needed,
The effects in the rat; are borderline and difficult to assess due to the
large steps in the dose levels. Effects on the Ilver are observed at the
similar dose levels for FRD-902 and PFCAe
The available information on the toxicity of El is limited but that
information indicates that El has a low to very low toxicity. This is
supported by the repeated dose t:oacic;lty information on some structural
analogues. However, all mailable studies were performed in male
animals only and were of limited duration only. The available in vitro
and in vivo data on mutageanlc.ity combined with the read -across data
show that: E1 is unlikely to be mut:agenic , In addition, the available data
indicate no requirement for classification for acute tonicity nor probably
for STOT RE via inhalation, The requirement for ciassification for ether
hazard classes inducting carcinogenicity, reproductive toxicity and STOT
RE aria oral exposure, however, is unknown.
A chronic inhalation exposure limit of 73 ng/m3 for FRD-903 and FRD-
902 is derlved in the present report in a worst -case approach, taking
into account an extra safety margin due to uncertainty in the
accumulation potential. The year -average air concentrations of FR.D-003
were calculated based on the permitted emissions, This led to estimated
concentrations in air- of about 20 ng/m' for the nearest populated areas
(along the dlke opposite side: of the river) and lower concentrations at
greater~ distances from the planate rased on the recorded emissions for
2014 the estimated concentrations for the nearest populate-d areas are
about lg ng/m-. Comparing these concentrations with the limit value of
73 ngjm-' leads to the concluslon that based on the available data, no
health risk is expected for people living in the Acinity of the Cheer ours
Dordrecht plant due to exposure to FRD-903a
The information on the toxicity of E1 is limitede The data are insufficient
for deriving an inhalation exposure limit for the general population. The
year -average air concentrations for El were calculated based can the
permitted emissions, This led to estimated concentrations in air" of about,
40 ng Jrrr3 for the nearest populated areas (along the dike at the
opposite side of the river) and lower concentrations at greater- distances
from the plant, Eased on recorded emissions for 2014 the estimated
concentrations for the nearest populated areas are about 20 ng/m3. Duey
to the insufficient health effects information mailable for E1,, these
concentrations cannot be evaluated as to the passible health risk they
aright passe for people liming in the vicinity of the Chemours plant in
Dordrecht,
Page 14 OF 92
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RMI; L. -_A :ear ,e potl 2016-017.1
Introduction
DuPont has developed the GenX technology as a perlymerizati€ n aid to
make fluoropolymers like teflon without the use of perfluorooctanoic acid
(PFOA)". PFOA is an important representative of the substance group of
per- and polyfluorinated .substances (PFASs)e PFASs consist of carbon
chairs of different: chain length, where the hydrogenatoms are
completely (perfluorinated) or parity (polyfluodnated) substituted by
fluorine atoms, The very statue bond between carbon and fluorine is
only breakable with high energy input. Therefore, perfluorinated acids,
lilac: PFOA, are not degradable in the environment, The hazard profile of
PFOA is well known. PFOA is a persistent, bioaccumulative, and toxic
substance (PBT), which may cause severe and irreversible adverse
effects on the environment and human health. Due to its PBT properties
and toxicity to the- reproduction, PFOA and its ammonium salt (APFO)
have been identified as substances of very high concern ('KWIC) € nder-
REACH1,3, Further, a proposal for restricting the manufacture and use of
PFOA is under discussion within the context of the REACH regulatrorr"
Chernours Dordrecht has started to replace the use of PFOA by the CenX
technology friary 2005 (in the USA) onwards and has completely ceased
the use of PFOA since 2012 at the plant in Dordrecht, This; technology is
also teased on pet -fluorinated substances. According to the manufacturer,
the resin manufacturing process includes the thermal transformation of
the GenX processing aid (FIND-902) into the hydrophobic, Boater -insoluble
hydride (EI.). The present assessment focuses on the GenX related
substances.
the precursor 2,3,0,0--tetrafluoro-2.-(heptafluoroprep€ xy)-
propanoic acid (FPD-900),
the processing agent arr€monium 2,0,3,-tetrafiuoro-2-
(heptafluoropropoxy)propanoate (FRD-902) and
the transformation product heptafluoropropyi 1,2,2,2-
tetrafluorethyl ether (El.). .
Another substance, perfluorisobutene, a by-product emitted during the
production of fluoropoiymers is cause for concern due to its highly toxic
properties. This substance is not covered by the current assessment:
because this substance is not specific to the GenX technology. This
assessment compares the specific substances used in the CenX
technology with APFO.
Concerns have been raised about: the hazard and risk properties of the
GenX techndogy used by Chemours (Dordrecht) and therefore the
Ministry of Infrastructure and Environment has requested RIVM to
Peguiation rEC) No 1907i 2r34E of the Eufopean P .flarnent and of the Council on thet�g(stratian,
Eva€uadon, Authorl<ratron and Retnctdon of Che3rrcals MCH).
I.I. Amex ex XV dv,,ssrer, tt3s<ttif�t:ha:�rr�t?�_�u��r�vi�u�.�un�ultat€t��es..r��..°estt�cfenrs•. �s rssa€�}.,
jtif3ksei:a¢;f:a--ra e 2 xM�Qi'F3Y.
r Page 15 of 92
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RIVM L;>_ftr repod: 201.E-01.74
evaluate the substances used in this GenX technology, More specifically
the Ministry asks I IVM to answer the following questions,
L What is known about the PB -properties of FRD-903 and El fz
1 What is known about the possible CMR-properties and STOT PE -
properties (especially the toxicity to Kidney and liver) of FRD-903
and El.?
3a What is known about the emission of FRD--903 and E:l. by.
Chemours (Dordrecht)?
4, What are the passible health effects (now and in the future) for
people living in the vicinity of the Chemours, Dordrecht plant due
to exposure to FPD-903 and El?
The assessment by fFIVM is based on ,available literature, which mainly
originates from REACH, For FRD-902 one REACH registration dossier Is
available (10-100 tonnes per year), FIND-902 is on the REACH
Community polling Action Plan (CoI P) for 2017 (for substance
evaivat€on on the potential PBT/vPvB properties, which will be conducted
by Germany). The acid and the hydride are not registered. There is no
harmonised classification available for any of the substances. FIND-902 is
described in the REACH Annex XV restriction dossler of PFOA under the
chapter- on alternatives, The comparison made between PFOA and FRD-
902 in this restriction dossier is used for the present assessment and Is
suppiemented with data from the registration dossier, s'udies provided
by Chemours and publications in the scientific literature.
No additional information was retrieved on the human toxicological and
environmental properties of FPD-903. Therefore, assessment of these
properties in chapter 3 and 4 Is based on read -across with the
arr€moniurr€-snit (FRD-902). For El available data proved to be limited
only and for this chemical the current assessment is therefore limited to
a screening and is mainly based on QSAR estimations and mainly old
data provided by Chemours,
It has to be noted that in accordance to the request from the Ministry,
the possible health effects for people living near the Chemours plant is
assessed. Exposure to these substances by inhalation is considered the
most relevant route for people living near the Chemours plant. Further
information is needed to ,assess the possibility of exposure by
contaminated cidn Eing water.
Deport structure
Some general information on the substances used in the Cerra
technology is given in chapter 2, In chapter 3 and 4 of this report the
PDT and human health (CM , TOT -RE) properties, respectively, are
evaluated, In chapter 4., exposure limits for the general population are
derived for bath FRD-903 and El. Chapter 5 presents the known
emissions of the substances by Chemours. In chapter 0 the possible
health effects are described. And finally, concluding rernarks are made
in chapter 7,
12 IFIdUritng P+ass€bie Other Fdevant sub,,Lance; fdnted to the Gwx technoe ogy..
Page 1.6 of 92
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RAIM Letter report 20 b-0174
General information
.1 Description GenX technology
FRD-902 is used as processing aid in tide Teflon PTFE and Teflon FEP
plants of Chermours, Other uses of FAD-902 are not described in the
registration dossier or in the literature, FRD-907 is manufactured by
mixing FRD-903 with an amnmonium hydroxide solution. FRD-903 is
imported.
FRD-902 controls the polymerization to make fluoropolyrnersa
Fiuoropioymer resins and finished goods are used in many applications
like wire cables and Teflon coating, During the resin manufacturing
process, F D-902 is transformed into the hydrophobic grater -insoluble
hydride (El), During the process, FPD-903 and El are emitted to air
from the Teflon PTFE and from the Teflon FEP piant:s. Furthermore, FRD-
902 and FAD-900 are en-lit.ted to wastewater. ,after removal of these
compounds, the wastewater is sent to Hie laical municipal sewage
treatment plant, Exposure of people living in the vicinity of the
Chemours is expected to be primarily through the emission to air.
,2 Substance identity and staters of FRD-- 0
Name:
ammonium 2, 3,3,3-tetraflu€pro-3-(h€�ptaf Li oropropoxyr)_
propanoate
CAS -number.
67037-80-3
EC -number-
700- 242.3
Synonyms:
FIND-903, C3-dirner salt
IUPAC name.-
ammonium 3,3,3,3-tetrafiuora--2-(heptatl€ oropropoxy)-
propanoate
Structure.
6H4 NF1103
F F 11
NH
FS
F �'
F
P
9.1::ACH, registered by C,hernotrrs Netherlands Bit. 10 — 100 TPA,
full registration
CLP'3' no harmonised classification, 28 notifiers to the CLP
inventory (19 September 20.16) (acute Tox. 4, 1-1302,
Eyre Damn, 1; I-1.310, STOT RE 2; H373 (blond)), see
table 1,
- Regulation (EQ No 127212008 on the ciassification, labelling and packaging of substances and mixtures (CLP
Regulation)
Page 97 of 92
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RIVM Latter report 2016-0174
Page 18 of 92

RNM Letter report 2016-0174
Q
Physical chemical prop l still
Melting point:
208 OC (99.411/a purity)
Freezing point
-2.1. uC (8611/o purity)
Vapour pressure,
0.012 Fa (99.411e purity)
Solubility in water,,
> 1000 g/L (99.4 % purity)
Form,
liquid (0611/a purity, marketed form), soli€! (dried
substance, 99.4% purity)
C€ or -.
c.€ louriess liquid
Density:
1118 g/L (99.4% purity)
Dissociation constant.
p .ao 3.02 (86110 purity)
Substance identity and states ofFRD-903
Namea 2,3,3,3-totrolluoro-2-(heptafiuoropr-opoxy)Propanoic,3cid
CAS-oumberr. 13252-13-6
EC -number, 2 6-206-0
Synonyms: FR.D-903, C -dimer
iUPAC name: 2,0,3,3-tetrafi€ oro-2-(hopt liLmroprop€ xy)propanoic
acid, pertluoro-2-methyl-9-oxeiiexanoic acid
Structure- C6HF1 1 D3
REACH: not registered
CLP, no harmonised classification, 99 notiliers to the CLIP
inventory (including Acute Tox. 4; I-i002, Skin Corr. IB or
IC; i 314, Eye Douro 1p H318, STOT 60 0; i-1 25
(Respiratory) and no classification), see table 2.
YS REACH registration data, i3 September 2016
Page: 19 of 92
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RIVIM LEMC-r -Wu t 2016--0174
Page 20 of 92

RI1. M Letter report 201-6-0174
2A4 Substance identity and status of El
Name:
heptafluoropropyl 1,2,2,2-tetrafluoroethyl ether
CAS -number:
3330-13-2
EC -number
7.1-353-1
Synonyms
propane, 1.r.1.,1,. ,2d s3-heptafluoro-3-(1,2,2,p_
tetrefluoroetboxy)- E1
1UPA name:
heptafluoropropyl 1,2,2,2-tetrafluoroethyl ether
Structure,
C5HFIIO
F.. F
1y� . F
F
J F
0.6 r
REACH, not registered
CLP. no harmonised classification, 3 notifiers to the CLP inventory
(29 August 2016)
Page 21 of 92
DEQ-CFW 00079608

0
r'
6
n
I
0
0
0
m
rn
0
cm
RIVM Letter report mrs-o174
Not ,nations to the CLP inventory for E! (I
Skin Irrit, 2 31
H31
................................
Irri
H2 31 3
H31
FEye
GHS07
€ €�g
STOT Sim 2
— _... .
. (Inhalation)
.... ----
Skin Irrit. 2
H315
31
..._
Eye Irri
...
.. 219
HS07
STOT SE 3
H33 (Not
W#22
i�'i�g
Specified)
Page 22 of 92
201
State/Form
IUPAC 2
Names
1

RIVM Letter report 2016-0174
Physical chemical properties (MSDS, 07)
Vapour pressure, 30 kPa
Solubility In Water. 7 mg/L
Henry's law constant, a.s4 * 1.02 P ,m-3/rncl (calculated)
Cider no Distinct Odor
Forma
liquid
Color
clear, colorless
Density,
1,54 g/mL
Relative density
1.09
visceslty:
0.0 cp
--+1.��5pp��-C,,77^^(-247 F)
gPour�^�gagoint,
Lcgl€ aw
JDQ�v7+bd.9 4
Freezing point,
- 4,90C
Boiling Joint:
490C (measurement 1) 40e611C (measurement 2)
Page 23 of 92
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RIVM Letter report 2016-0174
Page 24 of 92
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PIVM Letter report 2016-01.74
In this chapter a PBT/vPvB assessment according to the criteria for the
identification of PBT substances and vrPvB substances in annex XIII of
the PEACH regulation Is rnadel%
.1 Persistence E Dw D
Fi%D-902 is hydrolyt:ically stable, has surface --active properties and is not
readily biodegradable. In the ready biodegradation test: (OECD 301016)
0% degradation was observed after 20 slays, In addition, in an Inherent
biodegradation test (OECD 202C) no biodegradation was observed after
26 days. Simulation tests (which are performed to establish haif-life
values) have not been conducted for FRD -902.. As e result, no definitive
conclusion on the P and vP criteria can be drawn. However, as FRD-902
is a perfluorinated ether -compound, it is almost: certain that FIND-90"2
will be P and vP. This is strongly supported by all QSAR predictions
(especially the 0iowin QSAR models).
Given the log Ko, values of respectively 1,1 and 1,00, the lover Henry's
law constant; of 4.06E-06 Pa-rn-/rr d .and a water solubility of 207 ml /L,
FIND-902 is expected to have lour potential to bind to sludge and soil. On
the other hand, surface-active properties tend to increase the binding
potential. In grater FRD-902 will be dissociated at ambient temperature
at neutral phi (pKa= 3. 29 pleb=8,10t OECD 1.1.2 at 200C).
3.2 Bioaccumulation RD- 0
As the evaluation of PFOA pointed out, accumulation in fat tissue is not
relevant for assessing the bioacc€ mulation potential of pe fluorinated
compounds, Perfluorinated compounds bind to proteins, in particular in
blood and liver. The log K,,, is only indicative of binding to ilpids, not for
binding to proteins and sloes not provide an indication on
bioaccumulat:ion potential of perfluorinated compounds. To illustrate, the
log K,,, of PFOA (2.69) is far below the screening criterion for
bioaccurr uiation. Mill, elevated levels of PFOA in human blood and
excretion vela breastrnilk are observed widely. In addition,
biornagnification factors in the terfestdal food chain exceed the value of
1. Although such data are not available for FRD -902, based on the
per-fluoration and analogy with PFOA, it: is expected that FPD-902 will
bloaccurnuiate via protein binding.
It is unclear which substance properties determine the: protein binding
potential, but possibly the number of perfluorinated carbon atoms is
crucial for protein binding. FRD-902 has 4.5 perfluorinated carbon atoms
(one carbon atom contains a carboxyl group and is therefore not
completely perfluorinated), whereas PFOA (which is concluded to be
bioaccramulative (B)) has seven perfluorinated carbon atoms, Another
OECD guidei�ne'see
�ikFPi}�i7bN44?..£3C5.zE33'�Y339fz't�.Sc4F y$rF3s�3 i3,^-._zr�€itC°.�`,E?f3� Fi�f�5Q��7rESii2��837"3f y"$r5 '�r:Fi,
Page 25 of 92
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€ IVM Letter re€ or# 2016-0174
perfluod gated compound, PFHxA (which is concluded to be not 0) has
five perfluorinated carbon atoms, but dares not contain ether bonds,
Within this cornpar€a.on, the effect of the ether bond on the protein -
binding potential is unknown,
A biaconcentration testwith the acid FIND-903 shows limited
b€oconcentration in carps (<30; Elope et aL, 2016), which is expected
given the high water solubility arid is in agreement with PFOA.
Oral toxic kinetic studies (Gannon et al., 2016) with mice and rats
indicate that FRD-902 is easily absorbed arid fully excreted via the urine
without metabolism within hours rap to seven days. The clearance time
of F'PD-902 in mice, rats arid monkeys is an order of a magnitude loser
compared to PFC �
In view of this, FRD-902 may be expected to bloaccurrrulate to a lesser
extent compared to PFOA, However, the human clearance time for PFOA
is an order of magnitude higher as -4 yrs,) in comparison to all tested
animal species (rip to 60 days), It is not possible to draw a conclusion
on the bloaccumulation potential of FAD-902 in absence of data on the
human clearance time.
3.3 Toxicity E -90
As indicated 2. , there is no harmonized classification available for this
SUbstancea The self -classification notifications are: Acute Tox. 4, Eye
Maria, 1. and STOT RE 2 (substances presumed to have the potential to
be harmful to human health following repeated exposure).
In paragraphs 4,1 and 4.2 an assessment of the human health toxicity is
given. It: is concluded that for FIND-902 it is difficult to assess the
requirement for 3TOT RE pa Furthermore, it is concluded that FRD-90
will normally not result in ciassification for €nutagenicity and toxic for the
reproduction. For carcinogenicity, classification as category 2 is justified.
For aquatic organisms, this substance is not acutely toxic (LC/EC50>
.100 mg/L) or chronically toxic (i' OEC. > I mg/Li lowest I OEC 11.00
€ng/Q, Therefore, for ecotoxlcity, this substance dues not meet the T
criterion (a factor 1.00 above the criteria),
Given the available toxicity data it can be concluded that FRD-902 is less
toxic compared to PFOA. No conclusion can be drawn whether the
effects observed after repeated exposure, are sufficient proof of chronic
toxicity to meel: the'T-criterlor€.Baced on the data used for this report:,
the substance should be considered borderllne'r',
.4 Conclusion on PBT/vPvB statue for FRD-90
P/vP: Since FIND-902 is a perfiuorinated compound, the
substance is almost certain P/vP. All data and QSAR model
predictions point: in this direction,
B. FIND-902 is more rapidly eliminated than PFOA, Consequently,
FRD-902 is expected to bloa ccumulate less than PFOA, However,
it is not possible to reach a conclusion on the human
bioaccumulation potential of FRD-902 in absence of data on the
human clearance time,
Page 26 of g7
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RrVM Letter report 2016-0174
Tr FRD-902 is less toxic compared to PFOA; however, no
definitive conclusion on the T criteria can be reached since the
substance is considered borderline T for ETOT RE.
Overall, it cannot be excluded that FPD-902 meets the PBT/vPvB
criteria
Say Persistence,, bioaccuraaefation and toxicity FRD-903
No additional information was retrieved on the human toxicological and
environmental properties of FRD-903. therefore, no separate PBT/vPvB
assessment for FRD-903 is made, the conclusions on FRD-902 are valid
for FRD-903 as well.
The self--classiflcation notifications for the acid are also comparable to
FPD-90 (Acute To . 4, Skin Corr. 1C`1% Eye Darn. 1 and STOT SE 0).
3.6 Persistence El
El is potentially persistent based on the biodegradation QSARs
Biowin2&3 (0.00 era 1.11) and Siowin%3 (0°00 era 1.11). In addition,
the PE score tool, as developed by the RIVM, characterizes E1 as
persistent. Dane to the perfluorat€on, it is almost certain that El is
persistent and meets the P and vP-cr€ter€a,
3.7 Bloaccurnulation Et
E1 does not dissociate; estimated lag K,,; values are 3.44 (KDWWIN
v1.65) and 4,2E (Bloloom). The available bioaccLrmulation QSA s are
based on lipid -binding accumulation and are not suitable for perfluoro
compounds (such as E1), which are expected to accumulate via protein
binding (like PFOA). In comparison to PFOA and FP.D-90 , it is expected
that E1 has a higher bioaccumulation potential as it does not contain
any hydrophilic groups (presumably resulting in a lower water solubility
and .slower excretion rate). However, the high vapour pressure may
indicate that; the substance is excreted via exhalation.
3,8 Toxicity E I
The information on classification and labeling of El (no harmonized
classification and the following self -classification notifications: Shire Irrit
2, Eye irr€t 7 and STOT SE 0) gives no indication that E1 potentially
meets the T criteria for human toXicity. In paragraph 406 it is concluded
that although the available information on E1 is limited, it Indicates that
E1 has a low to very low human toxicity. No information on e€otoxiclty is
provided in the MSDS (2007).
The ecotaxicity QSAR ECOSAP estimates a chronic toxicity NOEC for El
of 0,66 mg/L for daphnids, used on this estimate, E1 does not meet
the `F criteria for ecotoxicitye
3,9 Conclusion on PBT/vPvB status for El
• P/vP, Since E1 is a perfluorinated compound, the substance is
almost certain P/vP. All QSAR. model predictions paint in this
direction.
• E/vEo Insufficient information is available to draw a conclusion
Page 2.7 of 92
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R3VM Letter report 2016-0174
about the bio acs:.uMUlation potential of El. Since E.t. contains no
hydrophilic group, the hur an clearance throe of the substance
and the bioaccurnUlation potential are expected to be higher than
for PF A (which meets the criteria for bioacs:umulatic n), although
El has the potential to be excreted via exhaletican.
• T El will most Ilkely not meet the T criteria.
1t cannot be excluded that E1 meets the vPvB criteria.
Page 28 of 92
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KIVf Letter report 2016-0174
4 Human health properties
The toxicological information as used in the present evaluation is mainly
based on the data as summarised by the registrant within the REACH
registration dossiers In addition, Chemours provided sorie of the study
reports on request of the RIVM. Further, two publications are available
on kinetics and chronic toxicity and carcinogenicity, respectively,
reporting studies also present in the registration dossier. Detailed
summaries of the individual studies are provided in annex I,
4.1 Haman health hazards Eli - 0
END--902 is classified as follows by the registrant:
• acute Toy. 4 1-100 : Harmful If swallowed
• Eye Damage 1 l"l318: Causes serious eye damage
: TOT 0E 2 1-1 73 May cause damage to organs <or state ail
organs affected, if krsown > through prolonged or repeated
exposure <state route of exposure if it is conclusively proven
that no other routes of exposure cause the hazard. affected
organs. Layer, Blood
Eased on the data available in the registration dossier, the RIVM agrees
with the classification as acute Too. 4; H302 and Eye Damage .1.; H318,
The classification with STOT RE 2 is based on the liver and red blood cell
effects, as indicated by the affected organs in the available repeated
dose toxicity studies. In table. 4, a comparison is made of the effects at:
or around the guidance values for STOT RE 2 for the respective study
duration with the effects which may support classification. Classification
for STOT RE is based on a defined level of adverse effects occurring
below specified dose levels depending on the study duration.
Tl ble 4. Comparison of the effects at or around the guidance values t-or
1.7 `ihks table. re4nrn In the ilterature references w, included in the REACH veggi kreUon Ar,rording w
REACH, the reaft:retc;e detoffs are considered confidential.
Faye 29 of 92
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RIVM Letter report 2016-0174
Overall, the requirement: of 6TOT RE 2 is difficult to assess because the
dose levels tested in ,mice, with effects that may or may not warrant
classification, are clearly below the ,guidance vaiues and this may be
taken as an indication that STOT RE 2 is needed. The effects in the rat:
are borderline and sometimes difficult to assess due to the large steps in
the dose levels.
The registrant does not classify FRD-902 as carcinogenic because the
observed increase in liver tumours in females and increases in pancreas
and Leydig cell tumours in ,Hale rats are not considered relevant to
humans, RIVM agrees that them are some species differences with
regard to the relevance of these typical tumours for peroxisome
prolife€-ators far humans. In line with RAC and IARC, we consider the
levei of evidence sufficient to show that these tumours are relevant for
humans, However, as turnours were only observed in one species,
classification as a category 2 carcinogen is justified (suspected human
carcinogen),
The available in vitro (OECD T'ti 47.1., 476 and 47 3) and in vivo (OECD
TC 474, 475 and 486) genetic toxicity and rr utaegenicity studies show
that FRD-902 Is not muta€genic. EFSA (7008) concluded that FIT-907 is
non-genotoxic based on the same dataset.
The registrant proposes no classification for reproductive toxicity, In the
developmental toxicity study in rats, the only effect on reproduction was
early delivery of the offspring at 100 and .1.000 ,nag/leg bw/day. However,
the adversity of this effect is uncertain as the offspring was alive and
there was no mcrease in resorptlons. In addition, these reproductive
effects were observed at dose levels also inducing maternal toxicity.
Therefore, classification based on the early delivery is doubtfui a.nd in
category 2 at most. Other effects include decreased foetal weights at.
100 and 1000 rang/kg big/day and increases in variations at 1000 mg/kg
bw/day. These effects in the presence of ,maternal toxicity do not
normally warrant classification.
In the modified one -generation study in mice, postnatal reduced bad}
weight and body weight gain was observed at the highest dose level in
the presence of maternal toxicity (liver effects). Secondary delays in
development were observed based on time after birth but not based on
body weight.
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RIVM Letter report 2016-0174
These effects, observed in presence of maternal toxicity, do not:
normally result in classification,
In Annex T an elaborated overview of the: available hurnan health data
for FRD-902 is given.
4.2 Conclusion on CMR and STOT RE propertiesEND- 0
Carcinogenic. As t€arnours were only observed in one species,
classification as a category 2 carcinogen is justified.
Mutegenic; The available in vitro and in vivo genetic toxicity and
mutagenicit:y studies show that FIND-902 is not: rr€€.€t:agenc.
Reproductive toxicity: The limited effects observed in presence of
maternal toxicity do not: normally result in classification.
TOT ICE; The regWrement of STGT ICE 2 is difficult to assess due
to dose levels tested in mice clearly below the guidance values,
which may be taken as are indication that STOT RE 2 is needed.
The effects in the rat: are borderline and difficult to assess due: to
the large steps in the dose levels.
As FRD-902 is used as a replacement of PFtOA and its ammonium salt:
(APFO) for the production of Teflon, a comparison of the toxicological
properties of both ammonium salts (FRD-902 and APFC) is considered
relevant. An exact comparison is not possible due to differences in
applied dose levels, The data in table 5 show that: excretion of FPD-902
is much faster in all tested animals compared to APFC. However,.
cornparable PPAR-o effects and tumour types were observed in the
available sub-chrmiic and chronic studies at roughly comparable
exposure levels. As comparable effects occurred at comparable external
dose levels, but at lower FPD-902 internal concentrations, the
interaction of F D-902 with its toxicological target is probably stronger.
Differences are observed in the type of developmental effect between
both sc€bstances4
Page 32 of 92.
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[ NM Letter rePart 2016-0174
- ..
...
..
'> '. ;
P tO�
.w.
90-day study rat
Effects L{OAEL
i PPAR- a related
Liver
,fie€[maker,
effects
hvoertroohy
2016
N OAEL/LfOAEL
: 0.1' 10 mg/k..g
OX6 / 0,64
_ Zeilmaker,
--------------
bw/da
-
l g � a=i .:.....w..
....
Chronic study
Effects LiOAEL
Increased A/C
Body weight,
US -EPA,
rat
ratio
liver changes
= 2016
PPP -a reiated
effects at
higher dose
levels
N OAE1./LOAEL
< 0..1. f .1..0 rnk
1.3 / .1.4:2 -
i� US -EPA,
bw1day
16,1 mg/kg
= 2016
badaF
Carcinogenicity
Type of
Liver cell
Liver cell
RAC, 2011 j
tumours
adenomas
adenamas
Leydsg cell
Leyd€g cell
aadeno€nas
adenomas
I
pancreas acsnar
pancreas acsnar
.:,......
..:..... .........
cell tumours
....... ........
cell adenomas
.........
i...
LCAOL/NOAML
50 / 1 mg/kg
16 / I mg/kgC,
2011
., bw/da 5...... ..........._..,
bw/da i .............
F
Developmental
Type of effects
Early delivery
No
RAC, 2011
toxicity rat
developmental
effects
t
«. «..........
«LOAELEI L....
_
_.1.00../u10.. mg/kg
-1 160 «.......
RAC, 2011 «...
.,............................................................:.,..,................................,
bS.i.Y
,..,,,,_,,,.,,,,,,,,,,,,..,,,.
Generation study
Type ref effects
No reproductive,
Resorpt€ons,
RAC, 2€011
mice
or
stillbirth,
developmental
postnatal
effects €
mortality, early
preputlal
senaration
LOAEL/N OAEL
5 mg/kg
1 mg/kg
RAC, , 2011
bsn�{d_._..
ba�sla
In c€ m arinq the
toxicity of both substances
it is useful to view toxicity
as being the result oaf toxicokinetics and toAcodynarnics. As to
toxicodynamics, as already stated, the data (in particular the chronic
,and semichronic studies) indicate that FR.D-902 interacts more strongly
with its toxicolo0ical target: than does APFiO. its to toxicok€net€cs,
however, the available non -human data or FpD-902 indicate a more
favourable profile compared to APF€0. As concluded in the present
report, human data on the bioaccumulation of FRD--902 are lacking. If
human data would confirm that F D-902 indeed is considerably less
bioaccurnuiative than AFRO, overall its long terra toxicity for humans can
be judged as being lower. '.it should be noted that: for the developmental
toxicity endpoint these considerations do not apply° For this endpoint
the mouse studies show a clearly lower potency for FIND-902 than for
APFtO. hereas in rats FR -902 was somewhat more potent (induced
early delivery in combination with maternal tonicity at a dose level
where AFFC induced no effect). Overall with a view to reproductive
Page a'a of 92
DEQ-CFW 00079620

toxicity the information on FAD-902 do not normally warrant
classification (see sections 4.1 and 4.2), whereas APFsO is classified as
toxic for the reproduction (category .13),
4.4 Hannan health hazard E D-90
All available toxicological steadies were performed with the am monialrn
salt (FRD-.902). lead -across of the toxs cologlcal properties of the
aarnmonisarn salt to the acid is considered justified for systemic effects as
after dissolution and dissociation of the acid and the salt the absorption
in the intestinal tract and the longs and distribution over the body of the
anion (2,3,3,3--tetrafl€ oro-2-(heptatl€ oropropoxy)propanoate) will be
the same, However, local effects to the lung may dlffsxr between the two
substances as acids normally have a hlgher irritating effect than neutral
salts.
4.5 Human health hazards El
Only limited toxicological information is available on E1, consisting of a
number of study reports provided by Chernours and a summary of the
EF A evoaluat:lsasa of the mutagent dty. C:hernaours could provide not all
steadies as some steadies contained information on several substances,
These are available upon request after redaction to remove all other
data,. Study summaries of the provided steady reports on E1 and further
details on the read -across are included in Annex 2,
The available oral kinetic steadies indicate bevy oral absorption of EI.`. The
observed effects after inhalation exposure indicate effects on the central
nervous system. This indicates that some absorption can occur via this
route. The absence of mortality after high dermal exposure indicates
love dermal uptake.
The available acute toxicity Studies via the oral (>17000 nig/kg bw),
dermai (> 37E00 rnglkg b ) and Inhalation route (:�E76000 ppm) show
rasa mortality at high close levels indicating low overall toxicity and no
requirement for classification.
The only repeated dose steady is limited to a 10-shay inhalation exposure
over a period of 1.2 days and was performed Lasing only male animals.
The results show love toxicity limited to CNS depression during exposure
A NOAE.0 of 29000 pprn was derived,
The available in vitro and in vivo steadies show no evidence of a
mutagenic potential of E1, as also concluded by EFSA, The Ames test
was negative, However, due to the likely evaporation of El in the in
vitro chromosomai aberration steady and the possibly limited amount of
E1 in the in vivo inhalation micronucleus test that reached the bone
marrow as no change in the 9CE/NCE ratio was observed, no concl€asion
on the mutaasgenic properties concerning chromosome aberrations can be
drawn from these steadies.
Read -across
Dead -across from FdD-902 to E1 is resat: justified because of the
differences in chemical -physical properties (solid versus liquid with high
vapour pressure, acid or salt versus ne€at:rai, rnore Ilpoplalllc substance).
page 3. of 97
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RUM LetE:er report: 201.5-0174
In addition, the available toxicological data indicate that E1 is less toxic
than FRD-902.
Expert systems including 'Cncoi.ogic', 'OECD toolbox' and `IS ' do not
indicate a strong concern for mutagenicity or carcinogenicity.
'The two closest analogues identified using the OECD QSAR. toolbox,
enflurane and isofl€arane are used as inhalation anaesthetic used for
narcosis at high concentrations and shoe low toxicity. A range of
fluorinated compounds collected from the RepDose database
(Frauenhofer) showed limited toxicity with NOECs arrays above EO ppm.
Exposure limits
Acceptable Exposure Limit (D€.rPont)e E00 pprn 8 and 12 hour TWA
(MSDS, 2007).
4.6 Conclusion oe CMR and STOT RE properties l
Information on the toxicity of E1 is limited but the available information
indicates that E1 has a low to very low toxicity. This is supported by the
repeated dose toxicity information on some structural analogues,
However, all available studies were performed in male animals and were
of limited duration. Overall, the available in vitro and in vivo data on
mutacgenlcity combined with the read -across data show that E1 is
unlikely to be mutagenico In addition, the available data indicate no
requirement for classification for acute toxicity and probably ETOT RE
aria inhalation but the requirement for classification for other hazard
classes including carcinogenicity, reproductive toxicity and 9TDT 8E via
oral exposure is unknown.
4s7 Derivation of a general population latio exposure limit for t'tD-902
4,7.1 Approach
For the derivation of an exposure limit for FRD-902 for the general
population the REACH method as describers in the "Guidance on
information requirements and chemical safety assessment Chapter R.8r
Characterisation of dose [concentration) -response for human health" is
used (version 2.1 November 2012), Although FRD-902 Induces
carcinogenicity in experimental animals, the mailable mutagenicity
studies and mechanistic information Indicate a non-genotoxic anode of
action and therefore a threshold approach can be applied.
The use of an Internal dose per ml of serum as close metric has recently
been applied for PFOA by RIVM I~2ei[maker et al, 2016). However,
applying this principle to FRD--902 is considered not feasible. The reason
for this is that in contrast to the critical studies with PFOA, no
information on the serum levels of FIND--902 is available from the critical
animal toxicity study. Furthermore, no Kinetic model Is mailable For
FIND-902 in humans. Moreover, the mailable data in test animals show
quick elimination of FAD-902 (TI./2 for elimination from serum in rats
2�8 h in males and 0.2 h in ferrules), which leads to the serum values in
the toxicity studies being strongly dependent on the time after the last
exposure. Crucially, no information is mailable regarding the half-life of
FRD-902 in humans or regarding serum concentrations in human,
Therefore, the derivation of a limit value on the basis of serum levels as
was done for PFCA, is unfeasible. Instead, for FRD-902 a method for
Page 35 of 92
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RTVM Letter report 2016-0174
deriving a limit value based on the external concentration in air is
applied.
Application of the GenX technology leads to emission of F D-902 via air,
As a result, the general population may be exposed to F D-902 via air,
food and/or drinking water, However, no information is currently
available regarding levels of F D-902 in drinking water or food.
..l..hereforex only inhalation exposure is assurned in the present
assessment and only a9 limit value for air is derived. As it cannot be
excluded that: this exposure will continue for yearsr a chronic inhalation
limit value is determined.
4.7.2 -6vicatystudies
The Nt" AELs derived from the card repeated dose toxidty studies are
SUmmarl.sed in table 0 below.
e 7.3
Selection of the nmst appropriate point of departure
Exposure of the general population due to emissions to ambient air is
normally limited to lama level of exposures over a long period. The
exposure can be intermittent depending on the applied process, release
and distribution in the environment. However, based an the available
Page .ate of 92
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RIVM Leiter rep*rt 20166-0174
emission data, only an average concentration per year can be estimated
for the general Population depending on the distance from the source.
Therefore, acute effects after a single high exposure and local effects
except local effects on the airways are considered not relevant for the
general population in the present case. Accordingly, the assessment is
Lased on effects observed after prolonged lour level exposure. For FRD-
902 this includes the NDAELsJLCAELs from repeated close studies,
carcinogenicity studies and reproductive toxicity studies,
As no inhalation studies are available with FRD-902 but only oral
(gavage) studies, an oral study is used and route -to -route extrapolation
is applied for deriving the exposure limit for air. Overall, the NOAEL of
0.1 mg/kg bJday in the oral chronic study in rats is considered: the best
available point of departure (POD) for derivation of an exposure limit,
This NOAEL is baser) on an increase in albumin and the albumin/globulin
ratio in male rats, an effect that indicates possible immunotoxic effects.
This effect was also observed with other PPA -a inducers and secondary
to binding to the PPAg-c€ receptor- (Cervois et al, 2004). As changes in
albumin and albumin/globulin ratio also occur in humans after exposure
to PPAP_o inducers (Cervois et al, 2004), this effect is considered
relevant to humans.
4.7,4 Inhalation exposure limit
The NOAEL of 0.1 mg/kg bw/day from the oral (gavage) chronic study is
used as POD. Via routewto-route extrapolation the corresponding POD -
concentration in air is derived. The chronic study used gavage exposure,
meaning that the whole daily dose was applied at since. The possible
inhalation of FPD-902 is expected to be evenly distributed over the
whole clay. Because of the half-life in male rats of only 3 hours, this
difference may result in a different internal exposure pattern. The pears
of internal exposure (Crnax) are expected) to be higher under the
conditions of the chronic rat study. However, the effect of this difference
on the tonicity of FIND-902 in humans is € nknown as it is not known
whether the pear: exposure (Crnax) or the integrated dose (AUC)
determines the critical toxicological effect of FIND-902, No additional
safety factor Is applied for this difference, In the route -to -route
extrapolation, an additionai factor for difference in absorption between
the oral and the inhalation route is required as the oral absorption has.
been shown to be 10011fa but the inhalation absorption is unknown.
Available information from comparable substance like PFOA show.
absorption after inhalation exposure in animals. However, no absorption
percentage is provided in the available summaries. Therefore, a default
value of 10011% is applied in line with the REACH guidance, This is further
justified by the absence of metabolism showing that first pass effects
are not relevant. Route -to -route extrapolation was performed by
dividing the point of departure of 0,1 mg/kg bw/day by 1.15 m-3Jk9
bw/day," resulting in a POD for the air concentration of 0,005 mgJm'.
Besides this allornelAr scaling factor of 4, normally an interspecies
factor of 205 for remaining toxicokinetic and toxicodynamic differences
la 137€3cl�dCiai3 Vr"Enn3e Par kg bw per day €o rats whkli is oi5n5pabMe with a factor 0,25 for aiiomeiric sCaiing f "-o f
rat, to €mnars, 7D kg bar and 230 nl'Jday as the daily ventilation voWme for human: (20 m /day " 4) 170 kg
bw = 1,15 r3 /kg bwlday
?age 37 of 92
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and an intraspecles factor of 10 are used in agreement with the REACH
guidance,
Additional factor for potential kinetic difference
However, there is concern regarding the potential difference in half-lives
between the tested animal species and humans. FFD-902 is used as a
replacement of PFOA and is also a fully fluorinated carboxylic acid. The
half-life of PFOA in humans is much longer than those in ell tested
animal species (mouse, rat, monkey) (2ellmaker et al, 201.6) probably
due to stronger reeabsorption from the lumen of the kidney back into the
blood by organic anion transporters (OATS) (Yang et al, 20.10), There
are genetic differences In OATS between humans and the tested animal
species (Yang et al, 2010). As FIND-902 is also an anion, this mechanism
cannot be excluded. The elimination of FRD-902 was tested in three
anlrnal species (Gannon et al, 2016) and the resdts show that In these
species the halo"' -life of FRD-902 was clearly shorter than those of PFOA,
suggesting that for FRD-902 reabsorpdon by OATS Is lower or absent
entirely, at least in these species. However, because of the genetic
differences of the OATs between the tested animal species and hurnans
(Yang et al, 2010) this cannot be directly extrapolated to humans, Thus,
for humans the involvement of OATS in the elimination of FIND-902 in
cannot be excluded, Moreover, contrary to other perflraarinated
compounds, no data are available for FPD-902 to confirm whether than
fast elimination and absence of accumulation as seen in several animal
species also applies to humans.
In view of the above, an additional toxicokinetic assessment factor is
applied to take into account the uncertainty in the human elimination
rate of FPD-902. This additional toxicoklnetic factor Is leased on the
difference in Ralf -lures between c:ynorridg as monkeys and humans as
determined for PFOA, rising a half-life of 1378 days in humans (mainly
males)(Clsen et al, 2007) and of 20.9 days in male cynomoigus
monkeys (Butenhoff et al, 2004), leads to an additional toxicokinetic
factor of 66 (1379 j 20o9)a
The PFOA half-life in male cynomcalg€as monkey Is used in deriving this
additional factor instead of the half-life for PFOA in male rats (the
species used in the pivotal chronic shady) because for FRD-902 the half-
lives in male rats and cynornolgus monkeys were similar in size whereas
for PFOA the half-life In cynomdgus monkeys is much longer than that
in male rats (20.9 days in male cynornolgus monkeys versus 0-7 clays in
male rats). This indicates that for F D-902 the use of the factor between
male rats and humans for PFOA is not: appropriate.
Interspecies remaining difference
Interspecies extrapolation corrects for the differences In the sensitivity
between experimental animals and humans. This carers differences in
toxicodynamirs and toxicakinetics, Some of the toxicokinetic differences
can be explained by body size in relation to the basal metabolic rate.
The latter- is linked to the inhalation volume per kg lair. By default, in the
extrapolation from animals to humans an interspecies correction for
metabolic rate is applied (a factor of 4 in rase of rats), are described
above. An additional factor of 2.5 for remaining differences, Le.
toxc cokinetic differences not related to metabolic rate (small part) and
Page 38 of 42
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RZVM Letter report 2016-0174
toxicodynamic differences (larger part). As the REACH guidance points
out, in case substance -specific information shows specific susceptibility
differences between species, which are not related to differences in
basal metabolic rate (not covered by allornetric scaling), the additional
factor of 2,9 for `re raaining differences' should be modified accordingly..
The potential difference In half-life of FIND-902 between the tested
animal species and humans is a potential difference In toxicokinetics
which is probably not related to the metabolic rate.
Therefore, the calculated potential difference in half-life is used to
replace the toxicokinetic part of the additional factor of 2a . As the
toxicodynamic part is the larger part of the remaining difference, a
factor of 1.8 is applied as the remaining factor for toxicodynamic
interspecies extrapolation, The factor of 1.8 was selected as being the
larger part of the 2.E factor which is not quantified in the ECH A guidance
R&
No assessment factor for duration of exposure is applied as the point of
departure is a chronic study, In addition, no factor is applied for the
dose -response relationship as the point of departure is a NOAEL. Also,
no factor is applied for quality of the database as repeated dose toxicity
studies in two species, a carcinogenicity study and reproductive toxicity
studies are available.
Overall, the following assessment factors are applieda
Additional factor for potential kinetic difference 66
Interspecies remaining toxicodynamic difference LB
Intraspecies 10
Therefore, the overall assessment factor is 1188. Combining this
assessment factor with the point of departure of 0.087 mg/m3, results in
an chronic inhalation exposure limit of 73 ng/m3.
Although local effects on the lung dine to the irritating properties of FItD-
902 at the inhalation point of departure of 0.067 mg m3 cannot be
excluded, it is considered unlikely that such effects could be critical for
the limit value as the derivation of limit values based on local irritating
effects dues not require additional assessment factors for passible
differences in accumulation, Therefore, the limit value of 70 ng/m3 Is
considered to be also protective for local irritating effects.
Using the additional toxicokinetic factor as above represents a pragmatic
worst -case approach based on the data as currently available. Additional
information on the bloaccumulation of FAD-902 in humans and on the
inhalatory absorption rate would allow derivation of an improved
exposure limit.
4.8 Derivation of a general population exposure limit for FRD-903
All available toxicological studies were performed with the ammonium
salt (FAD-902)0Read-across of the toxicological properties of the
ammonium salt to the acid is considered justified for systemic effects as
after dissolution and dissociation of the acid and the salt the absorption
in the intestinal tract and the lungs and distribution over the body of the
Page 39 of 92
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RTVM Letter repnri 2016-0174
anion (2,,3,3,3-tat€'afI€ioro,-2-(heptafluors)propoxy)propanoate) will be
the same.
Local effects to the upper airways and lungs may differ- between FRD-
902 and FRD-903 as acids normally have a Nigher irritating effect than
neutral salts. Thus the derived limit vaWe in air for FRD-902 might
underestimate the local toxicity of FRD-9€ 3, However, it is considered
unlikely that such effects are determinative for the lirnit vaiue as the
derivation of Ii€nit: values based on local irritating effects does not
require additional assessment factors for possible differences in
accumulation, Therefore, the limit vaiue of 73 ngjrn3 is considered to
adequately rover the local Irritating effects of FRD-903 and FRD-902.
4.9 Derivation of a general population pos re lima for El
As indicated before, the information on the toxicity of F1 is limited and
no studies were performed using female animals. However, the available
information indicates that F1 has a lour to very low toxicity. This is
supported by the repeated dose toxicity information or) some structural
analogues, However, the data are insufficient for deriving an inhaiation
exposure limit.
Page np or 92
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R VM Letter report 2016-0174
Indicative concentrations around the Chemours pleat due t0
FRD-903 and E1 emission
As indicated in section 2.2, FRD-900 and El are emifted to air from the
Teflon PTFE and from the Teflon F P plants (see tables 7 to 1.0). The
presented data are based on the maximum emission indicated in the
permits, the e-nission recarded in the Electronic Environmental Year
report of Chennours and additional data provided by Chemours.
7, Emissions to air of
2012 t600
0 I'197 40 _10
--- ---
2013 292 40 L27
2014 _.... 886 40«.. t 31
2015 0 288 40 127
of El for both ?-Wants its
2012
750 205
450
w11
-
201..
750 .........50
..
......... _.�I2
2014750
LL93
390 .............450
_��8
2015......._
[750 288
[450
46
Page 41 of 92
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RIVM Letter, report: 2016-0174
The characteristics of the stacks are copied from the request for revision
of the permit of 2013. These characteristics are presented in table 11.
At the moment the calculations were carried out no information about
the exact locations of all stacks was available. It was assumed all stacks
in the FEP-plant have the same location as TL20 and all stacks in the
FTPE plant as TL12. For FEP TL36 characteristics Were invalid, instead
TL20 characteristics were used. Same for FTPE TL01, here TL12
characteristics were used, Since not all information was available these
calculations should be considered as indicative.
df
Page 42 of 92
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RIVM Letter repent 2016-0174
coagulation or deposition Is available, in the calculations it is assumed
all substance maintains in the air without any (wet or dry) deposition.
This can be seen as e worst case. The distribution is calculated in e 50 x
50 km grid. Within this grid, the concentration is calculated in cells of
100 x 100 m. The calculated result does not gyre the exact
concentration at a certain point, but is the average concentration of the
cell
The calculated air concentrations in the nearest populated areas (along
the duce at the other side of the river) are around 20 ng/ 3 (permitted
emissions) versus 15 rig/M3 (recorded emissions) for F D-903 and
around 40 ng/M3 (permitted emissions) versus 20 ng/m3 (recorded
emissions) for El.
Page 43 of 92
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RIVM Letter report 2016-0174
Page 44 of 92
DEQ-CFW-00079631

RIVM LeUez MXOft 201-6-0 3 74
Possible health effects in residents in the vicinity of the
Chemours plant
In chapter 4, the available human health effects information on FRD-
902/903 Is evaluated, based on which a chromic inhalation exposure
limit of 73 n9/M3 is derived (paragraph 4.6.4)a In chapter E, the year -
average air concentrations were calculated, in first Instance Lased on
the permitted emissions and, secondly also for the recorded emission for
2014. This led to estimated concentrations in air of about 20 ng/m' for
the nearest populated areas (along the dire at the apposite side of the
river) and leer concentrations at greater distances from the plant
based on the permitted concentrations. used on the recorded emissions
for 2014 the estimated concentrations for the nearest populated areas
are about 13 ng/M3m
Comparing these concentrations with the limit value of 73 rag/m-3 leads
to the conclusion that based on the available data, no health risk is
expected for people living in the vicinity of the Chemours Dordrecht
plant due to exposure to FAD-903e
To illustrate the results, figure 1 shoves the calculated concentration
FRD-903 in air based can the recorded emission in 20:1.4 compared to the
exposure limit derived in this report. The data from 2014 have been
used, because in this year the highest emission was recorded. The figure
shows that only directly next to the stack, air concentrations above 73
ng/M3 are calculated, Annex 3 presents the calculated concentration
FRD-903 In air based on the permitted emissions.
In chapter 4 also the available human health effects information on El is
evaluated. The conclusion was that limited toxicological information and
structure -activity relations indicate that this chemical has low topic
potential only. However, the data are insufficient for deriving are
inhalation exposure limit, In chapter 3, the year -average air
concentrations for E1 were calculated based on the permitted emissions.
This led to estimated concentrations in .air of about 40 ng ,gym" for the
nearest populated areas (along the dire at the opposite side of the river)
and lover concentrations at greater distances from the plant. Eased on
recorded emissions for 2014 the estimated concentrations for the
nearest populated areas are about 20 ng m3.
Due to the insufficient health effects information available for El, these
concentrations cannot be evaluated as to the possible health risk they
might pose for people living in the vicinity of the Chemours plant in
Dordrecht.
Page 45 of 92
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RIVM Letter report 2016-0174
calculated FRD-903 concentrations in air based on recorded emissions for 2014 0 Stack
calculated average concentration in a gricicel
15 - 73 ng/mB MI
0,5
- 73 nqtM3 (derived exposure firyfit)
Figure 1, Calculated air concentrations FRD-903 based on the recorded
emissions (in nglm3).
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P.TV ! Leer report 2016-0174
7 Conclusions
In chapter 3 of this report, on P T-propertles, the conclusion is that it
cannot be excluded that the GenX related substances meet the
PBT/vPvB criteria. Ali evaluated substances (FIND-903, FIND-902 and EI.)
are perfluorinated compounds and should therefore be regarded as
certainly P/vP. Since FpD-903 and FPD-902 in animals are more rapidly
eliminated than PFOA, it is expected that both substances bioaccurnulate
less than PFOA. However, it Is not passible to reach a conclusion on the
human bioaccumulation potential in absence of data on the human
clearance time. For the substance El, insufficient information is
available to draw a conclusion about the bioaccum€ cation potential for
FRD-902 and FRD-903. Since Et contains no hydrophilic group, the
human clearance time of the substance and the bloaccumulation
potential are expected to be higher than for PFOA, although El has the
potential to be excreted Baia exhalation. Finally, FRD-903 and FPD-902
are considered less tonic compared to PFOA. However, no definitive
conclusion on the T criteria can be reached. El will most likely not meet
the T criteria,
Chapter 4 evaidates the CMR and STOT PE properties of the three
substances. It is concluded that classification as carcinogenic category 2
(suspected human carcinogen) is justified for FIND--902. The mailable
studies show that both substances are not mutagenica On reproductive
toxicity the limited effects observed in presence of maternal toxicity do
not normally result in classification, whereas PFOA is classified as toxic
for the reproduction (category 1B), The requirement of ` TOT. ICE 2 (like
liver and kidney) is difficult to assess due to dose levels tested in mice
clearly below the guidance values, which may be taken as an indication
that aT3T PE 2 is needed. The effects in the rat are borderline and
difficult to assess due to the large steps in the dose levels. Effects on
the liver are observed at the similar dose levels for FIND-902 and PFOA.
All available toxicological studies were performed with the ammonium
salt (FRD-902). Read -across of the toxicological properties of the
ammonium salt to the acid is considered justified for systemic effects as
after dissolution and dissociation of the acid and the salt the absorption
in the intestinal tract and the lungs and distribution over the body of the
anion (2,3,3,3-tetrafluoro-2-(heptaf uoropi-op€ xy)-propaiioate) will be
the sane, However, laical effects to the lung may differ between the two
substances as acids normally have a higher irritating affect than neutral
saltsa
Information on the toxicity of El is limited but the available information
indicates that El has a low to very low toxicity. This is supported by the
repeated dose toxicity information on some structural analogues.
Contrary to what is usual in toxicology, all mailable studies with El were
pet -formed in male animals only. In addition only studies of Bruited
duration are available. Overall, the available in vitro and in vivo data on
mutagenirity combined with the read -across data show that El is
unlikely to be mutagenic. In addition, the mailable data indicate no
requirement for classification for acute toxicity and probably STOT RE
Paqe 47 of 92
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RJVM Letter reparl: 7.016-0,€,74
aria inhalation but: the requirement for classification for gather hazard
classes including carcinogenicity, reproductive toxicity and ETOT ICE +eta
oral exposure is unknown,
Chapter 4 completes with the derivation of an chronic; inhalation
exposure limit: of 73 ng/M3 for FRD-903 and FRD-902 which includes are
additional toadc€ kinetic factor in a pragmatic worst -Case approach. The
avallable information on the toxicity of El is limited, The data are
insufficient for deriving an lnhalatlon exposure limit,
Based on the permitted and recorded emission to air, the aim
concentrations around the Chemours plant are calculated in chapter 3.
Comparing the calculated concentrations in air with the limit value of 73
ra>q'm3 in chapter 5 leads to the conclusion that: based on the available
data, no health risks are expected for people living in the vicinity of the
Chernoors Dordrecht plant due to exposure to FRD-903. Due to the
insufficient health effects information available for El, these
concentrations cannot be evaluated as to the possible health risk they
might pease for people living in the vicinity of the Chemo€ars plant in
Dordrecht,
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RIV.MLetter report 2016*174
The authors nfthis report would like bothank Prof. Dr. M.van den Berg
(Institute for Risk Assessment Sciences, Utrecht University) and Prof.
Dr. J. de Boer (Institute for Environmental Studies, VU University) for
reviewing the draft version of the report.
Page 49 of 92

RIVM Letter report 2E726-0174
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RTVM Letter report 2316-0174
References
Anonymous (1.965) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chemours.
Anonymous (1967a) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chemours.
Anonymous (1967b) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chemours.
Anonymous (1968) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chenriourse
Anonymous (1994) Unpublished report from Haskell laboratory.
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Anonymous (1995) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chemours.
Anonymous (2007) Unpublished report from Haskell laboratory,
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Anonymous (7008) Unpublished report from Haskell laboratory.
Performed for DuPont and provided by Chemours.
Anonymous (7009) Unpublished report from General Testing Research
Institute of Japan 00stuff Inspectors' Corporation. Performed for DuPont
and provided by Chemours.
Butenhoff, IL, Kennedy CL, Hindeliter PM, Lieder PH, Jung R, Hansen
KI,Gorrnan CC, Nokr PE, Thonford PJa 7004. Pharmacokinetics of
perfluorooctanoate in cynomolgus monkeys, Toxicol 8ci,, 82, 394 -- 406.
EFSA (7008) P€:rfl€aorooctane su fonate (PFOS), perfluorooctanoic acid
(PFOA) and their salts. Scientific Opinion of the Panel on Contaminants
in the Food chain, The EFSA Journal, 653: 1-1.31,
Cannon, S.A., Fasano, W.J., Mawn, M.P., Nabb, D.L,, Buck, R.C.,
Buxton, L.W., Jepson, C.W. and Frame, S.R. (3016) Absorption,
distribution, metabdisrn, excretion, and kinetics of 3,3,3,3-
tetrafl€aoro-3-(heptafluoropropoxy)propanoic acid ammonjum salt
following a single dose in rat, mouse, and cynomdgus monkey.
Toxicology 340. 1-0,
Cervois, Pe, Klee€ ann, R., Pllon, A., Percevault, Fa, Koenig, We, 3taels,
B, and Koolstra, T. (2004) Global Suppression of IL-6-induced Acute
Phase Response Core Expression after Chronic in Vivo Treatment with
the Peroxisome, Proliferator--activated Receptor- Activator Fenoflbrate.
The Journal of Biological Chemistry 779 (16), 1.61.54-161.60.
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RIVM Leuer report 2016- 0174
Hoke, R.A,Ferrell, B.D,Slmnmn,T.L,Buck, �C.and Buxton, LVV.
(2Q1G)Aquatic hazard, bioaccurnu|adon and screening risk assessment
for ammonium 2,3,3,3'tetraOuono-2-(heptaUuoropnnpoxy)-propenmabe.
Chennnsphere149: 336-342.
IARC (2016) 9erfluonooctanoicAcid, Tetnafl uoroethy|mne,
Dichionomethane, 1,2-Dichlonupropana,and 1,3-PropaneSu|tone. In:
I4RCMonographs onthe Evaluation ofCarcinogenic Risks toHumans
Vo|umne118.
bsu,{, Amito>e, K, Hodes, C, La!, D, Phahlee-Hutchens,A, Seed,].
(2QQ7)PerUomroa|kyiAcids: AReview uf Monitoring and
Toxicological Findings. TOXICOLOGICAL SCIENCES 99(2), 366-394,
Material Safety Data Sheet(MSDS) DuPont (2807), El Stable fluid
rovised31-ADG-2Q7.
Olsen GVV, Bun-isjM, Ehnesnnen CO3 Froehlich JVV, Seacat AM, Butenhoff
JL, Zobe| LR. (2807) Half-life of serum elimination of
perMuonooc±anesu)fnnate,penOuurohexaneou|fonateand
perOuoromcimooato in retired fluorochernica| workers. Env Health
Penapect, 115 (9): 1298- 1305.
RAC{Z011} Opinion proposing harmonised classification and labelling at
Community level ofAmnnnuniurnpentadacaflounoou±anoete. ECHA,
ECHA/RAC/DOCNoCLH-0-QQQ0QQ2225-82-01/F.
Rae, 3.M.C, Craig, L., Slone, T,@/., Frame, S.R. Buxton, L.W, Kennedy,
G.L. (2815) Evaluation of chronic toxicity and carcinogenicity of
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in
Spnague-Qavv|eyrats. Toxicology Reports Z: 939-949.
US -ERA (2015) Health affects support document for perMuorooctano!c
acid. EPA Document Nurnber:822-R-16-QO3.
Yang, C.R.,Glover, K.P.and Han,%. (2O18)Characterization ufCellular
Uptake ofPedluuroo«±onuate via Organic Anion -Transporting
Po|ypeptide IA2, Organic Anion Tnamsporter4, and UnateTnnnnpurter 1
for Their Potential Roles in Mediating Human Renal Reabsorpbon of
Pedloorocarboxy|atey.TOXICOLOGICAL SCIENCES 117(2): 294-302.
Zei[nnaker, M. ].,]amssen, P., Versteegh, A., van Pu|,A., de Vries, VV.,
8okkers, 8', VVuijte, WW., {)onnen,A., Merrernans,]. (3016)
Risicoschatt|ng ernissie PF0Awoormnuwanenden. R1VM Grieh-apport
ZD16-UU4Q.
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RIVM Leger report 2016-0174
Annex 1. Human health toxicity RD-90
Introduction
Most study summaries were copied from the robust study summaries in
the registration dossier. The summaries were checked and conclusions
by the registrant to which RIVM did not agree or were questioned were
removed or it was added that this was a conclusion of the registrant, No
attempt was made to have an RIVM conclusion on a parameter if the
parameter was not determinative for the derivation of the NDAEL The
RIVM conclusion on the NOAEL is included at the end of each study
summary. In addition, the study reports of the key studies (90-day
mouse, 90-day rat and chromic rat) were provided by Dh€:mours. A
comparison of the summaries in the registration dossier with the study
report showed that: the summaries were copied from the study report:. In
addition, the results were compared with the detailed study results and
additional details were added were necessary.
Cannon et al. (2016) tested the absorption, distribution, metabolism
and excretion (ADME) and kinetics of FRD-902 (the ammonium salt) in
rats, mice and cynomolgus monkeys. Fharmacoklnetics was determined
by measuring in Flood samples from rats and mice at multiple time
points after a single oral dosing at 1€0 or 30 mg/kg. In addition,
pharmacokinetics aver single intravenous exposure (10 mg/k.g) were
measured at multiple time points up to 7 days in rats and up to 21. days
in cynomoigus monkeys, ADME parameters were measured in tissue and
excrete up to 166 hours after oral closing in mice (dose. 3 mg/kg) and in
rats (dose: 30 mg/kg). A hepatocyte metabolism test indicated that
FRD-90 , is not metabolized by rat hepatocytes, which was supported by
the absence of metabolites and the complete recovery of the dosed FpD-
902 in rat and mouse urine. As shown in table Al, FpD-902 is rapidly
absorbed after oral exposure and shows biphasic elimination with a very
rapid alpha -phase and a slower beta -,phase elimination. The alpha -phase
elimination half-life was faster in fernaie rags compared to mate rats.
Furthermore, it is mentioned in the publication that because the urinary
elimination rate is very rapid (nearly the entire dose was eliminated
within 1 -24 hours), the sex difference observed in the plasma kinetics
was not readily apparent in t:he urine kinetics. No test: substance: was
detected in the blood of monkeys .1.6 days after dosing probably clue to
the much slower elimination in the Leta -phase. For both rats and
monkeys the alpha phase was very rapid and the contribution of the
beta --phase was considered negligible, Therefore, the authors concluded
that: the beta phase elimination did not: contribute to potential
accumulation after multiple dosing in rats or monkeys. nearly the: whale
administered dose: was eliminated In the urine (table A2) in rats and
mice. A small amount of the test substance was recovered in the faeces,
but this was likely due to contamination of the faeces with urine. Tissues
were net analyzed, because at the conclusion of the study (at 160 h) the
entire dose was recovered in the urine, faeces, and cage wash. No
metabolites were found.
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Phnrmacoknebcsdiffered between rats and mice, with a slower
elimination nsto in rn|oe compared to rats. The elimination rate in
monkeys was more similar tomale rats.
------- ----------------
In the REACH registration dossier, 10 studies in experimental anirno|y
and two /nvitro studies were available for basic toz!uokineUcs.The /n
vitro studies were carried out with rat hepatocytes (Exp Supporting
BaeicTox|cokine±ics.012) and trout hepatucytes (Exp Supporting Basic
Toxicokinetics.011) and showed no indication of metabolism, Several
pay°s4 ofyz
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RIYV; Letter report 2016..0174
steadies included in the registration were published by Cannon et al
(2016) and are described above. Other studies in orally exposed rats
(doses ranging from 10 - 30 mg/kg) showed that the test compound
was almost completely eliminated in canine and reported half-lives of
between 13.2 and 1.0.8 hours, clearance tires (98.4%) at doses of 10
and 30 mg/kg of 12 h and 22 h for male rate, and of 4 h and 6 h for
female rats, respectively. No test compound was recovered in the fat: of
male and female rats and no test compound was recovered in the liver
of female rats, in male rats, the tisscaeeplasma ratio in the liver was 2.2
at a dose of 10 mg/kg, and 006 at a dose of 30 mg/kg, respectively (Exp
Supporting Basic Toxicokinetics,008).
In another study (Exp Supporting Basic Toxicokineticse007), rats were
exposed by intravenous injection with 10 or E0 mg/kg. Deported
clearance times were 22 h and 3 h for male and female rats,
respectively, at a dose of .10 mg/kg. At a dose of 50 mg/kg, reported
clearance tirnes were 17 hours and 4 hours for male and female: rats,
respectively,
One additional study in mice was available (Exp Supporting Basic
'roxicokinetics.01.0), In which mice were given a single oral dose of 1.0 or
0 rug/kg, At 10 mg/kg, the plasma clearance time was 143 h and 57 h
for male and female mice, respectively. At 30 mg/kg, the plasma
clearance time was 1.39 h and 62 h for male and female mice,
respectively. The tissue, plasma ratio for fat was .0,1 in male rats
exposed to 30 mg/kg, 1n male rats in the 10 mg/kg dose group, no test
substance was detected in fat. The tissue. plasma ratio for the liver was
0.5 for male rats in both the 10 mg/kg and 30 mg/kg dose groups. in
female rats, no test substance: was detected in fat or liven
One study in cynornolgus monkeys is reported in the registration dossier
(Exp Supporting Basic Toxicokinetics.003), From the results presented it
could not be determined whether these data also refer to the Gannon et
al (2016) shady. Therefore, the steady report in cynornoirgus monkeys is
presented here as well. donkeys were exposed to 10 mg/kg by a single
intravenous injection, Blood was collected at multiple time points
(approximately 0.083 (5 min), 0.167 (10 min), 0.2E (15 min), 0.5 (0
ruin), 1, 2, 4, B, 1.2, and 24 hours past dose). Additional blood samples
were collected once daily on day 3 - 2:1.. Half-lives at a time interval of
0-12 h were 1.8 h and 1.6 h for male and female monkeys, respectively
(Table E). Clearance times were reported to be 11 hours for males and
10 hours for females.
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male A3. Half -fife in cy°raomoigus monkeys as reported in the REACH registration
dossier for amr2 opium 2,.3, 3, 3-tetralluo~-o-2-(heptaflajo-oi3ropcaxy)p'r opai?oate;
One study on toxi€ okinetir data in rats after prenatal exposure was
available in the registration dossier (Exp Supporting Basic
Toxa cokinetics.006), Pregnant rats were exposed to a daily dose of 5,
10, .1.00 or 1000 mg/kg/day by oral gavage during gestational days (CD)
6 - 20. Plasma concentrations were measured In the fetuses on GD20,
in dams on CD20, and additionally on GD6 in darns in the highest
exposure group (1000 mg/kg/day). A linear dose -plasma concentration
relation was observed between 6 and 100 mg/kg/day, levelling off at
1000 mg/kg/day. The mean plasma concentration on CD30 was less
than that on CD6, indicating that a steady state was achieved by GD6
and no accumulation occurred in the dams between CD6 and GD 0, The
plasmas concentradon in fetuses (pooled concentration) was
approximately one-third of the plasma concentration in the dam at
GD20e
One report on dermal absorption of FRD-902 (pear€ty 86%) was available
in the registration dossier performed according to OECD `T'C 428 in 2008.
Dermal absorption was studied in a static diffusion cell setup with rat
and humman skin at a concentration of 124 mg1ml. In rain skin, a lag time
of 0,82 ± die f7 hours was observed ;and in human skin the observed lag
time was 1.73 ± 1.01. hours, Steady state penetration was 70 ± 6.3
ug/crr 2/h and Kp was 5.7E 4 ± 4.3E-5 cm1h in rat skin. In human skim,
steady state penetration was 6.2 ± 53 €.€g/cm2/h and Kp was 3.OE-6 a
4.3E_5 cm/h.
Conclusions on 4Iaf6'k,
The available data Indicate that EP.D-902 is quickly absorbed after oral
and absorbed after dermal exposure, not metabolized, and eliminated
almost completely within approximately 24 hours Via urine in rats, mire
and monkeys, The substance distributes Into the fetus, The elimination
was significantly higher in female rats compared to male rats but no
such difference was observed in mice and cyn0M0lgUS Monkeys,
A1s2 Acute toxicity
Oral
Two studies in rats and one study in ,mice were available from the
registration dossier on acute toxicity by the oral exposure route, The
studies were performed according to OECD Guideline 423 and EPA
OPPTS 870.1100. Vest substance (866/a parity) was applied by oral
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€UVM Liter rePar, 201.6-0174
gavage at doses of 175, 550, 3.750, and 5000 mg/kg for rats and 175,
550 and 1750 mg/kg for mice. Animals were observed during 14 days;
and then necropsied.
All female rats in the highest dose group (5000 mg/kg) died; one at the
day of dossing, one the following day, and one 7 clays after dosing. In
those rats, lung discoloration, discoloration of the mandibular lymph
nodes, and liver were found. Hair loss, high posture, stained fur/skin,
wet fur, lethargy, clear secular discharge, prostrate posture, partially
dosed eyes, and/or salivation were observed in all female rats,
However, with the exception of hair loss, these clinical symptoms had
reversed after day 2, No body Freight loss was observed, The oral LD50
for female rats was 5129 mg/kg (Exp Support acute Tox ora1,00:1.),
All male rats in the highest dose group (5000 mg/kg) and one male rat
in the 1750 €ng/kg close group died. These rats showed lethargy, skin
stain, expanded lungs, eye discoloration and stomach discoloration. One
rat In the 175 rang/kg dose group also showed lethargy. Other clinical
findings in the 550 and 1750 mg/kg dose groups were vet fur and
stained fur or skin, which reversed after 2 days post -dosing, No body
weight loss was observed. The oral LD50 for €wale rats was 1750
mglkg, with 95% profile.11kelihood confidence interval 1259 - 4450
mg/kg. This study was selected by the registrant as the key study for
acute toxicity after oral exposure (Exp Ivey Acute T€a;co ora1.005),
In mice, all mice in the highest dose group (1750 mg/kg) died. 'These
mice exhibited lethargy and loan posture. One mouse in the 550 mg/kg
dose group exhibited wet fur. No effects on body Freight were observed,
A number of gross lesions was observed, including discoloration of the
lungs, cyst in ovaries of one mouse, and skin stairs in two mice, but
these lesions were considered nonspecific by the registrant, The oral
LD50 for mice was 1030 mg/kg (Exp Support Acute Too- oral.002).
Three additional studies in male rats were available in the registration
dossier, but have been marked as `root reliable` by the registrant
because the test substance composition was insufclently defined.
Based on the key study in male rats with an LD50 of 1750 mg/kg bw,
classification as Acute Tox 4; H302 is warranted.
Inhalation
One study on acute inhalation tonicity was available in the registration
dossier (Acute Tonicity. inhalation). The study +sofas performed according
to OECD Guideline 405. fiats were nose -only exposed to aerosol
concentrations of 13, 100, and 5200 mg/m3 for 4 hours. Animals were
observed for 2 - 14 days after exposure and necropsy and microscopic
evaluation of the respiratory tract tissues were performed, except in the
highest dose group. No mortality was observed. fiats in the highest dose
group (5700 mg/m) showed red discharge around the eyes, nose and
mouth, and red stained faces that lasted for 2 days. pats In the 100
mg/m3 dose group also showed red nasal discharge immediately after
exposure. No mortality, other clinical signs of toxicity or substance -
related microscopic findings were observed in any dose group in this
study (however, microscopic analysis was not performed in the 5200
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RIVM Letter report, 2016-0174
rnglrn= dose group), Body weight: loss between 2.5% - 5a8% as
compared to controls was observed in rats in the highest dose group,
Rats in the other dose groups also shoved minor decreases in body
weight, however, a sirniian minor decrease in body, weight was also
observed in the control group, The LC50 for agate inhalation toxicity in
€hale rats was reported as > 5200 Mg/M3, Based on this study
classification is not warranted,
Dermal
Two acute toxicity studies for the dermal exposure route were available
in the registration dossier; one in rabbits and one in rats.
Rabbits were exposed by occlusive patch for 24 hours to a dose of 5000
mg/kg. No mortality was observed (2 rabbits were used in the sty€dy).
There was no mortality. Moderate to mild erythema was observed that
lasted for 10 days after exposure and then decreased. Epidermal scaling
and sloughing was observed in both rabbits from 5 to 13 days aver
application and one rabbit showed a small area of necrosis outside the
test area (attributed to test substance running out of the test situ
between p — 5 days after exposure, An ALD of > 5000 €ng/kcg was
reported (Exp Supporting Acute Toxicity: dermai,002).
The study in rats was; performed according to international guidelines
(OECD Guideline 402 / EPA OPPTS 670A200 / EEC", Method Boa
Directive 92/69/EEC) and induded serni.-occlusive application for 24
hours, followed by :gash -cuff, post -exposure observation for 14 days and
necropsy, The applied dose was 5000 mg/kg (Exp Key Acute Toxicity,
dernaal,001). No mortality was observed~ Reversible local effects were
observed or the treated skin.
Eased on these studies class€fi€cation is not warranted.
A1.3 Irritation and corrosion
The available skin irritation shady according to OECD TG 404 (Skin
irritation/corrosion) showed lima ted and reversible erythema (scorel or
2) at 1 hour after rernoval of FRD-902 (86% purity), Based or this study
classificatio€a for ;skin irritation is not warranted,
The available stye irritation shady according to OECD TG 405 (Eye
irritation) showed irreversible effects in the tested rabbit including
cornea opacity, iritis and conjunctival chernosis and discharge, The
rabbit was eut:hantzed the day after treatment: for humane reasons,
Fused or this study classffication as Eye Damage 1, t-1518 is warranted.
A1.4 Sensitisation
1n a LLNA test according to OECD TG 429 (Exp Key Skin
sensitisatopne002), FRD-902 dissolved in di€nethylformanalde at: 0, 5, 25,
50 and 10€011/a induced no increase to the stimulation index above 3.
Therefore, this test was considered negative and does not warrant:
classification as skin senstt:isere
A second LLNA test was available in the registration dossier it which a
crude and undefined mixture was tested anti positive with an EC3 of
3711'u. However, the, relation of the tested substance with the marketed
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RIVM Lee ter report 2016-0174
substance was questioned. `therefore, based on the first test the
marketed substance need not to be classified for shin sensitisation
In are Ames test according to OECD TG 471 (Exp Key genetic tonicity in
vitro.001) up to 5000 ug,/plate using date incorporation, FIND-902 was
negative with and without metabdic activation. A, comparable study
(Exp supporting in genetic toxicity in vitro.003) with a test substance
which was not sufficiently characterised according to the registrant, was
also negative. In a mammalian cell gene mutation assay according to
OECD,TG 476 (Exp Key genetic tonicity in vitro,00 ) in which the pH
was adjusted to neutral, FRD-902 was negative with and without
metabolic activation, In an in vitro mammalian chromosome aberration
test according to OECD TG 473 (Exp Key genetic tonicity in vitro.005),
FIND-902 was negative attar 4 and 20 hour exposure without metabolic
activation but positive after 4 hour exposure with metabolic activation at
the highest exposure level of 3471 ug,/rnl, In the first test, there was no
statistically significant increase at this concentration but the control
value for numerical aberrations was outside the historical control range.
In a confirmatory trial, the structural and numerical aberrations were
Increased compared to the concurrent control at the highest dose level.
A comparable study (Exp, supporting in genetic toxicity in vitro,004) with
a test substance which was not sufficiently characterised according to
the registrant, was negative.
In a mouse micronucleus test according to OECD TG 474 (Exp Key
genetic toxicity in vivo.001) at dose levels up to 1300 mg FRD-902/kg
bw by gavage, a reduction in PCE,/EC was observed in the bone marrow,
showing that the substance reaches the bona marrow, but no increase in
rnicronucleated PCE. Some mortality was observed at the highest dose.
In a mouse chromosome aberration test according to OECD TG 475 (Exp
Key genetic toxicity in vivo.003) at dose levels up to .1.300 mg FRD-
90-7/kg bra€ by gavage, a decrease in the mitotic index, of bane marrow
cells was observed but no increase in structural or numerical
chromosome aberrations. Some mortality was observed at the highest
dose. In a rat unscheduled DNA synthesis test according to OECD TG
486 at close levels up to 2000 mg FIND-902,/k:g bw by gauge, no
Increase in net grains per nucleus was observed.
The available In vitro and in vivo genetic toxicity and mutagenicity
studies show that FRD-902 is not mutagenica EF A (2009) concluded
that FRD-902 is non-genoto is based on the same dataset,
1.6 Carci og nicity
In a combined chronic and carcinogenicity study performed according to
OECD Guideline 453, 80 rats per dose and seat were exposed to FPD-902
(purity 8411%) by gauge (water). The dose levels were males: 0,1, 1, 50
mg,/kg bw/day and females,, 1, 50, 500 mg,/kg bw/day. Interim necropsy
was performed on 10 animals after .1.2 months. The remaining animals
were necropsied after 101 weeks (females) or 104 weeks (rnales)(Rae
et alp 2015).
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In high dose females, a significant increased incidence of hepatocellular
adenoma and hepatoceilular carcinoma was observed. In high dose
males, a statistically significant increase was observed in the incidence
of pancreatic acinar cell adenoma/carcinoma combined, but not
adenoma or carcinoma alone. The incidence of interstitial cefl adenoma
of the testes was increased in males at 50 rncl/kg/day, and one
interstitial call adenoma was also present in one male in the EO
mg/kg/day group at the inter"€m necropsy. also the incidence of
interstitial cell hyrperplasia was increased in this group and outside the
historical control range, These findings were not statistically significant,
amongst others due to a relatively high incidence of these lesions in the
controls. The increase in uterus stfomal polyps was within the range of
the historical controls, -i"herefore, it is uncertain whether this statistical
significant increase in polyps is substance related.
Table A4, Tumor incidences area retated histological cal changes in the OECD 453
. fUM' in rafs.
It was suggested by the study authors that the observed increase in
tumors was induced by non-genotoxic pero isome proliferation, which is
specific for rodents. We agree: that: the available data do indicate a non-
cgenotoxlc mechanism, However, we do not currently agree, as furl -her
substantiated in the chapter on the made of action, that it is sufficiently
shown that these types of turnours via this €ne?c,hanism are not relevant:
for humans, The NOAEL for carclnogeniclty is 1 mg,/kg bw/day in males
leased on an increase in combined adenoma and carcinoma of the
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Ri1+'h' Le ter repatl 2016-3171
pancreas and 50 rig/kg b /day in females based on an increase in liver
tumours at 500 mg/'kg bw day,
1w7 Reproductive toxicity
A study on developmental toxicity (Developmental
toxicity/teratogenlcity) was conducted in rats, according to OECD
Guideline 414. Pregnant rats were exposed to FpD-902 (84% purity) at
10, 100, or 1000 mg/kg b ,/day by oral gavage during Gestation days
6-70, Darns were sacrificed on Gestation day 21, Organs including the
ovaries and uterus, and fetuses were examined.
One femaie in the highest dose group died on CD 20, due to liver and
kidney damage. Four and 9 females in the 1.00 and 1.000 mg/kg,/day
groups, respectively, delivered early on gestation day 111. The mortality
in the 1000 mg/kg/day group and early deliveries in the 100 and 1000
mg,/kg/day groups were considered test s€,rbstance-related. Test -
substance related clinical findings (yellow material on various beady
surfaces, salivation), higher mean kidney weight, and redaction in
maternal body weight gains occurred only in the highest dose group.
Decreased gravid uterine weights were found in the 100 and 1000
rnglkg/day groups. Increased liver weight was found in the 100 and
1000 mg,/kg/'day groups and was considered in the report to be related
to PPARa activation. In addition, focal necrosis was observed in the liver
of some animals at these dose levels and hepatocelluiar hypertrophy at
the highest close level. Mean fetal weight was reduced by 8,811/'o in the
100 mg/kg/day group and by 78.1%la in the 1.000 mg/kg/day group, No
effects were found on fetal survival, on malformations or on variations,
except a higher incidence of 14th rudimentary ribs in the highest dose
group which was not considered adverse by the registrants
The increase in early delivery was confirmed in a second study at 1000
mg/kg bwjday in,whlch 3 early deliveries were observed in an unknown
number of darns versus none in the controls. The fetal weight was
decreased.. In addition, comparable maternal effects were observed as in
the main study.
The no -observed -adverse--effect level (NOAEL) for maternal toxicity was
considered to be 10 mg/kg/day, based on mortality and lower mean
body weight galas and food consumption at 1000 mg,/kg/day and early
deliveries, and microscopic findings in the liver (focal necrosis) at 100
and 1000 mg/kg/day,
The no -observed -adverse -effect level (NOAEL) for developmental
toxicity was considered to be 1.0 mg/leg/day, based on early deliveries
and lower mean fetal weights at 100 and 1000 mg/'kg/day.
In a one --generation study (OECD "T'C 471) in mice (n=76).with exposure
by oral gavage at dose levels of 0.1, 0.5 and s mg FRD-907,/kg bw/day
(parity 8411/o), the FO males were dosed during study days 0 to 84 (70
days prior to pairing through 1. day prior to euthanasia), for a total of 84
to 86 doses. The females that delivered (with the exception of those
females selected for toxlcokinetic evaluation) were dosed from study
day 66 through the day prior to euthanasia (14 days prior to pairing
through lactation day 20) for a total of 68 to 64 doses. The females that
Page 61 of 92
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were selected for t:o icokinetic evaluation were dosed through the day of
euthanasia (lactation day 21) for e total of 54 to 65 doses.
Parental animals, no effect can mortality. In the higher dose groups, an
Increase in body weight was found with a corresponding increase In food
consumption, Increased liver Freight In the 0.5 and 5 mg/kg/day dose
groups. In the highest dose group, an im-Tease in kidney wdght was
found (only significant In females). Hypertrophy was found in the liver of
males and females in the middle and high dose groups, and in the
Kidneys of €hales in the middle and high dose groups. Liver necrosis
(focal or single cell) and are increase in the presence of rnitotic figures
was observed at the highest dose level. An Increase in single cell
necrosis of the liver was also observed in males at O5 rng/kg bw/day.
There was no effect can reproductive performance. Mean € u ambers of F.t.
peps born, live litter size, percentage of males at birth, postnatal
survival, and the general physical condition of the F1 pups were
unaffected by test substance admin€ strat:ion at: all dosage levels. F1
s€�rvivai was € naffct eed by test substance administration at all dosage
levels following weaning. At the highest dose level, a reduction In body
Freight gain was observed in male paps, and In female pups only during
the pre -weaning period. Minimal delays in sexual maturation were
observed, but were related to the reduction In body weight. For both
maternal ranirnals and their offspring, male and female €nice behaved in
a kinetically similar manner, with an approximately linear relatlonsNp
between dose and blood levels of the test substance. The plasma level
in pups on post -natal clay (I ND) 4 were -4 fold below the maternal
levels and on PND 21, 40-60 fold lower, On PND 40, after direct gavage
exposure of the F1, the plasma levels were comparable between the
dams and offspring. Based on these resWts, the no -observed -adverse -
effect level (FiOAEL) for reproductive toxicity was 5 mg/kg/day, as no
effects on reproduc:tJon were observed at any of the doses levels tested.
The results Indicate limited transfer of FRD-902 via lactation, The NCAEL.
for systemic toxicity In parental animals was 0.1 mg/kg/day based on
the low incidences of single cell necrosis observed in the liver of males
at Lies mg/kg/day. The t OAEL for syst:e€nic toxicity in the offspring was
0,5 mg/kg/day bared on body weight decrements in the F1 males and
females in the 5 mg/kg/day group during the pre -weaning period.
A1.8 Specific target: organ toxicity ® repeated exposure
mice
In a range -finding study not performed according to OECD and CLP,
male mice (n=5) were exposed to FRD-902 (86a611/o purity) by garage
(water) at: 30 mg/kg bw/day, Body (10511/6) and liver weight (200%)
were Increased, Histopathology shored an increase in liver hypertrophy,
single cell necrosis and mitotic figures (Exp Supporting Repeated dose
toxicity. oral .006).
In a 26-day study according to OECD TC 4.07, gro€aps° of 1.0 or 20
Crl-CD-1(iCR) mice per dos€, and sex were exposed to FRD-90 (68%
purity) by gauge (water) at dose levels of 001, 5 and 30 mg/kg bw/day.
The reversibility of the effects in the high (lose mice was determined
after a 4-week recovery, period (Exp Supporting Repeated dose
toxicity:oral.005).
Page. 62 QY 92
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r1"IVM Letter mpo , 201.G-0174
Body weights were significantly higher compared to controls in the 30
mg/kg/day group males and females at the end of the dosing period.
Body weight gain slowed during the recovery period and body weights in
the 30 mg/kg/day animals were comparable to the control group by the
end of the study. Statistically significant, test s€ bstance-related
decreases in red cell mass parameters (red bred cells, hemoglobin
and/or hernatocrit) were present in the 3 and 30 mg/kg/day group
males. The changes In red cell mass parameters were minimal
(decreased lass than 1.0% compared to controls). Test substance -related
seam chemistry findings included changes in liver enzymes and serum
proteins in males and females administered 3 or 30 mg/kgfday, Liver
enzyme levels (alanine aminotransferase, alkaline phosphatas€a and
sorbltol dehydrogenase) were higher in the 3 and 30 mg/kg/day group
males and 30 mg/kg/day group females at study week 4, Aspartate
aminotransferase levels were also higher In the 3 and 30 mg/kg/day
group males at study week 4. These liver enzyme level changes were
consistent with hepatocellular injury, and single cell necrosis was noted
microscopically in some animals in these groups. Liver enzyme changes
were reversible in both males and females, as levels for all liver
enzymes were similar to controls following 4 weeks of recovery. Minimal
changes of higher albumin, lower globulin, and associated changes of
increased total protein and increased albumin/giabulin ratio were
present In the 30 mg/kg/day group males. Decreased globulin and
increased alburnin/globulin ratio were also present in the 3 mg/kg/day
group males. A similar pattern of change In serum proteins was present
In females administered 3 or 30 mg/kg/day, These serum protein
changes were reversible, as there were no statistically significant
changes in these parameters in males or females by study week 8e
Blood urea nitrogen was slightly increased In the 30 mg/kg/day group
males at the end of exposure, Blood urea nitrogen was similar to control
values following the 4-weep recovery period. The slight increase in urea
nitrogen in 30 mg/kg/day group males was not associated with changes
in related clinical chemistry parameters or with test substance --related
microscopic findings in the kidney. A statistically significant decrease in
cholesterol was present in the 3 mg/kg/day group males, This decrease
was not dose -related, as mean cholesterol in the 30 mg/kg/day group
males was not statistically different from controls and was higher than
that of the 3 m.g,rkg/day group males. However, several individual
cholesterol values in treated male groups were below the .study control
range, and thus, a test substance -related effect of decreased cholesterol
cannot be ruled out. However, individual cholesterol values in treated
groups were within the testing laboratory historical control values (with
the exception of one male in the 3 mg/kg/day group),
Test substance -related gross necropsy findings included enlarged liver ire
the 30 mg/kg/day group males at the primary necropsy. There were no
test substance -related gross necropsy findings at the recovery necropsy.
Liver weights were increased in the 3 and 30 mg/kg/day group males
and females at the end of the exposure period. These changes
correlated with hepatocellular hypertrophy microscopically and with
increases in beta -oxidation. Liver weights were mostly, but not
completely, reversible in the 30 mg/kg/day males and females. At this
dose, liver weight relative to body weight in the 30 mg/kg/day group
males was increased by 163.1% above controls at the end of exposure,
Page 63 ed 92
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RTVM Lette.rmport 201e174
and was reduced to21.5%ofcontrol after the 4-*eekrecovery period.
Similarly, [n38nng/kg/daygroup females, liver weight relative tobody
weight was increased by182.7%above controls atthe end ofexposure
and was reduced tm14'396ofcontrol after the 4-vveakrecovery period.
Adrenal gland weights (absolute and relative to body and brain weights)
were increased Inthe 3 and 30nog/kg/daygroup males atthe end of
the exposure period. In the 30 rng/hg/daygroup males, these adrenal
weight changes correlated with minimal adrenal cortical hypertrophy
rn|cnoscopica|ly. Adrenal weight changes were reversible following the 4-
week recovery period. Decreased uterus weights (absolute and relative
to body and brain weights) were present inthe ]Q mg/kg/daygroup
females atthe end ofthe exposure period, There were oo
hiatopatho/ogical changes in the uterus that were correlative to the
uterine weight changes. Minimal adrenal cortical hype/trophy was
observed microscopically inthe 30rng/kg/daygroup males atthe
primary necropsy. This change correlated with increased adrenal weights
inthis group. Adrenal cortical hypertrophy was not observed !nthe 2O
rng/kg/daygroup males at the recovery necropsy.
'
MapatoceUu|arhypertrophy was observed inthe 3and 30rng/kg/dey
group males and females atthe primary necropsy, This change was
consistent with increased liver weights noted inthese groups. The
hepatoce||uiarhypertrophy was characterized byexpansion ofthe
hepotoce/|u|arcytoplasm bynumerous fine eoeinopMlicgranules. Other
findings in the liver included rnu/tifucal singla,ce|i hepatnce||u|mrnacrms|s
inthe ] and 38mng/kg/daygroup males and 3Orng/hg/daygroup
#arna/as at the primary necropsy, and increased rn|tooea distributed
nnukifucal!y throughout the liver section in the 30 mg/kg/day group
rna|em and females at the primary necropsy. Incidences of these changes
were higher inthe males compared tothe females. Hepatocei|u|ar
hypertrophy, single cell hepatocellular necrosis and increased mitoses in
the liver were not observed inthe 3Urng/kg/daygroup males and
females at the recovery necropsy.
There was an increased number of animals in the dieatrus stage of the
estrous cycle inthe 3Orng/kg/daygroup females compared tocontrol
group females atthe primary necropsy. However, ovarian morphology,
including number and maturational stages ofcorpora |uteawere similar
between treated and control groups, suggesting normal estrous cycling.
The significance ofthe differences inestrous stage distribution between
the 38 rng/kg/daygroup females and control group females is uncertain.
The number of animals in the diastrus stage of the estrous cycle was
equal inthe control and 30nng/kg/daygroup females atthe recovery
necropsy.
The test substance was aminducer ofhepatic permxisomn7beta-oxidation
activity, a measure ofperox!sonne proliferation, in male mice after
administration ofB.1, 3 and 30 mg/kg/day and in hennm|e mice after
administration of3 and 30mg/kg/dayfor 2Qdays. Total hepatic
rn(cmmsonno| cytochrome P-450 enzyme content was decreased at
dosage of and 30 mg/kg/day in male mice but not in females. Beta -
oxidation activity in both male and female mice had returned Locontrol
levels after approximately 28 days of recovery, while total cytochrome
P-450 content remained below control levels in the males,
Page **myz
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P,IVM Le ter report 2016-0174
The NOAEL in this study was 0,1 mglkg bw/day based on several effects
mainly in males including liver single cell necrosis, reduction in red blood
cell parameters, increased liver weights, hepatoceilular hypertrophy, and
changes In albumin/globutin ratio at 3 mg/kg b /day.
In a 90-day study according to OECD TC 408, groups of 10 Cri.CD-
1(ICR) mice per dose and sex were exposed to F D-902 (8411/0 purity)
by gavage (water) at dose levels of 0.1, 0.5 and 5 mg/kg b /day,
Additional animals were exposed for evaluation of the plas€na
concentration of the substance at 2 hours after exposure on day 0, 28
and 95 (Exp Supporting Repeated dose toxicltyrorala007)a
There were no test substance -related clinical observations or deaths. i'`•,lo
adverse, test substance -related effects on rnean body weight or mean
booty weight gain were observed in any female group. Statistically
significant increases in mean final body Freight (test day 91) and overall
body weight gain (test days 0-91) were observed in the male 5
mg/kg/day group, relative to control. Dean final body weight and overall
body Freight gain were 108% and 1 36% of contro], respectively, The
difference in body Freight and body weight gain in the high dose males
was attributed primarily to increased liver weight. No adverse, test
substance -related effects on ,mean Food consumption or food efficiency
were observed in any female group. Statistically significant increases in
mean overall (test days 0_91) food consumption and fond efficiency
were observed in the; male 5 mg/kg/day group, relative to control. Mean
overall food consumption and fond efficiency were 111.11% and I270/0 of
control, respectively, The higher food efficiency is likely doge to Increased
body weight due to enlarged livers in this group. No ophthalmological
signs were observed in any mouse in any group. There were no adverse
or treatment -rafted changes in group mean hematology parameters at
test day 96 (males) or 97 (females). Test substance -related increases In
a number of liver -related clinical chemistry parameters were present: in
male and ferrule mice administered 5 mg/kg/day (see Table A5),
Increases were mlid to severe, were consistently more severe in males
compared to females, and included increases in aspartate
aminotransferase (AST), alanine aminotransferase (,ELT), sorbitoi
dehydrogenase CSDH), alkaline phosphatase (ALKP) and total bile acids
(TBA). Changes in these parameters were consistent with hepatoceli€alar
darnage and/or cholestasis, correlated microscopically with
hepatoceilular single cell necrosis in male (10/I.0) and ferrule (1/10)
mice at this dose, and thus were considered to be adverse effects. Total
protein (TP) and albumin (ALB) were minimally increased in male mice
dosed with 5 mg/kg (110% and 114% of control, respectively). ALB was
also minimally increased in female mice at the same dose (104% of
control). These changes were considered to be treatment -related due to
the consistency of charge among individual animals. However,
minimally increased total protein and albumin have no toxicological
significance; therefore, these changes were considered to be non -
adverse by the registrant, Cholesterol (CHOL) was mildly decreased in
male mice dosed with 5 mg/kg (24% of control), There are no known
adverse effects associated with minimal decreases in cholesterol,
Therefore, these changes were cmisidered test substance related but
non -adverse by the registrant. Potassium ( )eras decreased in male
and female ,nice dossed with 5 mg/kg (67% and 91% of control,
Page C5 of 92
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RIVM Letter 3 ppott 2016-01 4
respectively). Decreased K typically occurs when there is a shift of K
from extra cellular fluid to intracell€aiar fluid (e.g., in metabolic
alkalosis), a decreased dietary intake of K, or an Increased loss of K via
kidneys (e.g., poiyuria), alimentary tract (e.g., diarrhea) or skin (e.g.,
sweating), In the present study, the relationship of this finding to test
.Substance adrninlstrat€or€ is uncertain. However, there were no clinical
;signs suggestive of hypokalernia and no test: substance -related
alterations in sodium (Na), Therefore, the minimal change in K was not.
considered to be adverse. Chloride (CL) was slightly higher (1.0211/o of
control) In male mice dosed with 5 mg/kg. lased on the minimal nature
of the change and lack of any correlative findings, this change was
considered to be unrelated to treatment and non -adverse by the
registrant. Under the conditions of the study, the test substance had no
effect on neurobehavimral parameters in either males or females.
Organ weights
A test substance related increase in mean IN weight parameters was
observed in mice exposed to :,!� 0.5 rng/leg/day In rnales and 5
mg/kg/day in ferrules (see Table A6). In the 5 mg/kg/day males, mean
absolute and means relative (% brain Freight and 11/b beady weight) liver
weights were increased to 6311rb, 247%, and 230% of control,
respectively. These increases were statistically significant. In the 0.5
mg/kg/day males, mean absdute and mean relative (% brain weight
and % body weight) liver weights were also increased (€scat statistically
significant) to 112%, 11311r'a, and 111% of control, respectively, In 5
mg/kg/day females, mean absolute and mean relative (% brain weight.
and % body weight) liver weights were Increased (statistically
significant) to 16911% , 167% and 16911/b of control, respectively.
Increased liver weight parameters were considered test substance
related in males given � 0.5 mg/kg/day and in ferrules given 5
rng/kg/day. The increase: In liver weight parameters in both sues
correlated with a treatment -related increase in enlarged live and
microscopic hepatic changes.
Mean relative (to brain) weight of kidneys was Increased (statistically
significant) in male mice given 5 mg/kg/day of test substance as
compared to controls. Although minlmai renal tubular hypertrophy was
present In Uii s group, the charge In kidney weight relative to brain
weight was not associated with changes in mean absolute or relative: (%
beady wdght) kidney weights, Roar€ weights of brain and epidldymides
relative to body Freight were louver, and mean weight of heart relative to
brain weight was higher In male mice given 5 mglkg/day of test
substance as compared to controls (ell statistically significant). These
changes occurred without correlative changes In other weight
pararneters for these organs or with microscopic findings,
Gross pathology
At: the terminal sacrifice, enlarged and/ or discolored livers were
observed In 4/10 and 9/10 male mice exposed to 0.5 €rag/kg/day and 5
nig/kg/day of test substance respectively. In the 5 mg/kg/day group
3/10 female mice had enlarged livers (see Fable A7). These gross
changes were considered test substance related, Liver enlargement and
discoloration corralated with test substance related increases in liver
Page 66 of 92
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17T1M Le ter report 016.-D 174
Freights and microscopic hepatocellular hypertrophy,
Histopatfaology: non-raeoplastic
Test substance related and adverse microscopic findings were present in
the liver of male and Female mice administered 5 mg/kg/day of the teat
substance (see Table A0). At 0.5 rng/kg/day, test substance related
microscopic charges were limited to male mice which had minimal
hepatoceilular hypertrophy, without evidence of liver- cell injury. In the 5
mg/kg/day male and female groups, toast substance -related
hepatocellular hypertrophy was present in all animals. Hypertrophy was
graded as mild (grade 2 out of 4) in males and minimal (grade 1 out of
4) or mild in females. The distribution of the hepatocellular hypertrophy
was centrllobufar when of rninimal severity and diffuse when of mild
seventy, Hypertrophy was morphologically consistent with peroxisome
proliferation and was characterized by increase in the sire of
hepatocytes due to Increased amount of finely ?granular eosinophilic
cytoplasm and enlarged nuclei with occasional bi€ ucleated cells.
Additional liver changes in the 5 mg/kg/day group occurred most:
consistently in males and induded increased numbers of mitotic figures
(males only), increased pigment (likely lipofuchsin) in Kupffer cells, and
single cell hepatocell€alar necrosis, The latter change was characterized
by isolated eosinophilic bodies with occasional pyknotic nuclear
fragments and € naccompanied by inflammation, and thus was
consistent: with apoptosis, Hepatic lesions correlated with increased
absolute and relative liver weight and Increaser) total bile acid and liver
enzyme levels (SST, ALT, SDH, ALP). Minimal bile duct hyperplasia was
present in the liver of one male mouse in the 5 mg/kg/day group, Since
similar changes were not seen in any other treated mice, the
relationship of this finding to test substance administration is uncertain.
In the 0.5 mglkg/day groups, liver changes were limited to minimal
hepatocellular hypertrophy in males only, In females, Focal necrosis was
present in both treated and control mice with slightly increased
incidence in the 5 mg/kg/day Females (1/10, 0/10, 2/10, 5f 10 in
control, 0.1, 0.5, and 5 mg/kg/day groups, respectively). Focal hepatic
necrosis is a common background lesion in mice, and there was no
difference in morphology or severity of this lesion in treated ferrule mice
as compared to controls. In addition, test substance -related focal
necrosis slid not occur in wales, the more sensitive gender for liver
effects, Therefore, the minimal increase in the incidence of this lesion in
high dose females was considered spurious and unrelated to treatment.
Test substance related changes In the kidney were limited to minimal
tubular epithelial hypertrophy in 9/10 male mice given 5 mg/kg/day of
the test substance. Hypertrophy was characterized by .slightly enlarged
epithelial cells containing increased amounts of fine granular eosinophilic
cytoplasm. Tubular epithelial hypertrophy was not associated with renal
tubular cell deg eneratio€-/necrosis. Also there was no change in clinical
pathology parameters indicative of renal injury.
Plasma Concentration Evaluation
The test substance concentration in blond was almost similar on days 0,
25, and 95 in femaid mice, indicating that steady-state concentrations;
were almost achieved on the first day of dosing, This is consistent with a
test substance that was cleared rapidly from the blood within one dosing
[Page 57 of 9"
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RTVM Letter report 2016-0174
interval. The test substance concentration in blood from male mice was
lower mnday Qthan onday 28,and for the high dose the concentrations
onday 28were slightly lower than day gSconcentrations, indicating
steady state may not have been achieved byday 2@.Compared to
female mice, male mice took longer to achieve steady-state
concentrations in blood, The plasma concentration was linear with dose,
implying that absorption was not saturated over the range ofdoses
tested in this study, Test substance was not present in plasma from
control animals.
Page mof 92

RIVM Utter reprint 2016-0174
Rr't9M op€niom Several statistically significant effects observed in this
study were considered substance related but not adverse by the
registrant because of the small effect size. We agree that not all
statistically significant effects are also biologically significant. In
addition, a minimal effect size is applied in the Bench Mark Dose
approach to derive limit values, However, for some of the effects in the
current study, the justification for the absence of adversity based on the
effect size is trio limited and not accepted. The NOAEL in this study is
0.1mg/kg bw dayr based on an increase In liver weight and hypertrophy
observed at 0.5 mg/kg bw/day, ,according to the EFSA opinion on PFOA
(EFSA, 2000) "These changes [liver] are often classified as adaptive and
reversible. However, as these represent biological changes possibly
related to effects such as tumour promotion and/or changes in drug-
metabdizing enzyme activities, [,o.] the findings should be critically
evaluated.". In additions the reversibility is of less relevance for
substances with potential continues and lifelong exposure.
Page 69 of 92.
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RIVM Letter repait 2016-0174
Rats
In a screening study not according to OECD and GLP, 3 Cri,. CD(SD) rats
per dose and sex were exposed by gavage (water) to FRD-902 (86,611/o
parity) for 7 days to 30, 300 and 1000 rng/kg bwjday (Exp Supporting
Repeated dose toxicity: oral,004), Additional antrnals at 30 mg/kg
bsawjday were used to collect toxicokinetic information which was not
reported in the robust study srarnmarye
Effects on body weight was significant at the high dose legal in male
rats, 92.4% of control ± 2. 0%;statistically sig-nificant decreases in red
cell mass parameters (red blood cell, hemoglobin and hematocrit) were
observed in male rats at: 300 and 1000 mg/kg/day and in females at
1000 mg/kg/day, Statistically significant increases rn red cell distribution
width, reticulocytes and ne utroph€ls were also present in 1000
mg/kg/day females, Decreases in serum lipids (trlglycerldes and/or
cholesterol) and globulins were present in all dosed male groups and in
ferrules at 300 and/or .1.000 mg/kg/day, Other changes in clinical
chemistry parameters occurred at 300 and/or 1000 mg/kg/day and
included increased alanine aminotransferase (A l`), aspartate
a€ inotransferase (AST), Urea nitrogen (BUN), and Glucose; and
decreased sorbltol dehydrogenase ( DH), creadnine, and calcium,
Increased liver weight parameters were present in males at all dose
levels and in females in the 1000 mg/kg/day group, These liver weight
changes were correlative to rnicroscoptc hepatoceliular hypertrophy in
the livers Other organ weight changes included decreases in heart
weight parameters (1000 mg/kg/day males) and increases in some
kldney weight parameters (.1.000 mg/kg/day females). There were no
correlative microscopic changes in these organs, "Test substance -related
microscopic charges were limited to hepatoc,ell€alar hypertrophy in the
liver. Minimal to rnlld hypertrophy was present in male rats at all doses
and in females administered 1000 mg/kg/day, Microscopic and organ
weight changes in the liner were associated with increases in beta -
oxidation and/or increases in total cytcochrome P-450 enzyme activity,
A statrsUcally significant increase in peroAsornal beta -oxidation activity
was present in the 30, 300, and 1000 mg/kg/day male groups and in
the 1000 mg/kg/day female group at the 7-day sacrifice, A statistically
signldcant increase in total rmic€-osomal cytochrome P-450 content was
present in the 300 and 1000 mg/kg/day male groups and in the 1000
mg/kg/day female group at: the 7-day sacrifice..
In a 78-day repeated dose toxicity study according to OECD 407, groups
of :1.0 CrIeCD( D) rags per dose and sec were exposed to FpD-902
(pL10ty 8 11%) by c3avage (water), bales were exposed to 03, 3 and 30
mg/kg bwjday whereas females were exposed to 3, 30 and .300 rngjkg
bwjday. Additional animals were used to determine the recovery within
4-weeks (Exp Supporting Repeated dose toxi€ it:ysoral.001)a
All animals survived to the scheduled necropsies, 'yellow material around
the urogenital area was noted occasionally for 9 fernales in the 300
mgjkcgjdey group at 1 to 2 hours past -dosing from study day 3 to 25,
This finding was not noted during the recovery period. There were no
test: substance -related effects on body weight, Minimal, statistically
Pape 70 of 92
DEQ-CFW 00079657

significant decreases In red cell mass parameters (I BC, hemoglobin and
hematocrit) were present In the 3 and 30 mg/kg/day male groups.
These decreases were associated with minimal increases In absolute
reticulocyte courts. The decreases in red cell mass parameters were
minimal (".W7a9% below the control mean for all parameters), and values
for red cell mass parameters and reticulocyte counts in individual
animals In the 3 and 30 mg/kg/day male groups were within the testing
laboratory historical control ranges for the respective parameters. There
were no statistically significant changes in red cell mass parameters or
reticulocytes following the 4-week recovery period. "Test substance -
related and statistically significant decreases in cholesterol' were present
in all treated male groups, Decreases were minimal (not reported), as
values for most animals were within or only slightly below the testing
laboratory historical control range. Based on the minimal nature of the
changes, as well as the direction of change (decreased rather than
increased), these changes in cholesterol were not considered to be
adverse by the registrants however, as the effect size is unknown this
conclusion is not agreed by the BtVM, Comparable reductions were
observed in other studies and can be related to the increased beta-
obldatiod. Effects on cholesterol were reversible as cholesterol values
were actually increased compared to controls following the
approximately 4-week recovery period, although cholesterol values for
all animals In the 30 mg/kg/day recovery group were within the testing
laboratory historical control range, Higher albumin and lower globulin
levels, as well as associated increases in alburni€ /globulin ratio, were
present in the 3 and 30 mg/kg/day male groups. Increased albumin and
albumin/globulin ratio were also present in the 300 mg/kg/day female
group. Changes in globulin were minimal (not reported), as individual
values for all animals in the 3 and 30 rnglkg/day male groups were
within the testing laboratory historical control range, with the exception
of one rat in the 30 mg/kg/day group whose value was just below the
testing laboratory historical control range. Similarly, increases in
albumin in the affected male and female groups were within the tasting
laboratory historical control range, or, for some animals in the 30
mg/kg,/day male group, were only slightly above the testing laboratory
historical control range. The changes in serum proteins were considered
to be test substance related. However, these changes were not
considered) to be adverse based on their minimal mature avail dose
levels by the; registrant. In addition, all serum protein changes were
reversible, as mean values were similar to controls following the 4-weep
recovery period, Urea nitrogen was minimally increased in the 30
mg/kg/day group males. This increase was not associated with charges
in c;reatinlne or with treatment -related microscopic changes in the
kidney. The minimal increase in urea nitrogen is likely of non -renal
origin. The pattern of changes in area nitrogen, as well as those noted
above for serum proteins, is consistent: with those reported for other
peroAsome proliferaatorsa Changes in urea nitrogen were reversible in
males, as there were no statistically significant changes in these
parameters fallowing the recovery period. Glucose levels were minimally
increased (15.2% higher than the control group mean) in the 30
mg/kg/day group males at study week 4, but were lower than the
control group at steady weak €I. These Increases were within the testing
laboratory historical control ranges and were not considered adverse.
Mean triglycoride values in treated male groups were lower than
Ra�3r Il cf t�2
DEQ-CFW 00079658

RIVM Letter report 20/euz74
controls. These decreases did not occur in a dose -related manner and
were statistically significant only inthe 3rng/kg/daygroup. The group
means for the treated groups were actually similar to the historical
control mean, while the concurrent study control group mean of7Z
rng/dLwas higher than the mean of the historical control data, which
was48 rng/dL Individual thg|yuerideva|ues in animals from all treated
male groups were within the testing laboratory historical control range.
While some peroxisonnepnm|!fenatmnyhave been shown tolower
thg|yceridee in rodents, it is unclear ifthe trigiyoehdeeffects in the
current study are test substonca-ne|ated.The effects are not considered
to he adversobythe registrant, as changes were minimal and individual
trig|ycehdeva|ues intreated groups were similar tothose seen normally
in this species and strain. There were nosignificant elevations in group
mean liver enzyme values in test substance -treated males and females.
SignMlcantly higher liver weights occurred in a dose -related manner in
rna|as administered 3or30nng/kg/daygroup and infemales inthe 300
mg/kg/day group, These findings correlated with histologic evidence of
centh|oholarhypertrmAhy' Following the recovery period, the absolute
liver weight and organ -to -body -weight ratios ofmales from the 30
rng/hg/daygroup and females from the 3OQnng/kg/daygroup did not
significantly differ from the control group values, There were 000ther
test aubstance-related effects on organ weights. However, some
statistically significant differences were observed when the control and
test substance -treated groups were compared. The absolute kidney
weight was higher for the 3and 3Urng/kg/daygroup males relative to
the control group and kidney weights relative to body orbrain weight
were higher for the 3Onng/kO/daygroup males relative tothe control
group. These differences were small |nmagnitude and lacked a
morphologic urclinical pathology correlate. Therefore, the kidney weight
effects were not considered tobeadverse according tothe registrant.
Test substance -related changes of multifocal centrilobular hypertrophy
were observed inthe liver of3and 3Qrng/bg/daygroup males and the
300nng/kg/daygroup females. The tissue alteration was characterized
by enlargement mfhepatocytes surrounding central veins. Changes,
graded minimal and mild, were diagnosed asarelative change when
compared to pehporta| hepatocyten. Although females were
administered higher doses of test substance, changes were more subtle
than in males. Histologic examination of the liver from recovery animals
revealed noevidence ofcmntri|obu|arhypertrophy.
In -male rats, beta -oxidation activity was statistically significantly
increased at the 28-daytirne point a1all dosage levels. At0.3
mng/kg/daythe increase was minimal (about 1.4-fold higher than
comtmo|),with more moderate increases nfabout 3.7-and 8.7-fo|dabove
control in the 3 and 30 mg/kg/day male groups, nespectiveiy. In female
rats dosed with 30 and 300 rng/kg/daytest substance, beta -oxidation
activity was statistically significantly increased (about 1.5- and 3.0-foid
higher than controls, respectively) at the 28-day time point. Beta -
oxidation activity had returned to control levels after approximately ZO
days of recovery in both male and female rats. A minimal, statistically
significant increase in total cybzchrorne P-450 was present in the 30
nog/kg/doymale group a{the 28-daytime point, but had returned to
Page 72m92

€ IVM Letter report."0tf-01.;4
control levels after approximately 28-days recovery. There were no
effects on total cytochrorne p-430 content in female rats.
No NCCAEL could be derived from this study because at the lowest dose
of 0.3 rng/kg bwfday in males, a decrease in cholesterol levels was
observed, The level of decrease is unknown. However, reductions in
cholesterol were also observed in rather studies and could be related to
the increase in beta -oxidation. Therefore, currently this effect cannot be
discounted as non -adverse. In addition, an increase In beta -oxidat!on of
1.4 times the control level was determined. This effect at such low level
of increase is not considered adverse. If the additional details of the
study report provide .sufficient justification to conclude that the decrease
in cholesterol is not adverse, a hlOAEL of 0.3 mg/kg bw/day can be
derived from this study,
In a 90-day repeated dose toxicity study according to OECD 408, groups
of 10 Crl CD( D) rats per dose and sex were exposed to FRD=902
(purity 84%) by gavage (water). Males were exposed to M, 10 and 100
mg/kg bw/day whereas females were exposed to .10, 100 and 1 000
mg/kg bwjdayra Additional animals were used to determine the recovery
within 4-weeks (Exp Supporting Repeated dose toxicity orai.002),
There were 2 test -substance -related deaths and 1 death of uncertain
relationship to test substance administration in the 1000 mg/kg/day
group females. Female no. 7323 was euthanixed in extremis on study
day 0 with clinical observations of impaired use of the hlndllmbs and
forelimbs. Female. nos, 7313 and 7318 were found _dead on study days
21 and 37, respectively. All 3 females were noted with clear material
around the mouth and/or yellow material on various body surfaces at
approximately 1-2 hours post -dosing on study days 7 and 8 (no7323)
or intermittently from study days 0 to 20 (no, 7313) and 27 to 36 (no.
7318). At necropsy, the ferrule e€athanixed in ext:remis (no. 7323) had
gross lesions of red areas in the stomach, urinary bladder, and thymus
and microscopically observed necrosis, hemorrhage, and thrombus of
the spinal cord, thrombosis, myocardial fiber degeneration, and necrosis
in the heart:, necrosis of the glandular stomach, and hemorrhage in the
bang, thymus, and urinary bladder. The first female found dead (no,
7315) had renal tubular and papillary necrosis, hepatoceliular
hypertrophy, and lymphold depletion in multiple tissues. The second
female found dead (no. 73,10) had renal papillary necrosis and necrosis
of portions of an adrenal gland, hyperplaF is of the transitional
epithelium of the urinary bladder, hepatoceilular hypertrophy, and
lymphoid depletion in multiple tissues. The early death of female nos.
7315 and 7318 was considered to be test substance -related because
both females shared similar microscopic findings (renal papillary
necrosis, hepatocellular hypertrophy, and lymphoid depletion in multiple
tissues). The other early death female (no, 7323) in this group died
earlier (study day 0) than the unscheduled death female nos. 7315 and
7313 (study days 21 and 37, respectively) and had microscopic findings
that were not observed in the other animals in this group. Thus, the
relationship of this early death of female no. 7323 to treatment was
uncertain.
There were no adverse clinical observations or effects on survival for
any test: substance -treated male groups and for the 10 and 100
Pi�ge 73 of 92
DEQ-CFW 00079660

mg/kg/daygroup females. Clinical observations in the 1000 mg/kg/day
group females were noted in at least half ofthe surviving females and
included clear material around the mouth, neck, and/or fona||mnb(o),
yellow material onvarious body surfaces (at time ofdosing and
approximately 1-2hours post-dosing)and red materialonvarious body
surfaces (1-2 hours post -dosing) beginning on the third day of dosing
for some females,
There were notest substance -related effects unbody weight atany
dosage level. Mean body weights for the high -dose group males (108
mg/kg/day) and females (100S mg/kg/day) were approximately 9796
and 102% of the control group mean value, respectively (neither
statistically significant). Mean overall food consumption during the
dosing period for the high -dose group males (1O8nng/kg/day)and
ferna|ee(1UU8 mg/kg/day) were 100%mnd 11196 ofthe control group
value, respectively (statistically significant in females). In males,
significantly lower mean food consumption was recorded for study week
8 to 1 for the 10 and 100 mg/kg/day group, and from study week 1 to 3
for the 1QOnng/kg/daygroup.
0oophthalmic lesions indicative oftoxicity were observed |nany ofthe
test substance -treated groups.
Testsubstanca-ndated hematology changes in red oe|| mass parameters
(red blood cell counts, hemoglobin, and hemnatoqi[) were present inthe
high -dose group males (1DQmng/kg/day) and females {10DO nog/kg/day}
atthe end ofthe dosing period. These parameters were approximately
1196-1396lower inmales and 18%-28Y6lower infemales when
compared to the respective control group. In addition, individual values
for these erythrocyte parameters in sevens{ animals at these dose levels
were below historical control reference ranges. The lower red cell mass
parameters were associated with higher absolute retioo|ocyte counts in
both sexes, and in females, were associated with changes in red cell
parameters, including higher mean corpuscular volume (;4CV)and mean
corpuscular hemoglobin (MCH),and lower mean corpuscular hemoglobin
concentration (MCHC).The changes in net[cu)ocyte counts and red cell
parameters indicated aregenerative response tothe lower red cell
mass. Consistent with their regenerative nature, the red cell changes in
the high -dose group males and females showed recovery following the
approximate 4-vveekrecovery period. In females, recovery was
complete as values for some red cell mass parameters were statistically
higher (along with lower reticu}ncytesand an equivocal hiyher;4CV)
when compared tothe control group. In males, recovery was present
but was not complete asslightly lower (about 596below the control
group) red cell mass parameters were still present atthe end of the
recovery period when compared tuthe control group. In addition,
absolute reUcu[ocyte counts remained minimally elevated in this group,
Based onthe regenerative response noted inthe high -dose group males
stthe recovery evaluation, complete recovery would beexpected with
increased recovery time. Statistically significant lower erythrocyte
parameters were also present inthe 1Qrng/kg/daygroup males when
compared tothe control group. Atthis dose level, the magnitude mf
changes were rn|nirnai (approximately 796 below the control group), and
values for individual aninno|o were within historical control reference
Page 74 of 92
OEQ-CFVV_00079661

RIVM Leger report 2016-0174
ranges (except for the hematocrit values in 2 males which were 0.2
percentage points below the reference range), Consistent with the
minimal nature of the erythrocyte-, changes at this dose, there were no
statistically significant charges in absolute ret€culocyte counts. Based on
the minimal nature of the effects on red call parameters, the lack of an
increase in reticuiocyte counts suggesting a lacy of an erythropoietic
stimulus, and the absence of anemia in individual animals, the
erythrocyte effects In the 10 mg/kg/day male group were not considered
to be adverse by the registrant, Sorne other statistically significant;
differences In hematology parameters were noted when the control and
test substance --treated groups were compared. These findings included
lower activated partial thromboplastin time (APTT") at the recovery
(study week 17) evaluation for the 100 mg/kg/day group males and
lower absolute basophil counts at study weep 13 for the 100 mg/kg/day
group males. These group mean differences were not considered teat
substance -related because according to the registrant they did not occur
in a time -related manner or they were not of a magnitude that would be
considered toxicologically Important.
Test: substance -related and statistically significant changes in several
serum chemistry parameters were present in the 1.0 and 100 mg/kg/day
group males and the 100 and 1000 mg/kg/day group ferrules when
compared to the control group, Most changes were consistent with
PPA o activation, Test substance -related lower (variable statistical
significance) cholesterol values were present in the 1.0 and 100.
mg/kg/day group males (-31.%) and the 1.00 (-20%) and 1000
mg/kg/day group (-31%) females. The differences from the control
group were minimal, as values for most animals in the affected groups
were within historical control reference ranges. There are no known
adverse effects associated with minimally lower levels In cholesterol
according to the registrant. As such, these changes were considered by
the registrant to be test substance --related but: non -adverse, However,
this is questioned by the ltiiVM. Test substance -related effects on
cholesterol values were reversible In both males and females as there
were no statistically significant changes in cholesterol values in the high -
dose group when compared to the control group following the 4-week
recovery period. In addition, there were no test so bstance- related
changes In triglycerldes in male or female rats at any of the dosage
levels tested. Nigher albumin (males only +10% and 12%) and lower
globulin levels (both sexes -1211% and-131/6 and-3311/6), as well as
associated higher albumin/globulin ratios (+2611/`o and +33% and
+aB%), were present In the 10 and 100 mglkg/day group males and
the 1000 mg/kg/day group females when compared to the control
group, A lower total protein level (due to lower globulin) was also
present in the 1.000 mg/kg/day group females (-1.0%). Individual values
for these protein parameters were outside the historical control
reference ranges in 2 high -dose group fernales, All serum protein
changes were reversible, as mean values were similar to the control
group following the 4-week. recovery period. The biological significance
of the changes (lower) in total protein levels is uncertain. The pattern of
change in serum proteins (lower globulin and higher albumin lever) was
consistent with the known anti-inflammatory properties of a PPARa
agonisto The anti-inflarnmatoryr response to PP Ro activation Is
characterized by lower lever of acute phase proteins (which contribute
Page 75 of 92
DEQ-CFW 00079662

RIVM Letter mpor,2Gm-0o+
bzthe globulin fnacton),and higher levels ofnegative acute phase
protein (a|hurn|m).
The urea nitrogen level was minimally higher (+]0%)inthe 1ND
nng/kg/daygnoup males when compared tothe control group, This
higher level was likely nfnon-renal origin, asitwas not associated with
changes in creatinine, urinalysis parameters, or renal histopatho|mgy.As
with the serum protein changes, the pattern ofchanges inurea nitrogen
was consistent with those reported for other peroxisome proliferators,
Changes in urea nitrogen levels were reversible in males, as there were
no statistically significant changes in these parameters when compared
tothe control group following the approximate 4-weckrecovery period.
Alkaline phosphotaselevels were minimally higher |nthe 1Q(+4896)
and 100 rng/kg/daygnnup (+10696) males and in the 1000 mg/kg/day
group females (+6G96) when compared tothe control group. Alkaline
Ahoophatase levels may be higher in association with chn!eotatic liver
disease/ however, in this study, other markers ofcho|estaUo liver injury
were not increased (bil|rubin and gamma glutanny|transferase levels
were actually lower inthe 1QQQmng/kg/daygroup ferna|es),and there
were noeffects mnother enzymes indicative ofhepatmcel|uiarinjury
{n|aminearninotnansferase, ampadateanminutransherase, andsodbitu}
debydrngenoae[evels).Additionally, there was nohis±opathoiugical
evidence ofliver cytotoxicity. Therefore, these minimally higher alkaline
phusphatase levels were the result ofextra-hepatic factors and were
likely due to induction ofliver moicposorna| enzynnes. Total bi|irub|n and
gamma g|abanny[tranafsrasevalues were lower in the 1000 mg/kg/day
group females when compared tothe control group. Total bi|irobin was
also lower in the 100 rng/kg/dmygroup females, These changes were
considered to betest substance -related but non -adverse based on the
direction ufchange (lower rather than higher).The changes inboth
parameters were reversible following the approximate 4-week recovery
period. At study week 17 (recovery evaluation), |oxvercraabn|ne and
higher potassium levels were noted for the 1OOrng/kg/daygroup males
when compared tmthe control group. These group mean differences
were not considered to batest substance -related because the values did
not show atime-related response, were ofamagnitude that would ha
considered tobetoxicologically unimportant, orinvolved achange ina
direction of no known biological importance.
There were notest substance -related effects on urinalysis parameters in
tHaB.1, 10, and 100 nmg/kg/doygroup males and the 10 and 100
mg/kg/day group females. Test eubstance-related higher urine volume
(statistically significant) and a lower urine usrnolali1y (not statistically
significant) suggestive ofdiuresis were present inthe 1UUDrng/kg/day
group females at study week 13ascompared tmthe control group.
Lower urine pH (statistically significant) was also present in the 1808
rng/kg/daygroup females atstudy week 13as compared tothe control
group.
There were nmsignificant changes }nthe functional observation battery,
Testsubatunue-relatedorganweghtchangeaconsistedofhigherkidney
and liver weights. Higher liver weights in the 10 and 108 mg/kg/day
group males and the 1000 mg/kg/day group females correlated with
Page 76m92

:t1i Pt I_.E'Rer f putt 2016-2174
microscopic hepatocellular hypertrophy, but they were not associated
with degeneration or necrosis In the liver or with changes to serum
chemistries suggestive of liver toxicity, Therefore, higher liver weights
were not considered to be adverse by the registrant. However, this Is
questioned by the RIVM, In the 100 mg/kg/day group males, liver
weight changes were reversible except for liver weight relative to bogy
weight, which was mostly, but not completely reversible. In the 1000
rng/kg/day group females, liver weight changes showed partial
recovery, but were not completely reversible following the 4-week
recovery period.
All kidney weight parameters (absolute, relative to body and brain
weight) were minimally higher in the high -dose group males (100
mg/kg/day) and females (1.000 rng/kg/day) when compared to the
control group. In the 1000 mg/kg/day group females, these charges
were associated with € vidence of diuresis (increased urine volume and
decreased urine osmolaRy) and microscopic changes in the kidneys,
most commonly In the early death animals, In the 100 mg/kg/day group
males, there were no clinical pathology or microscopic changes
suggestive of kidney Injury. Minimally higher kidney weights were also
present In males at the recovery evaluation but: not In females.
Kidney weight relative to body weight was also higher and statistically.
slgnlficant In the 10 mg/kg/day group males and females and the 100
mg/kg/day group females when compared to the control group,
However, at these dosage levels, there were no changes in other kidney
weight parameters (absolute and relative to brain weight), and no
correlative changes in serum chemistry, urinalysis, or histopaithology
suggestive of renal toxicity, Thus, higher kidney weights relative to body
weight in the 1.0 mg/kg/day group males and females and the 100
mg/kg/day group females were not considered to be adverse by the
registrant.
There were € o test substance -related macroscopic findings noted at the
scheduled necropsies, Macroscopic findings of uncertain pathogenesis
were noted for the 1000 mg/kg/day group female (no, 7323) euthanized
in ext:remis on study day 8 and consisted of red areas in the stornach,
urinary bladder, and thymus.
In addition to the microscopic changes observed In the 1000 mg/kg/day
group females found dead or euthanized In extremis, one 1000
rng/kg/day group female (anhnnal no, 7279) had minimal renal tubular
necrosis and regeneration at the study weep 13 primary necropsy.
Minimal hepato ellular hypertrophy was observed in the liver of some
males in the 10 and 100 mg/kg/day groups and some females in the
1000 mg/kg/day group at the primary necropsy (see Table A10)a
I- tepatocellular hypertrophy was associated with Increased eosinophiilc
granularity of the hepatocyte cytoplasm consistent with peroxlsome
proliferation, Hypertrophy was not associated with microscopic changes
indicative of liver injury (such as degeneration or necrosis) or with
changes in serum chemistry Indicative of liver injury, nor was
hypertrophy observed In animals at: the recovery necropsy.
DEQ-CFW 00079664

RIVM Letter report 2016-0174
Table A9. Test Substance Related Organ Weh,�ht Chamles.
.....................
_gec and, 64iiii1eve
... .......... .... r Poo FTJO�
ecrop y
........ ....
Page 78 of 92
DEQ-CFW-00079665

KVM LeUer report 2016-0174
A NOAEL of 0.1 mg/kg bw/day was derived from this study based on
decreased red blood cell parameters, cholesterol and increased A/
ratio, liver weight and hypertrophy and kidney weight at the nest higher
dose level of 10 mg/kg bw/day.
In a 2-year oral exposure study according to OECD TG 455, rats (n--=80)
were dosed by gavage with 0.1, t, or 50 mg/kg bw/day for asp to 104
weeks (male rats) or with 1., 50, or 500 mg/kg bw/day for up to J.D.I.
weeks; (female rats), Interim section was performed on 10 animals per
dose and sex: after one year (Rae et al, 2015).
Exposure to FRD-90 (parity 84%) did not affect survival, A single test
article -related cause of death/modbundity was inflammation/necrosis, of
the kidneys which occurred in seven of this 500 mg/kg/day females and
was characterized by papillary necrosis. In males the most common
causes of death/moribundity were pituitary tumours and undetermined,
In ferrules the most common causes of death/rnoribund€ty were
mammary tumour and pituitary tumour. Females were terminated
during Week 101, prior to scheduled termination, due to low survival in
all female dose groups, especially control and 50 mg/kg/day groups.
However, this did not impact the study as this vias approximately 2
years of test article exposure. Even though survival among all female
groups was loaf there were no statistically significant differences and
survival was comparable arnong all groups. There were no test article-.
related clinical observations,
Mean body weight in 50 mg/k.g/d y males was statistically significantly
below control over most of the First year, although mean body weight
was only 411/b below control in males atWeek 52 (riot statistically
significant), and exceeded the control valve at termination. bean body
weight gain in this group was 611/o below control in males over Weeks .t.
to 52 and exceeded the control value over the two year period. used
on the small magnitude of the changes, the effect among males at: 50
rng/kg/day was not considered adverse. Exposure, to 500 mg/kg/day of
the test substance produced adverse reductions in body weight and
body weight gain in females. In this group, statistically significantly
lower ,near€ body weight was observed from weeks 50 through 86. mean
body weight was 1 a'--1la below control at: Weer 52, and mean body weight
gain was 2011/a below controls over Weeks 'I to 52 (both statistically
significant). mean final body weight (week 100) and overall body weight
gain (Weeks 1-100) were comparable to the control value. However,
these body weight changes were considered adverse at: this dose based
on the difference during the first year on study.
Pdge'iq of 92
DEQ-CFW 00079666

&TVP4 Letter ae.pxt 016--0114
There were no adverse test articie-related effects on food consumption
in either seas or In food efficiency In males at any dose. adverse effects
on food efficiency were observed in 500 mg/kg/day females, 1n this
group, food efficiency was 23% below control (statistically significant)
over the first year and 1.1 % below control (statistically significant)
overall (Weeks 1-1.00). Lower mean food efficiency was noted over the
first year in males at 50 mg/kg/day. However, overall (Weeks .1.-104)
food efficiency was comparable to controls. No effects were rooted in any
other dose group. No test: article-rc-wlat:ed findings were noted in the
interi€m or terminal ophthalmoscopic examination,
t the 5, 6, and 1.2 month intervals there were €mild decreases in red cell
mass (erythrocytes, haemogiobin, and hernatocrit In females receiving
500 mg/kg/day, Effects were mild in females (tap to 28% less than
(.66trol) and were not associated with any test: artcle-related effects on
erythrocyte morphology, ,appropriate increases in retictalo€:ytes (:t 0611%
above respective) occurred in response to the decreases in red cell
mass. The Increases In reticulocytes were associated with expected
decreases in MCHC and Increases MCV. This collection of findings is
suggestive of red cell lass or haernolysis although the exact mechanisms
involved are unknown, Statistically significant decreases in red cell mass
were also present in males receiving 50 mg/kg/day at the 3 - and 0-
month interval, However, the decreases were small (-9 to -7%) and raid
induce a non -statistically significant increase in reticw.€locytes. In
addition, red mass changes were transient---- at the 12 month interval
there were no statistically significant changes in any red cell mass
parameter, and values in individual animals in the 50 mg/kg/day group
were similar to controls. Therefore, the red cell mass? changes in 50
mg/kg/day males were considered to be test: article -related but: non -
adverse by the registrant. ISllir€lbin levels were statistically significant
reduced in 'females at the mid (-21 to-5111/ae) and high dose groups (--33
to -47%) at almost: all intervals.
At the 1.2-€month interval in males receiving 50 mg/kg/day, there were
mild increases relative to controls in enzymes indicative of liver injury
including alkaline phosphatase, ALT, AST and sorbitol dehydrogenase
(sorbitol dehydrogenase and AST not statistically significant). These
enzyme changes correlated with microscopic findings of minimal cystic
degeneration and minimal to mild focal necrosis in the liver of males at
50 mg/kg/day. Therefore, these enzymes changes were considered test:
article -related and adverse, Minimal but ,statistically significant increases
in alkaline phosphatase were also present at the 3- and 6-month
Intervals in the 50 mg/kg/day male group. ,at these intervals, increases
in alkaline phosphatase were less than those present at 12 months and
were not associated with statistically slgnlflcant changes in other
enzymes indicative of hepatic or hepatobiliary injury, Therefore, the
changes in alkaline phosphatase in the 50 mg/kg/day male group at the
and 6 month intervals may be dace in part. or in whole to test article -
related enzyme induction, as the test article was previously shown to
produce an increase In total P450 enzyme activity in male rags at 50
rng/kg°day, There were no test article -related changes in Ilver enzymes
in males receiving 1. or 0A. mg/kg/day or in females at any of the dose
levels tested (Lap to 500 mg/kg/day),
Page: 80 of 92
DEQ-CFW 00079667

RI M Letter report 2016-01 4
erurnProteins: Minimal, statistically significant increases in albumin
were present in males receiving 50 mg/kg/day at: all intervals (up to
16% above controls) and in females receiving 500 9lkg./day at the 3-
month interval (10% above controls). In addition, statistically significant
decreases (of up to 17% below control) in globulin were present in
females at 500 mg/kg/day at all intervals (an associated decrease in
total protein was also present in this group at the 6-month interval). No
statistically significant decreases in globulin were present in males at
any dose or interval except for males at: 50 mg/kg bw1day after 3-
months, small decreases in individual values for these parameters in
individual animals in the 50 rng/ gjday rnale group may have been test
article -related, The changes in albumin and globulin in the high -dose
male (+1.8 to +28%) and female groups (+20 to +2 %) also resulted in
statistically significant increases in albu€nin/globulin ratio in those
groups at all intervals. The test article is P peroxisome proiiferator, and
the pattern of change in serum proteins observed in Nigh close males
and females-iower globulin and higher albumin -is a well -established
response to PPARa activation. Pero isorne proliferators are anti--
inflammatory, produding decreases In acute phase proteins (which
contribute to the globulin fraction), and increases in negative acute
phase protein (albumin). However, no adverse biological outcomes have
been associated with such changes in these serum proteins according to
the registrant. -Therefore, these changes in serum proteins in high dose
males and females were considered test article-reiated although they
were not considered biologically relevant by the registrant Lased on
their small magnitude and lacy of association with known adverse
outcomes. In addition to the serum protein changes noted above,
minimal, statistically significant Increases in albumin/globulin ratio were
present in the 1 mg/kg/day males (+16%) and 50 mg/kg/day females
(+9%) at all Intervals. Also, in some individual animals In these groups,
albumin tended to be higher and globulin lower than controls. However,
group mean albumin and globulin in these groups were not statistically
different from controls (with the exception of elevated albumin in the 1
mg/kg/day male group at 12 months and decreased globulin in the 50
mg/kg/day female group at 6 months), and differences from control
group means for both albumin and globulin were �581,/a at ,all intervals.
Therefore, the statistically significant changes in albumin/globulin ratio
in these groups were also considered by the registrant to be test article -
related but raga -adverse based on the minimal nature of the changes.
However, the changes in albumin and albumin/globulin ratio are
indicative of effects on the acute phase response of the immune system.
These effects were also observed with other PPAR-a inducers, occurs in
humans and is secondary to binding to the PPAR-a receptor (Cervols et
at, 2004). Therefore, these effects are considered adverse by the R..IVM.
Phosphorus was statistically higher than control in the 500 mg/kg/day
female group at the 12-month interval. The relationship to treatment for
this difference Is uncertain; however values in individual rats in this
group were similar to controls except for one animal, and there were no
statistically significant changes in phosphorus in any treated group at
any other time point, Therefore, based on the minimal nature of these
changes, they were not considered to be adverse, Phosphorus was
statistically Nigher in the 0.1 at the 3-month interval and 50 mg/kg male
groups at the 3 and 6-months interval and non -significantly after 1 -
paga? 'sl of 92
DEQ-CFW 00079668

R1VM Le[kea, rppori: 2016.0174
rnonthsa Theses differences at 0..1 mg/kg bw/day were considered to be
unrelated to test article administration ;since they did not occur in a
dose -related rnanner and there, were no statistically significant
differences in phosphorus in any treated group relative to control at the
6- and 12- month intervals. Calcium was statistically higher in the 50
nig/kg/day males at the 12-month interval. One fraction of serum
calcium exists as'bound'to albumin, and increases in albumin are
necessarily associated with physiologically appropriate increases in
calcium. Changes in bound calcium have no effect on unbound
("ionized') calcium, which is the physiologically active form of calcium,
Therefore, the increase in calciurn in the 50 mg/kg/day male group at
12 months was considered to be secondary to albumin changes,
physiologically irrelevant:, and thus non -adverse, Urea nitrogen was
statistically higher than the respective control in the 50 mg/kg/day male
group at the 3 and 6-month interval, Theses differences were were not
consistent across time, and there; were no correlative changes in related
clinical chemistry parameters or with microscopic changes in the
kidneys. Chloride was statistically higher than control in females at 1
and 500 mg/kg/day (beat not at 00 mg/kg/day) at the 6-month interval,
These differences were not considered to be test article -related as they
very slight (only 211% above control), did not occurin a dense -related
manner, and were not associated with changes in chloride at any other
Interval
In females receiving 500 mg/kg/day, minimal, stat:Ist:ically significant:
increaser, In urine volume and pH and decreases in urine specific
gravity -suggestive of a minimal diuresis -were present: at both the 6- and
12-month intervals, Although minimal and not associated with changes
in kidney -related chemistry parameters (e.g., area nitrogen, creatinine),
these changes may be correlative to increased incidences and severity
of chronic progressive nephropathy observed microscopically in this dose
group at the 1-year interim sacrifice,
Urine pH was increased and urine volume after 12--months decreased in
males at all dose levels. These charges are of uncertain relationship to
administration of the test article based on the lack of a clear dose
response across the affected groups, Fused on the lack of any
correlative findings suggestive: of an effect on the urogenit l system, the
changes were considered nonadverse , In addition, no such effects were
observed in males in the 00-day study rip to 100 mg/kg bw/day,
Interim Test article -related organ weight changes were limited to the
high dose groups. Increased liver weights occurred in rnales at 50
mg/kg/day and it ferrule rats at 000 mg/kg/day, In males, the increase
was small and only the rnean liver relative to body weight was
statistically significantly increased (14,5311% above control), In females,
the liver weight increase was larger (mean liver relative to body weight
was 66e751'lo above control) and all parameters (absolute and relatives t:o
berth brain and body weight) were statistically significantly increased.
The liver weight changes it the affected male and female groups were
associated with microscopic changes in the liver (discussed below),
Mean final body weight: at: the interim necropsy was 19,51.11,1:F less than
control l it the 500 mg/kg/day ferrates, As a result of this decrement in
mean final body weight, the brain, kidney, and thyroid/parathyroid
relative to body weight were statistically significantly increased. Aside
Page 82 of 92
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€dIVM latter report 2015-617 d
from a slight Increase In severity of chronic progressive naphropathy in
the kidneys, there were no microscopic changes in these organs
associated with the increased weights, and mean absolute weights were
not increased, Thus, these. changes were considered secondary to the
body weight decrement at 500 mg/kg/day, Additionally, mean absdute
and relative to brain weights of the spleen In the 500 mg/kg/day
females were statistically significantly lower than centrals, These
differences were not considered test article -related by the registrant, as
there were no microscopic changes in the spleen in either sex,
Terminal., No test article- related or statistically significant organ weight
Changes occurred in males, to females, the only test article -related
effect on organ weights was an increase in liver and kidney Freights at
500 mg/kg/day, glean absolute and relative to both body and brain
weights were Increased compared to control, with mean liver relative to
body weight 41,61% greater than control. There were several test
article -related microscopic: changes to account for the increased weights,
as describer) below, Absolute and relative to bodywelght kidney weights
were increased and relaters to microscopic changes.
Interim: A test article -related macroscopic observation, 'irregular
surfacer' of the kidneys, was noted in the kidneys of one 500 mg/kg/day
(high dose) female, This observation correlated with mild chronic
progressive nephropathy In this animal and was indicative of a slight
increase in severity of chronic progressive nephropathy in the 500
mg/kg/day female group at one year.
Terminal: No test: article -related macroscopic observations were noted in
males, In females; test article -related macroscopic observations were
noted In the kidneys and liver, In the kidneys, 'irregular surface' was
noted in tin of 70 animals at 500 mg/kg/day (not present in controls or
any of the lower dose groups), while in the liver, "tan focus/foci, was
noted in 1, 1, 1, and 0 of 70 animals each at 0, 1, 50, and 500
mg/kg/day, respectively, and "mass nodule" was noted In .1.4 of 70
animals at 500 mg/kg/day (not present in controls or any of the lower
dose groups), These macroscopic observation were correlative to test
article -related microscopic findings described below.
Interim,, Test article --related microscopic findings were noted1n the liver
of both male and female rats, and in the kidneys of females, in the high -
dose groups (50 and 500 mg/kg/day for males and females,
respectively), In males, there was a slight Increase in minimal focal
cystic degeneration of the liver (0, 0, 0, and 5 at 0, 0.1, 1, and 50
rng/kg/day, respectively), This finding was more pronounced in the
terminal portion of the study, also in males, there was a slight: Increase
in minimal to mild focal necrosis of the liver (1, 1, 0, and 5 at 0, 0�1, 1,
and 50 mg/kg/day, respectively). In females, the only microscopic
finding in the liver was centrllobolar hypertrophy, which occurred in all
10 of the 500 mg/kg/day ferrules. This change was of minimal or mild
severity and was characterised primarily by a .slight increase in size of
centrHobular hepatocytes with increased red granularity to the
rytoplasrn and is consistent with peroxisome proliferation. also in
females, there was a very slight Increase in incidence and .severity of
chronic progressive nephropathy in the kidneys at 500 rngflcg/day. This
Pago. F; of 92
DEQ-CFW 00079670

change was characterized by foci of basophilic tubules, some with
thickening of basernent membranes. in the 500 mg/kg/day group, most
incidences were of mild severity, while in the other groups, including
controls, the incidences, were primarily of € animal severity, although in a
single control female the incidence was of moderate severit, In males,
there was a single interstitial cell adenoma of the testes at 50
mg/kg/day; incidences of interstitial cell hyperplasia were 1, 0, 0, and 5
at 0, 0.1., 1, and 50 mg/kg/day, The incidences of these changes in
treated groups were not statistically different from controls (historical
data for rots of this age were not available), proliferative interstitial cell
lesions are discussed in more detail under microscopic: findings for the
terminal sacrifice. Ali other microscopic findings were considered
incidental, and typical of those seem in rats of this strain and age,
Terminal: Test article -related non-neoplostic microscopic changes were
observed in the liver and adrenal of males and in the liver, kidneys,
nonglamdUler stomach (limiting ridge), and tongue of ferrules at the
highest doses tested, 50 mg/kg/day in males and 500 mg/kg/day in
females. Focal vac€.€olatiom of t:he adrenal in males was reduced at: all
dose levels compared to controls but showed no dose response relation.
Therefore, this effect was not considered substance related. In the liver
of males at 50 mg/kg/day there were statistically significantly increased
incidences of focal cystic degeneration, centrtlobular hepatoceihilar
hypertrophy, and cemtrilobolar hepatocellular necrosis. periportal liver
vacoolation was reduced. Cystic degeneration was characterized by the
presence of multiloc€alar cystic; spaces containing finely granular or
flocculent material without endothelial or epithelial cells liming the
spaces, Centrilobuiar hypertrophy, morphologi€.ally consistent with
peroisome proliferation, was characterized by hepatocytes with red
granular cytoplasm sometimes containing small amounts of pigment
morphologically compatible with llpof€asclm, Centrilobuiar hepatocellular
necrosis was typically of the coagulative type with strongly eosinophMc-
stain€rig cytoplasm and pyknotic: nuclei, 'Test article -related findings in
the liver of females at 500 mg/kg/day were similar to those noted in
males at 50 mg/kg/day, and also included low incidences of panlob€alar
hepatoceiMar hypertrophy and individual cell hepatocellular necrosis.
paniobular hepatocellular hypertrophy was characterized by enlargement
of hepatocytes (as described above for centrilobolar hypertrophy)
throughout the entire liver, Individual cell necrosis was characterised by
the presence of scattered single hepatocytes with features characteristic
of apoptosis. Liver periportal vacuolation was reduced at the highest
dose in females.
Statistically significantly increased microscopic findings in the kidneys of
females at 500 mg/kg/day included tubular dilatation, oedema of the
renal papilla, transitional cell hyperplasia in the renal pelvis, tubular
mineralization, renal papillary necrosis, and chromic progressive
nephropathy. Tubular dilatation frequently occurred in an ascending
pattern extending from the papilla to the outer cortex, while at other
times it was more prominent In the papillae Oederna of the papilla was
characterized by increased rarefaction or myxomatoras change in the
papillary interstitium, sometimes with polypold protrusions from the
lateral surface of the papillae 1-he oedema and tubular dilatation were
often associated with hyperplasia of the transitional cell epithelium llnin€g
Page 84 of 92
DEQ-CFW 00079671

the papilla and pelvis. In some animals, necrosis of the tip of the papilla
was present. In some 500 mg/kg/day females with the rental papillary
changes, lesions diagnosed as chronic progressive nephropathy (CPN)
were comprised of dilated tubules (often in an ascending pattern as
described above), mononuclear cell infiltrates, and basophilic tubules,
but with less thickening of tubular basement membranes than typically
seen in CPN. In these animals, the constellation of lesions diagnosed as
CPN may be more representative of retrograde n€aphropathy, rather than
typical CM
The nongla€-rdular stomach (limiting ridge only) and the tongue had
statistically significantly Increased incidences of hyperplasia of squarraous
epithelium at 500 mg/kg/day. Inthe tongue, subacute/chronic
inflammation occurred in association with squamous epithelial cell
hyperplasia. There is no data describing incidence of epithelial
hyperplasia of the limiting ridge of the nonglandular stomach in the
historical control database for 2 year studies. The incidence of squamous
cell hyperplasia of the tongue at 500 rng/kgjday (18.6%) exceeds that:
historical control range of 0-3.3%. There was also a single incidence of
squamous cell carcinoma (144111e) in that tongue of females at 500
mg/kg/day. This is will within the historical control range of 0-1,70/0 and
the finding of a single such tumour was not considered a direct result of
test article administration.
A statistically significant increase in the incidence of alveolar
hlstiocytosls was present in females at 500 mg/kg/day. The incidences
were 22, 20, 21, 42 (61 %) at 0, 1., 50, and 500 mglkgfday,
respectively, The incidence at 500 mg/kg/day was statistically significant
by both the Fisher Exact toast and the Cochran -Armitage trend test and is
at the upper end of the histoarical control range of 9.2--61.7%. The
increased incidence of this common background finding may be
secondary to aspiration of dosing formulation at this high concentration;
however, a definitive mechanism for this Increase could not be
determined. A slight but statistically higher (by the Cochran -Armitage
Trend test) incidence of pancreatic acinar cell hyperplasia occurred in
females at 50 and 500 rng/kgjday� Incidences were 0, 2, 5, 5 (7,1 %) at
0, 1., 50, and 500 mg/kg/day, respectively, The incidences of acinar cell
hyperplasia at the two highest doses slightly exceeded the historical
control range of 0-4.6%, but were not significant by the Fisher Exact
test and were not associated with pancreatic acinar cell tumours. In
addition, acinar cell hyperplasia did not occur in a clear dose response
manner, as incidences in the 50 and 500 mg/kg/day groups were the
same despite the order of magnitude difference in dose. In contrast, all
other test article -related changes observed at 500 mg/kg/day occurred
with a clear- dose response. Therefore, the slight increase in acinar cell
hyperplasia in the 50 and 500 mg/kg/day females was considered by the
registrant most likely spurious and not test article -related. A statistically
significant increase (by both the Fisher Exact test and the Cochran -
Armitage trend test) in the incidence of alopeciafhypotrichosis was
present in females at 500 mg/kg/day, The incidences were 1/70, 2/48,
5/55, and 9/70 `1.2.911'b), However, the relevance of
a alopecla/hy*potrichosls Is more appropriately made by interpretation of
the incidence of this finding in the clinical observations of the study
Page 85 of 92
DEQ-CFW 00079672

RIv1A nett er report 201 -Ul'T4
rather than the microscopic observations, therefore, for rnlcroscoplc
Purposes, this was not considered at potential target; organ,
Finally, incidences of cataract of the lens of the eye, pelvic
mineralization of they kidney, and angiect:asis of the liver- were
statistically significantly increased, Cataract of the eye and angiec:tasis
of the liver were statistically significantly increased by the Cochran -
Armitage trend test at 500 rng/k.g/day while pelvic €ni€ erallxation of the
kidney was .statistically significantly increased by theCochran-Armitage
trend test and Fishers exact: test: at 5€ 0 mg/kg/day, and Fisher's exact:
test: at 1 mg/kg/"day, Incidences of cataract of the eye were 0/69, 0/48,.
0/55, and 3/°70 (4.2911/"o) at 0, 1, 50, and 500 mg/"kg,/day, respectively,
The historical control range for cataract is 0 to 10v611/`o. Incidences of
pelvic mineralization of the kidney were57/'70, 63/70, 58/70, and 6 3/70
(90.011/o) at 0, 1, 50, and 500 mg/kg/day, respectively, The historical
control range is 45.0 to 87.7% (note: two studies in the historical
control database with are incidence of 0/60 reflect that this change was
simply not tracked as pelvic mineralization in the st€adies). Inddences of
angiec:tasis of the liver were 1/°70, 0,/70, 3/70, and 5/70 (7.1411/0) at 0,
50, and 500 € g/'kg/day, respectively, The historical control range is 0
to 10.0%. For each of the changes, the incidence was well within the
historical control range, except pelvic mineralization, which Is a very
common background finding, only slightly exceeded the historical control
range, 'Thus, these changes were not considered test. article -related.
This study was used as a key study in the REACH registration dossier for
repeated dose toxicity and carcinogenicity. A NOAEi_ of I mg/kg bw/day
for male rats was established by the registrant based on liver effects
and equivocal increases in pancreatic and Leydlc3 cell tumours. For
fe€Male rats, a NOAEL of 50 mg/"kg bw/day was established by the
registrant, based on reductions in body weight and body weight gain,
mild decrease in red cell mass, effects on the liver, kidneys,
nonrglanduiar stomach and tongue, and increase in liver t€arr Curs, The
RIVM derives a NOAEI_ of Oat mg/kg bw/day based on an increase in A/G
ratio in males at the next higher nose level of 1 mg/kg bw/day,
AL9 Mode of action
In view of the RIVM, the observed effects with FR,D-907 including
€€creased beta -oxidation, liver hypertrophy, reduction in serum
cholesterol, increased albumin / globulin ratio and observed tumour
types are typical for Pero isome proliferators, Peroxlsome proliferators
act; mainly by binding to the peroxisorne proHerator-activated receptor
alpha (PPAR-a). However, no direct; information on the interaction of
FRD-902 with f°PAR-a is available, A large volume of information on this
interaction is available for the structural analogue PFOA which lndu es
comparable effects in repeated dose tonicity studies and carcinogenicity
studies. The results indicate that substances like PFOA and therefore
passible also FRIG-902 can interact also with other nuclear receptors,
According to published reviews, the human relevance of the hepatic and
carcinogenic effects of PFOA cannot be excluded (EF A, 2006) (US -EPA,
01.6) (RAC, 2011) (1ARC, 20.16). Therefore, the observed effects with
FKID-902 are also considered relevant for hurnans,
Page 86 o€' 92
DEQ-CFW 00079673

RIVM Letter report 2016-0174
Annex 2. Human health toxicity El
Kinetics
Three male rats (CrL:CD( D), 6-9 weeks old) were orally exposed
(9avage In water) once to 20 rng El/kg bw. The concentration of El In
urine collected at several time points after exposure was determined
using LAC/CIS. The E1 concentration In urine was below the LOD of 0,04
ug/mL or below the LOQ of 0.02 ug/mL in all animals at all time points
(Anonymous, 7007). This Is a very limited report. It Is unclear haw the
rats were dosed as the stated concentration of 6 nag El/ml water Is
above the water solubility of 7 mg1L..
Three male and three female rats (CrL.CD(6D), 7-17 weeps old) were
orally exposed (gavage In water) once to 10 or 30 mg E.I./kg bw. E1 was
determined in blood samples at 14 time points after administration and
once before administration and In liver and fat samples after necropsy.
E1 plasma levels were 'below the LCQ (LCQ level not stated) at all time
points. Also all l€are€_ samples were below the unstated LD a Some fat
samples appeared to contain low concentration of El., The results (not
stated) were not proportional with dose or consistent within or across
the sexes. The spectrum of the analyte could not be confirmed
(Anonymous, 2008), This is a very limited report lacking details on the
LDQs and the measured concentrations.
In are in vitro test on metabolism using male rat 99 no metabolism and
difference between active and heat treated S9 was observed indicating
absence of metabolism. This study was not provided but Is available
upon requests
Acute Toxicity
In an acute oral toxicity study a single male rat was exposed to 7500,
11000, 17000 or 25000 mg/kg bw E1 by garage, The rats were
observed for 14 days after which liver weight was determined and liver
histopathology performed, No mortality occurred but some limited tonic
signs were observed. No effects upon final body weight, liver weight or
liver pathology was observed (Anonymous, 1967a)e This is a very
limited report of a shady using only a single animal per close whereas
normally several rats per dose levels are required to estimate the LD�;a.
Rabbits dose de€rmally with 73000 or 37E00 mg/kg bw E.I. did not display
mortality or systemic histopathological effects. Slight CNS effects
occurred during exposure. Local irritation in the form of reversible
erythema was observed. This study was not provided but is mailable
upon request.
In an acute inhalation toxicity study groups of 4 male rats (Chr-CD)
were exposed whole body for 4 hours to El at nominal concentrations of
5000, '15000 or 30000 pprn as a vapour. The rags were observed for 14
days after which the relative liver weight and lung pathology was
determined, No mortality was observed. Clinical signs of toxicity
exhibited during exposure were mild lacrimation, red ears, inactivity and
deep respiration at the highest concentration with lesser effects at lower
Page 87 of
DEQ-CFW 00079674

RIVM Letter report 2016-0174
concentrations. There was no effect on relative liver weight. Mild
irregular lung congestion was observed atthe two highest
concentrations at14days after the exposure (Anmnyonnus,1g65).The
study report was very limited,
In an acute inhalation toxicity study groups of male rats (ChpCD)
were exposed whole body for 4hours boE1ntnominal concentrations uf
5870,13130or23548,6222Gor1g5114pprnasmvapour. Some ofthe
tasted batches ofE1 contained a mixture ofn-propy| and isopropyl
isomers, At El concentrations above 108000 pprn, additional oxygen
was supplied toenrich the air. The post exposure period was not stated,
No mortality occurred. Several clinical effects were observed during
exposure including tremor and convulsions but not after exposure. The
clinical effects indicate respiratory irritation and possible effects onthe
central nervous system (Anonymous, 1967b).
In an acute inhalation toxicity study groups of 6 nno|e rats (ChpCD)
were exposed whole body for 4hours tmE1atnominal concentrations of
396800or57GQQUpprnasavapour, Additional oxygen was supplied ba
enrich the air upto2896 oxygen. Gross and hiatopathm|ogica/
examination was performed mnday 1,2and 7mfexposure on2rats per
dose. No mortality occurred, Several clinical effects were observed
during exposure including tremor but not after exposure, The clinical
effects indicate respiratory irritation and possible effects mn the central
nervous system. Nuhistoputho(mAicel changes were observed inerange
of tissues including liver and lungs (Anonymous, 1968).
Anadditional acute inhalation study iodogs challenged with epinephrine
resulted ina NQAECmf18D000pprnand a LQAECmf2OOODOpprn.This
study was not provided but /s available upon request.
Repeated dose toxicity
lmatwo-week repeated dose inhalation study, groups of1Dmale rats
(CrL:CQ@BR) were exposed whole body during 10 days for hours a
day tmnominal concentrations of0,50UU,2500Oor175O88ppnnE1ama
vapour, Additional oxygen was supplied atthe highest dose level to
ensure anoxygen content ofaLleast 1996.The test atmosphere was
produced by evaporation of El and resulted in mean analytical
concentrations within 196 ufthe target concentration. Necropsy was
performed on5rats per group directly after the last exposure whereas
the other 5 nets were sacrificed 2 weeks after the last exposure. The
determined parameters included body weights, clinical effects,
hematology, clinical chemistry, urine analyses and macroscopic and
microscopic pathology. In addition, micronuclei were determined as
described below.
The mean analytical concentration was within 196 ofthe nominal
concentration. No mortality mreffects on body weight were observed.
There were no changes in hematology, clinical chemistry, organ weights
and urine analyses. Acompound-related increase inthe hyaline
droplets within kidney tubules mf3out ofSrats exposed ta1758Q8pprn
was observed microscopically, This observation inthe kidney was
minimal inseverity, unaccompanied bycell necrosis, and judged not to
be biologically or toxicologically significant by the authors. A lack of
response toanalerting stimulus and occasional tremors was observed
Page uomyz

RIVM Letter report 201-6-0174
during exposure at the highest concentration, The NOAEC is determined
at 25000 pprn. The absence of an increase in fluorine in urine compared
to controls indicates the absence of metabolism resulting in the release
of fluorine from El (Anonymous, 199E).
Mutagenicity
In are in vitro study on the mutagenicity of El In Salmonella
typhlmurium (ernes test, DECK 71) using strains TA100, TA153E, TA97
and TA98 with and without exogenous metabolic activation, no increase
in reverse mutations was observed at dose levels up to 5000 ug/plate
(Anonymous, 1994). However, considering the low water solubility of
the substance and the high vapour pressure of the substance it is deemd
Mely that most El evaporated from the plates during incubation at
3711C, as taping of the plates to reduce evaporation is not mentioned.
"therefore, this study cannot be used to demonstrate the absence of a
mutagenlc potential.
In an additional bacterial revers: mutation test of El in 13al,monella
typhimurllum (Ames test, OECD 471) rasing strains TA100, TA15 T TA97
and TA98 and scherichla call using strain WP2 uvrA- with and without
exogenous metabolic activation, no increase In reverse mutations was
observed at dose levels up to E000 ug,/plate (Anonymous, 2009)a Pre -
incubation was performed using Ice cold E1 in acetone in sealed test
tubes and plates were sealed with a vinyl sack per concentration and
experimental condition to minimise evaporation. The study was
negative,
In an In vitro test for chromosome aberrations In human lymphocytes,
El was stated to be negative with and without metabolic activation.
However, considering the low eater solubility and the high vapour
pressure it is deemed likely that E1 evaporated from the culture vessel
during incubation, Therefore, this study cannot be used to demonstrate
the absence of a mutargenic potential. This study was not provided but is
available upon request.
An in vivo micronucleus test was performed as part of a two weep
inhalation study as described above. An additional group containing 5
male rats exposed by IP injection to cyclophosphamide 24 hours before
necropsy was included as positive control, Directly after the last
exposure, bone marrow smears were prepared. Two thousand PCEs per
animal were evaluated for micronuclei after staining with acridlne
orange. In addition, the PCE/NCE ratio was determined, No increase in
micronuclei or change in the PC.E/NCE ratio was observed except for the
positive control ( nonyrnous, 199E).
Read -across
Dead -across from FRD-902 to El is not justified because of the
differences In chemical -physical properties (solid versus liquid with high
vaporer pressure, acid or salt versus neutral, more lipophilic substance).
In addition, the available toxicological data Indicate that E1 is less tonic
than FRD-902a For example the acute oral LD50 of FIND-902 was 1750
mg/kg bw in male rats. This is at least 10-times below the LD00 of El in
resale rats.
Page 69 of 92
DEQ-CFW 00079676

nm*Leuer repm^zu16-0174
Several expert systems including `Unco|ogic','OECD toolbox' and ]SS'
indicate that E1 is an alpha, beta-ha|nether or alpha ha|oethervxhich
could bedirect-acting a7ky|adng agents leading to nnutagenidtyand
carcinogenicity. However, the alert is based onch|oro-ethers, limited to
nnonoha|omethyl orethyl ethers and probably less relevant for Muoro'
athensas the C-F bond is more stable and less relevant for di ho|m ethyl
ormethyl ethers. Inaddition, noinvivo nnutagenidoywas observed for
the FR0-902, which also fulfils the alpha ba!oetheraiert, and the
carcinogenicity was limited to an increased number of tumours typical
for peroxisome proliferators in rats. This confirms the limited relevance
of the alert horfluoro'ethens. Overall, the expert systems du not indicate
a strong concern for rootogan|cityorcarcinogenicity. However, these
systems are only designed to detect (sub) structures that could result in
o specified effect but not for identifying the absence of effects.
Tharefona,nnutaganic and carcinogenic properties cannot beexcluded
based omraad-across.
Read -across based onstructural analogues aaidentified using the OECD
QS4Rtouibax indicates limited toxicity after repeated dose inhalation
exposure. Two fluorinated ethers were identified asthe closest
analogues and are shown below. However, both contain one chlorine
atom instead ofonly fluor atoms. Asthe bond between fluor and carbon
isstronger than between chlorine and carbon, the reactivity and toxicity
lsexpected tobmlower for the fluorinated compound. Therefore, these
analogues have some benefit for the assessment ofEl.
1.Enmflumane
CAS: 13038-10-9EI@ECS: 237-553-4
Name: Enflmrane;ethane, 2-ch|oro-1-(di#uoronnethoxV)-1,1,2-trifluorn-.
Enflurane is an inhalation anaesthetic used for narcosis in concentrations
mf5Q08to 15800 ppmn. A MAKva|ue of2D ppnn (150 rng/rn3) is available
RQqjfull). The kinetic data show limited metabolisation,
F_�_._jyF
CAS: 26675-46-7EINECS: 247-897-7
Name: Isofurane| 2-chioro-2-{difluonmmethoxy}-1,1,1-trif|ooroethane.
Isofluraneis an inhalation anaesthetic used for narcosis in
concentrations of 12080 or230DD pprn. No MAKm/es derived because
the available database was inadequate
.D2jfull). The NOEL from chronic studies in mice was 1000 ppm (7470
Mg/M3) and nervous system effects were observed in humans after brief
exposures to 1150 ppm.
Page 90 of 92

RIM ?etterreroft 2015-0174
In addition, information can fluorinated compounds was collected from
the RepDose database (Erauenhofer). However, the available fluorinated
alicanes did not contain ethers and no generai conclusion on the
repeated dose toxicity via inhalation couid be determined as the NOEC
values from these studies varied more than 1000 fold but all NOECs
were above EO ppm. Overall, the information on analogues medicates
limited toxicity for E1.
Page 91 of 92
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RIVM Letter* repot 2016-0174
Annex 3. Calculated air concentrations FRD-903 based or
the permitted emissions (in ng/M3)
calculated FRD-903 concentrations in air based on permitted emissions for 2014 * Stark
calculated average concentration in a gricicel
15 - 73 ngle Idlompter
73 ngl,,O (dedved ex poswe rhyd)
Page 92 of 92
DEQ-CFW-00079679

DEQ-CFW 00079680

OEQ-CFVV_00079681

From emiss.ion sources to human
texposure t - and.
polyfluoroalkyl substances
Melissa Ines Gomis
Academic dissertation for the Degree of Doctma ol'Fbiloso iry in —Applied Enviror mental.
Science at > tockb€ bil University to be publicly defended or). Friday day .12 May 20171 at 10.00 in
ordens idldsalen, Geovetensi apens l us, Svartte Arrhenius vdg, 12.
Abstract
Produced since the .idlsll 9, per- and polyfluoroalkyl (1"FASs) substances, are persistent, bic,Accurnnlati%�e and toxic;
compounds that are ribiplritous in the envirournent.:Bciu pre+teffiophilir, with a tendency to paTiition to lay-stein-richtissues,
PFf Ss have been found in hurnan seram wnrldvide and in wildlife. path a predominance of long -chain pefflar ro alkyl
earboxilic: acids ;t9:k'CAs) and. perfluoroal-kyl sulfor& acids ('Cc -Cs P& SA.,-,). Due to rising coucern. regarding their
hazardous properties, several regulatory actions and voluntary industrial phase -outs have been conducted since early
2000s, shifting the production towards other fluorinated alternatives, This thesis explores the human exposure to long-.
chain PPA:7,s and their.altematives using dill.'event modclling; methods and aims to 1) lime comprehensively the past and
crrra rrt iradnsirial paoeln.ctiorr with the human body burden gnd2) assess the potential hazardous properties of legacy Pia ASs
replacements, on which information is very limited. In Paper 1, the historical daily intakes in Australia and USA were
reconstructed from cross-scctional biomonitoring data of perfluorooclranesulfonir, acid (PFO n), peafluorooetauoic. acid
(Pl OA) aardpeafluorohe xane rrl.f:orai.e acid (PEMS), 'ne results, indicate that humans experienced similar exposure levels
and trends to PFOS and PFOA in botla regions, sraggestin,g a eorranon historical exposure, pessibly dominated lry consumer
products. The model could not be fill l to F'&'H\S concentration in serun.j. In paper 11, the relative contribution of indirect
(i.e. subsequent metabolism of precursors into legacy PTASs) versa,, direct exposure was evaluated on occupationally
exposed skiwax technicians. The indirect €,Xposure contributed by rap to 45% to the total body burden (if PF 1.A. In :Paper
HL the: physicochemical properties, the persistence and the, long-range transport of fluarina:wd altematives were predicted
u4ir3.p different is riarie:o took Finding suggest that fluorinated alternatives a� libel p sirxlil.ae to their predecessors, era toraars
of physicochendcal. properties and enviromnenta .fate, Finally, Paper lv compares the toxic potency ofPRIS, PI~f)A and
their alternatives as a frmction, of external and internal dose:. While alternatives are less portzut than their predecessors wvhen
considering the administered dose, they beooane similarly poteaat when the assossinent, i% based on levels in the target tissue.
'11is thesis demonstrates, that pharmaooldnetic models are, effective tools to c:onrprehensively reconnect the body burden
to the expoaure ofphasod-out. chemical Is —More importantly, the "tudies on fluorinated. ,alternatives raise tbo necessity to
provide more information and data on the potential hazard of these navel and emerging products,
ll:epvor ds, PEMs, PI OA, PTO , 7`luo?lnatee arI*ar ar ayc4, }rutrwn expovuav:, jdyarnaracoidnedc ra,odrlling, hazard
ta$ess-rarent.
Stockholm 2017
blip:/Irma.lcbose,`ro olv .raaaa::: raar:nl�n se s rAiva-bill}:34
ISBN 979-91-7649-712-8
r.5BN 979-91-7649-71 3-5
410
Department meat of Environmental Science and AnalyticalRoCkholm
Stool hohn l lniver dry, 106 91 Stoo cbohn
DEQ-CFW 00079682

DEQ-CFW 00079683

From emission sources to human tissues: modelling
the exposure to per- and polyf1uoroalkyl substances
DEQ-CFW 00079684

DEQ-CFW 00079685

s
m
From em.l.ssion sources to human tl.s-
sues:. x per-
aper-
and polyfluoroalkylan
Melissa Ines - 1
DEQ-CFW 00079686

(g)Meiissa lees Gomis, 5tockhoinj University 2017
Craver fliustradon by Meftsa Ines Gomis
ISBN print 978•-91-7649-712-8
ISBN Pi. F 978--91-7649-713-5
Printed in Sweden by US -AB, Stor:khoki 2017
Dis,tributor< € epar-tment of Ed'vii'4?d'kE'yrentai Science
and Analyt.icaChemistry (ACES)
DEQ-CFW 00079687

DEQ-CFW 00079688

DEQ-CFW 00079689

Contents
Abstract............. 0000.................. ..,.................. ,........ . ve,............................,--
amn—in1`attttl a:..— ...... .r.,...... 000...,.v......—.... ............ --- ................... —2
ommaixe.............— ......... , Dove.,"Dove,.......00e..,,o,vas........ 0000,.,.00es.......,a000a.,oaooeeee
.csmien—....... ............. ..................... —.Dove... ........ --.................. — .............
5
Listof papers ..r....................— rev,,..............................................--..............7
1. hitro ixt n...—....--.................000,,,aee,,......, o00 ,...eve,,...............r...—.....-
1.1. BackgYround ............. oo,,........ ,....... ,.......... ........ ,,,,,.,,...... ........... --- .......... .,...8
1.2 The role of human. exposure in the risk assessment ofchemicals ..................lid
1.3 Knowledge gaps in the state-ofthe -scie .ce oo—.......... ooao....................a
103.1. Linking, prod.iiction changes with time trends in serum levels.:,......—,, —Al
1.3.2 171:reet'versus indirect sources of lunnan exposure ....... .... — .............. —1
2
1.3.3 Are flonnated alternatives an improvement on legacy PF s? ... - .....
13
1.,4 Objectives...........,s000000a000............... --....... .............. —... - .......... -- ................
13
Methods............ ..... T0000..—........,a000,,.vaea......,v00000,,..............0000a,,,...........1.6
2.1. Predicting, b sicochecal properties of organic contaminants ........ -- ......
1
2.2 Erviromnental pate modelling ...... ........ __........... �,Dove.. ................ „000aoo—.....
r`r
2.3 Pha:rniacAdnefle modelling .................
18
s1s....... ......... ....-- .................o
2A Sensitivity and uncertainty ana.ly21
3 Results and discussion..aoos,...r....... __......r ........ _ ,.0000,.........-- ... ......2:
3.1 bast and current exposure to PFAA.s ......... ,, _..................- ....... - .......... - -22
3.2 Response of the body burden to exposure dy imi s .... —...,,,
33 The elimination half-life. as a determinant factor of body burden .................25
3A The lock -in problem € f stu. cturally sinfilar replacements .............. ..............
2€'s
3,4.1 Persistence (la) and. long-range: transport potential. (.LR 1'P).................26
3.4.2 Potency ranking of legacy pFCAs and alternatives .............0000 .o.........26
4 Canchxsion ............- ... ......... r......._..................... 0000... ee,.....28
5 Futuxe perspectives. ........ ....... ......... .................... ....D
References- ... .......31-
7 Ack-nowlecigeme ts,9000,,,aeea,......,, oP.,,Dove,.........000....... ...... - .... ..41.
DEQ-CFW 00079690

Acronym. Definition
AUCSS
Area under the curve at steady-state
CTD
Characteristic travel distance
FTOH
Fluorotelomer alcohol.
Olen X
Ammonium- 2,3,3,3-tetrafl-uoro-2-(heptafluoro-
propoxy)-propanoate
KAW
Air ---water partition coefficient
KOA
Octanof---air partition coefficient
Kos_
Octanol—water partition coefficient
LFER
Linear free energy relationship
PBT
Persistent, bioaccumulative, toxic
PFAA
Perfluoroalkyl acid
PFAS
Per- and polyfluoroalkyl substance
PFBS
Perfluorobutane sulfonic acid
PFCA
Perfluoroalkyl carboxylic acid
PFOA
Perfluorooctanoic acid
PF.HxS
Perfluorohexane sulfonic acid
PFOS
Perfluorooctane sulfonic acid
PFSA
Perfluoroalkyl sulfonic acid
pK.
-log,oK,,, where Ka is the acid dissociation constant
PBPK
Physiologically -based phannacokinefic
PTA
Pbarmacokinetic
POV
Overall persistence
QSAR
Quantitative structure —activity relationships
QSPR
Quantitative structure —property relationships
REACH
Registration, Evaluation, Authorisation and. Restriction
of Chemicals
SSRW
Suni of squared residual weighted
TE
Transfer efficiency
US EPA
US Environmental Protection Agency
DEQ-CFW-00079691

Abstract
Produced since than 1950's, per- and polyfluoroalkyl (PF Ss) substances are
persistent, bioaccumulative and toxic compounds ih.st are ubiquitous in. the
environment. Being proteinophilic Frith a tendency to partition to protein -rich.
tissues, FFA s have been found in. hai .z�.aa. serum worl(h ide and in wildli.lb
with a predominance of l n-chain perfluoroa<all l c arboxil.ic acids (C-,- °aj.
PFCAs) and. perfluoroalkyl saalf€ uic acids (C6-C9 P.F As). Due to risingcon-
cern. regarding their hazardous properties, several regulatory actions and vol-
untary industrial phase -outs have been conducted since early 2000s, shifting
the. production towards other flan rirast d alternatives. ` bis thesis exploras the
human exposure to long -chain PFA.Ss and their alternatives -using different
modelling methods and air s to 1) link comprehensively the past and current
industrial. production with the huma body burden. and 2} assess the potential
tisl
hazardous properties oflega y . FAs replacements, on which information is
very limited. 'I Paper I, the historical daily int;al­es in Australis and USA.
were reconstructed from crass -sectional bion onitoring data, of pel luorooc-
t s lfn r acid (..l�FOS), perfla.€.�a oocta . is acid (?FOB) aa, d erdaaorohex -
anesulfonic acid (.PF. xS). The results indicate that hwnaixs experienced. sh -
il.ar exposure levels and trends to PF OS and P.FO . in both region s, Suggesting
a cominoaa, historical exposure ossibly dominated by consumer pr.rod cts. The
model could not be fitted to PFHxS concentration in serum. In Paper 11, the
relative contribution of indirect (te, subseque t metabolism. of precursors into
legacy PFA.Ss) versus direct exposure was evaluated on occupationally ex-
posed. ski wax. technicians. The indirect exposure contributed by up to 45% to
the total bodge burden. ofPFOA. In Paper III, the physicochemical properties,
the persistence and the long-range transport of fluorinated alterai tives were
predicted using different in ,silica heals. Findingssuggest that fluorinated al-
te.matives are likely similar to their predecessors, in terms of physicochemi.eal
properties and environmental -fate. Finally, Paper IV conipare's the toxic po-
tency of P.b'O S, .PF A and their alternatives as a. function of external and ire-
tonal dose. 'while alternatives are less potent than their predecessors when
considering the administered. dose, they become similarly potent when the ss-
scssi crat is based on Levels in the target tissue. This thesis demonstrates that
ph.armacokinetic models, are effective tools to comprehensively reconnect dac
body burden to the expostue of phased -out chemicals. blare im-porta.ratly, the
studies € n fluorinated alternatives raise the necessity to provide more infor-
mation and data. as the potential hared of thesenovel and emerging products.
1
DEQ-CFW 00079692

Samnianflattliffig
Per- oeb polyfluorerade (PFASs) knneu 5y lAnglivade, bioack-umulerande ocli
toxiska dnmen scam producerats sedan. 1950-Wet och fiterfirins dverallt j
rniljft. Dal de dr protein.-fila, har HAS dmuen.b.ittats i m5nskligt serarn i hela
v�rlden. och i vilda djur, framfOrallt i fbirn. av la'ugk.ectj'ade perfluaralkyl.
karboxylsyr(yr (C7-Cj,} PFCAs) och perfluoralkyl sulfonsyror (C6-Cq PFSA.s-'
Pa graind. av den stigande oron g5liande deras skadliga egenskaper Naar flora
lagstiftningshtg5rder och -15avilliga. industriella utfasningar geDOMENIS sedan
b6rjau air 2000-talet, vilket skifl-at produktionen. ruot andra, fluorerande
aftemativ. Denna avhandling unders6k.er m�itniskors exponcring fOr
lhn.gkedjade RFA.Ss flmnen och deras ersRtare erred hjdll) av ofika
modellefingsmetoder och syftar till att 1) p' eft om-fattande s5tt Mmka den
tidigare och navarande industriella produktioneii med rnk-asklig belastning
och. 2) becibma de potencielft skadliga ege.risk-aperna hos 51dre PFAS alternativ,
om vilka kauskapen 5r vAl.digt begr5nsad. I Paper 1, har de historis.ka dagliga
intagen i A-ustralien och U"SA rek-onstmerats frAn tvdrsnitts., biologisk
6vervakningsdata av perfluorokfai-i,,--,ul.-fousyra (PFOS'), perfluorkarboxylsyra
(PFOA) och perfluorhexan sulfonat (P.F.H.xS). Resultaten indik-erar att
m5nniskor har up.plevt liknande e)cponcringsnivaea och tronder foOr PFOS och
PFOA j ba'da regionema, vilket tyder pA en geniensana b-istorisk expo.nenng
potentielft dare inerad av k-onsumentprodulctere Modellen kunde into anpassas
till PFH.xS koncentrationen i semm. I Paper 11, utvarderas bidraget av indireld
(dvs. a efterfoljndemetabolisms a.v prekursorer fill aldre HAS dinnen.) kontra direk-t exponering av yrk-esexponerade skidvamingstelmdker. Den ixidirekta
exponeringen bidrog med upp till 45 % av den totala kroppsbelastningen av
PFOA. I Paper III, fbrutsa'S;s de fysikalisk-k-emiska egenskaperna,
persistensen., och 18-ngdistans transporten av fluorcrade altemativ erred h Hp av
j
olika insifico veyk-tyg. Resultaten tyd-er per att fluorerade -fltemativ say-molik-t
lAmar sina f6regfingare ndr det galler deras persistens och. fysikalisk-kemiskca
egensk-aper. Slutligen, Paper IV j amf6r toxis], t ns a
- po.e v PFOS PFOA Och
deras alternativ sneer en fmiktion av yttre och jnre dos. Medan alternativen dr
mi-ndre potenta ffn. shia f6regahgare ndr man 6vervager den administrerade
dosen, blir do lika potenta n5r bed&nxringcn ar baserad p& m'va'e,.r. 1
mh1vaNmaden., Donna aviiandling visar att -famiakokinctiska modellor ar
effektiva vefktyg fdr aft ph ett ornfattan.de sdft fiterkoppla kroppsbelastning till
exponering av avvecklade kemikaher, Amu vik.-figare, studiema. av do
fluorerade altemativen'belyser n6dvkidigheten. av aft, go mer infonnation och
data om deer potentiella fiaran n-.a.ed. dessa nya och.,frarnviixande produkaer.
DEQ-CFW-00079693

Sommaire
Produ.ites dep is les ann6&s 19501, les substances per- et pol luor es (FF Ss)
soot des produits persistants, bioaccumulabl s, to iques et ornnipr6sents daps
Penvironneme t..Etant pr tdinophil s avec uric; forte t ndanc e A mi rc r daps
les tissus riches eta. p.rot6i es, les PFASs se retrouvent, A l"66-lle zr ondiale,
days le s rum hurn i. et ds s la fauna, principaleme t les asides c rboxy-
liques perfluords (PFCA.s de 7 A 14 carbones) et: les aCi.des sulfoniq es per-
lluor6s (pl'S� s de d A q resrbones) pass dant use longue drains carbon6ee En.
raisort de Phiqui6tude grandissante suscit6e parr le ss propridtds dangereuses,
phi.sieurs mesures rd leme taires ainsi que l'dlimi ation volontaire par les
principaux product urs ont dtd dd6cid.6es depuis le ddbut des a 6es 2000, o
o.ri ntant, entre csu.tres, la production viers d'a tres produits de remplac enient
ll.uor6s. watts these explore Pe position hu aine aux. PFASs A longue churl e
c arbon6e et A 1. urs produits do remplaceme t en utilisant dif ere t s mdthodes
de moddli.sation. et vise A: 1) associer d fa o e l ustive la production indccs-
trl llf. asson et actuell.e, d la. concentration. des . FA s dais le sand; hurn i ; et
6valu.er les p.mpri6t6s potentie11C ent dan eraus s des produits c;himiques
floor s re plagant les PF Ss sous r glementation., au sujet d sq elles les in-
fomiation.s derneur nt trios li it&so fans I Article t, les expositions quoti-
diennes A Pacide peg uorooctan stAfo iqu.e FOS), A Pacide peril uoroca.r-
b x li.que (PFOA) et A l'acide erfl.uorohex,- ns-ulfo c)il.iq (PFif ) subies
pr6c demurent par les populations australi. nne et tats-unienne cent W sti-
m6es A partir de donn6es aimu lles sur la concentration d.a s lc sang. Les r6-
sultats indiqlent que les nivea€ x d'e position au PFOS et PFOA ainsi que les
to dances to por lles soot relstivem nt shnilaires darts les deux r6gi ns do-
aphi.ques, sugg6rant une exposition hlstorique l.c�baleme t commune, pro-
bablernent domin6e par l'erposition. aux produits de consommation. Le mo-
d.dle n'a pas pu titre appliqu au Pp`H-xS. 1. ans l� rticle H, is contribution de
l'e position— indir c;t (10e4 absorption de, prod �pxrcars s�irept�er l ur
in6tabolisnic en. PFCAs ou PFSAs) par rapport � Po position direc;tc: a W va-
lu6e sur un grortpe de technicie s fait urs do slds expos6s anpFOA et A I'm
do ses pr6curseurs daps le Cadre de leur travail.. Jusgq'A. 45% de is concentm-
tion de PFOA mc.s .rde daps le sang a. pu 8tre, attribude A Fexposit:ion indirect .
bans IArficle M, les propridtds physicochimiques des produits de, rem plai ce-
ment fluore's ainsi que lour persistmce et leer propensi.on A titre tra sport6s sur
del ngu s distances ont Ltd estirn6es d F id.e do diffdre is moM s inforr a-
tiquesa Les r6sultats incliquent que les produits d.e remplacer ent, fhior6s Soot
3
DEQ-CFW 00079694

probablenaeat semblables A leers ])r6,d.&zsse-Lir.s, en tern es de persistatice,cue
compoitement dans 1'e-avironnement et do propri&,ds physicochi.iniques. Fina-
lement, I'Article IV compare le potentiel tf-)xiqjie de PFOS, de PFOA et do
leers renTlacements en fonction de la dose exteme et inteme� Lorsque Pana-
lyse so base sur la dose adimnistr6o, les produits de remplacements Ont. un
potentiel toxiclue nloins Ocv6 clue lours pr6d6cesse-urs. Cependant,lees poten-
tiel toxique s6galise lorsque P&aluabon est. basc'e surla concentration dans
le tissu cible. Cette these d6nontre quo les in.od&les.l)hi=icocin&,tiq-ces sont
des outils off caces pour Eta blir exhaustivcment un lien Conne e.ntre la Con-
centiation de PFASs dais le sang huma in. avec leur niveau d'expositioll, De
plus., les 6wdes sur les produits de remplacemetitfluorris S'accordent sur ]a
n6cessit6 de fournir rapider.nent plas ffinformations et do donn6es sur les
n.sques potentials do cues produits 6mergents.
M
DEQ-CFW-00079695

Prrrd.ucidaaa desde la ddc;ada. de 1950, las s .sta c;ias per- e poli.fluoroa:l lrilo
(PFAEs) soy c;o prrestos parsisterrtes, hioacuinuladvos y Oxic os que sou u im
cups, on. el. medio ambiente. Al sar prat in6filicc5 coy t radenc:ia. a repartarso a
tq l.dos ricos arr proteinars, PFA s so hatr enecyntrado, on el suero, huni.aw y en
la fararra era todo 61 mundo, con un predorninio do a cidc, parfluoroallryl c:arho-
.f de c,adena l.arpa (.PFCAs corn Qs ha.sta CI,4) y aic; dos pert`l oroalkyl sill-
fdrricos (PFSAs con C5 pasta C-9). Debidc, a la preocupaci6n creciarrte por tars
propiedades noc.iva.s de esters cornponentes, desde prirrc:ipios d la d c;a.da del
2000, tarrto la rrorrrrativa. ad.optadar oticialrrren.te. corrraa las medidas voluntarlas
aplicadas por parte de la i dar.striar hair€ dosplaaado la prod c idrr hac a crtras
arlt rrrativ s .31aoradaso :Esta tesis explora la exp sici& humaraa a los PFASS
de Cade a lar a y sirs altarrrati.vas rrtilizando difererrtes rzrdtodos de modeliza-
ci6n y bene c.omo ohjetivo de l.) vi solar i t gralmente, la pr€rdarc ci€ n. irrdusm
trial pa.sa.d.a. y actual con el nivel d P:PASs, en el cu.eipo hu ano y 2) e valuar
las p tarrciales prapi dads peligrosas do las altarrrativas flrroradas reerripla-
zarado los PFA,Ss'bajo r l laci6n, cuya in.forr..ac: drr es rally lim ta.da. E.1. el
Axticalo I., se reconstiuyeron la, exposicidn d arla hist€sri.ca al dcido per uo-
roo to osaalffii ion (ppt.IS), al kick, p rfluorcrcanco:�illc;c, (PpOA) y al kido
peal-u.orohexanoc-,ixlf'Oni.co (.PF.l:l ) en Austraha y era leis Estados U dcos a.
partir de dat s de Carte transversal. Los r sulta.d.os iradic;arr que los stirs h€rm
manos experimentuon rriv les similares do exposicio'n al PFOS y .l FOA. err
arzrhas regiones, lra clue sugiere una exposkidxa histdrica cornfin posihlera. ente
dominada por el co tacto con productos do consra o..El modelo no prado arjras-
tarrse a las c one entrac16n ,s de P I-IxE en el suero, l n el. Ard'eulo .I. , se evarhO
la ccrrrtrihrrd6n. do la ekposi.cida i directa. (i.e. metabolismo de los precursores
en leis PFCAs y FSA.$) tren.te a la e posi ion dire to era air grupo de sp ciam
l.istas err tratarmientos tiara ceras a Leas esquis de altaa. Corrapetic i6n expuestos por
sir profosidrr al PFOA y a tinier de sus precursoresa :pasta im 45% de la Ccaa cen-
trara.drr de PFOA medida on el suero fae atrihrzida a la e posic,idrr indireata.
Err el r°ticul ..111, se predijero las propiedades fisicoql4micas, la. persi.se -
cia y el tra .sporte de largo alc;anc e de vaariaas alt rrr.ati as fluorad.as rrtilizando
diferentes metodos in Wico. Los resraltardos sugieren cluo las alto rrrativaas firrcr-
radas sort prohahlc rr: ente shnilares a sus predec woos, err tdrrrrinos do su. per-
sist lieu, transports de largo alcance y propiedades fisicoq imicaso Pr �1-
thno, el !fir ticrrla IV c ompara la pat ncia trl ica de PFOS, Pls O. . y sirs alter-
rrativa.s err fund6n do la dosls externa e i terrra, unque las al.temativas soli
DEQ-CFW 00079696

rr enos potentes q c sus predcccsores al consider r lay d sis wjhninistr da, sc
clven sin.i la -r.nentc potentes cuando la € valuacl6n se brie en los nivel.cs
btenidos erg el tcjidc objeto do es udio. Esta tcsis den-tuesti que los rr odclos
farrnacccin6ticcs srarr lrcrrs:micntas cficaccs pa$:ra rccon.cctar exhaustivamcntc
el nivel do Pl: AS,, en cl cucil?c hur ano con la cx osici6n a pr ductos qulrrii-
cos eliminados y regula.dcsr Mis import me a ftn, los cstudics sobre ]as altcr-
nativas fluoradas plantean ]a -neccsialaal do proveer mds €iiform.acidrx y datos
s brc el peligro potcrxcial do csics productos em r entes.
0
DEQ-CFW 00079697

Paper : Historical human exposure tcrper, croaAyl acids in the 1,51itcd
States andAustralia reconstr ctt<d`f rcr. biorrrcrtitcrirag data us -
in,, `Ise,) trTcrtiora1 be7scdIa12ar �rcokirtetic rraodeffirt . Grais, M. L,
Vesta rc ., R., MacLeod, eod, M., Mueller, J. F., Coush s, L `I Man -
script, submitted.
Paper H.- Contribution of direct and indirect expom.ir°c to human aser uni
concentrations Of perf'lueNN ocfanoic acid in an occupationally
ewposed grrrga of sk.i waxers. Goners, A L. Vestergrcra, K,
Nilsson, II., Cousins, Ie T. Divircr rr entaI Science & 'ecl nol--
o , l £�, 1 , 11 -7046, Reproduced. with perrral.ssion
from American Chan cal Society.
Paper .M.- modeling assessment l'the p,lysicochemic& properties and
envirortmentalfaate qfe"wrging and novel per°-ca `po4afla.aoro al-
1 substarxes. G r is, M. I., Want;, Z., ched-roger, M., & Cous-
in s, I, ` .a Science oj'the T'crta.f Envircrrtment, 2015, 505, 9 81-991.
Reproduced with permission. from Elsevier.
PaperIV Comparing thepotency in Fir°o oj'.PF,4 " alternatives and their
predecessors, t"laarnis, M. I., Vestergren., R-, .Borg, .D., Cousins,
s,
L To Tian script, not yet submitted.
Statement of contribution
I parametrized. the models axrd perfcrr. cd. all simulations iu paper 1., 11 and IV.
1 carried out the uncertainty analyses vv-ith the help of M. MacLeod in. Paper I
and .H. I generated. the �physicodae n cal. properties together with Z. Wang and
,performed the environmental fate simulations in Paper HL I developed the
st ly design. together with L Cousins and R. Vesta ;ren for Raper II and with.
R~ Vest r re -for Paper INT. haterpretardons of the results were made together
with the co -anthers for all four papers. I took the lead role in writing the four
rain scripts,
DEQ-CFW 00079698

I Introduction
I - I Background
Pv,r- and polyfluomilkyl subst.a.11ex, s (PFASs) re -present a large fwni [v of o r-
gM.1.1,C compounds o-vera-whiug di ffe rentappi ications f hat ha -en use ve ty- d sinc-
the, 193T's by industry and con,-wnefs. PFAS.V moletul. � su t U v C C'mi IT- st -U-C
nedcally describeda-, 'ti (or muldole ch "' s) wh re. I hydr,
ail aliphatic chal ffln C . al
gene havt bexii replaced by, fluorif"Ic (Le, perm) or paA!v replaced (ix, poll�)
such a �vqY that they compWri at Jewst one perfluoro- alkyj nioiin,: "Me
aliphatic dMis can be Wini nated lky 1-unotiorial groups that may knipart acidic
properfics tothe molecu.1c, Thcse AS that are red zorhated mid have an
acid fitnctionality aN- referrW to as perfluo--rod k%,1,aci4s (PFAAs), The most
=11-mudied PFAA subgro-aps are tile" parfluoroWkyl carboxylic acids
(PFCAsl mid parfluoroaalkyl suff'onlicacids (PFSAs), chavicterized by aarbox-
alkvt chnnut tongfins- An example of polyfluoreal kyl substances are fluorotc-
loaxx alcohols (1701t).. diffbringT from., PFAAs by their perfluannated cMin
ten.-n-Inated with two rwhylenes -gmd amailcohol moiety.,
PFAS
X,
per- (PFAAs) poly--
H!
F-C- -X F-� -
3..
F F F H
PFCAs PFSA5 FMH-s
c F —ca H -C F-1 F-�
FT,
F F F F F l!1
-Y�-) andsome � #Vk"s qf their (PFTAs, PESAS andlfilfvrow-
lomer okohoA (17011 .
-S
DEQ-CFW-00079699

Because the fluorine -carbon bevel is extren. rely stable and hardly polarizable,
PF,kAs are highly resistant to degradation ender even. extreme laboratory con-
ditions (e.g. high tern eratar , and they display lower surface tensions corn -
pared to their non-fhrorizrated analogues.' Due to these unique. physico-c.hera-
ical properties, PFs have been. wsed in. both i cl stfial and commercial a -
plicatiorr.s. Examples include surface treatment of textile, carpet, and food.
packagirr. , .fire-fi hting foams, cookware but also as processing aid in fluor-
opolymer manufacture, as wrist suppressants for rnet l plating and in thepro-
duction of semi-conductorso1 The extensive use .for € ver 5 decades co-uple
with the persistent nature of the perflaorinated moieties has resulted. in the
accimmlation. of PFASs in the environment and distribution to remote regions
far away frorrr emitting sources.' Despite that organof u.6rine compounds. were
detected already is human serum in the late 605s,' the first co p road -specific
analysis of PFAAs in. haaran serum occurred only in 2001, thanks to refir:red
- ass spectrometry rrr�t}r.crd�,¢b Since then,, PF.A s, more specifically erf7.uc�-
rooctane sulfonic acid (PFO ), perf7uerooctanoic; acid (PFOA) and. longer
chair-. P.FC s and PFS s, have been. globally measured in. wildlife- and hag
mans,1 highlighting their hicaccrrr alation potential." Concerns over the
passible hazard of these substances resulted in a joint effort by industry and
regulatory authorities to gradually phase out lcra _chain.PFC s (`—,C?), Pf _As
-..Q) andtheir precursors, As a resat, 3M, the - ajar PFOS and erfluorooc-
tarr.esulfo yl fluoride (POSI `)-derivative manufacturer, voluntarily discontin-
ued the production and use of periluorchexyl,-octaayl and -decyl chemistry -
in 2002." In 2006, eight major inarru.facturers made an a reeraent with the US
Environ-i e tal..ProtectioAgency (US EPA) to remove PFOA and lore -chain
pF As fermi their products and. to elimimr:t:e point -scarce emissions ley. 2015, "
In 2009, PFOS was listed in Annex B (i.e. restricted use) of the toc.lchrrlrrr.
Convention on Persistent Oggarric Pollutants.11 Additionally, PFO , C9, CIO,
t.:11-C1 PFCAC, and their sodium and armor urn salts were included is the
Candidate list of Substances of Very High Concern flrr Authorisation arrrder
the European Chem Gals Regulation on the 'Re istration. Evaluation, Author-
ization, and Restriction of Chemicals (-REA.t.;H),rs
This shift is production. initiated in the begins-iirrg of the 21." century resulted
in. the replacement of the legacy P"FA-As and. their l reclirsors with shorter -
chain. h.oniol€ goes. The rationale behind these substitution- s is arcrtivated by
the lo'%,er bicra.ccur lation 1)oterrtial and levier toxicity of shorter -chain
PFC s and PFS s," despite a similar tendency for environmental. persis-
tence. Other .fluorinated substances 0rerea..f`tcr° referred to as "aherrrad es")
have been recently identified as being used as surrogates for PFO.A. and.
PFOS.17
9
DEQ-CFW 00079700

1.2 The role of human exposure hi the risk assessment of
chemicals
A.chieving performant products and cost-effective marLufacturing processes
are two important objectives of the chemical industry in terins of chemical
design. Nevertheless, the chemical properties displaying un.iclue performance
capabilities can also be potentially hazardous and pose a risky for the environ-
ment, humans and animals, if exposure occurs, In term. s of human health, the
ri.sk-, defined. as the probability of a hazardous cher.nical to cause harna, is char-
acterized. by 1.) the potential toxicity of the chemical at a given concentration
and 2) th.e magnitude of exposure experienced by the individual. Under
REACH, as hazard assessment of industrial. chernicals based on their persis-
tence (P), bioaccumulation potential (B) and toxicity ("F) is required." How-
ever, since hazardous properties are inherent to the -molecular structure, ad-
dressing the potential risk is usually done by reducing tb.e exposure through
phase outs or mitigation actions. In this respect, comprehensivelylinks ng the
chemical emissions and the human body burden is of paramount importance
for introducing effective, preventive and mitigative steps. Assessing the bu-
man. exposure should therefore integrate both the external (i.e. levels in the
envirom-nemal media) and internal (i,e, levels in the human body) exposure.
The external. exposure aims to identify and quantify the sources and potential
exposure pathways which., in the case of industrial chemicals, can be grouped
in two categories, namely, the contact to consurner products containing the
chernical or the contact to contaminated environmental media. The internal
exposure is deaed as the amount of chemical in the burnan body, from its
total body burden to the concentration in target tissues, resulting from th.e ex-
te.mal exposure and subsequent intake of a substance.
1.3 Knowledge gaps in the state -of -the -science
Since their identificatiori in human serum in 2001, the subsequent intense sci-
entific attention on. PFASs, especially long -chain PFCAs and PFSAs, has shed
much ligbt on the origins of hur-yum. exposure. Nevertli.cless, the numerousfla-
orocliernicals produced for various applicario.ns,' the historical and ongoing
changes in production," 11 the existence of n.ndtiple potential exposure path-
ways" combined. with the scarcity of infbrmation provided. by industry"
makes exposure assessment of PFASs a challenging task. The following sub-
sections introduce the state of the science and .Imo pled; e gaps in the field of
human exposure to legacy PFA-As and their alternatives when this doctoral
thesis work was initiated.
10
DEQ-CFW-00079701

L11 Linkingprodnedon changeswith time trends i s uin ha
Since the, bi,jgnningg of tho XXII, centun,7, a jecline is the Concent rations
PFOS =- & to a lesser extent, PFOA M semm �as beev monitored .m ffemnt
ri,d stnafigio s :h as Europe. Australia, �poi and USA,"WI
these changes in senim lovels i= thoughthoughi to be correlaled to the sudden shift
of -PFAAm—d ov, there is still itolknowledge about thelink tx.-wce is -
Currently, die; ibelieved o O h doming exposure pathway to n
° .'" �wcw �r i i i nowu hoiv is relative im tnce �r �� r g
a wkys have, chaikqed as a consequence of the phase -out. Diet.-iry intakes
estimated from uinvrapped food, € m v k-?cn relauvely constant betwecn.
-M49-9 and . ;" FnahemioLm,tho tempora � d i aan bion-ton]-toning
data.aw, diffex fhx.n these u wildlife nple- %%-,hich do not shoe a clear
dcclhi over the wine time oriid.A' m the- obsemations,
Vestergron and Cousins R hypothesised that the. m ufa-atirinphase-
out in 0 _002 l ed d rasti c de crease J. n - ixto copsumer
dus."s this historical source of exposure was induced., dieconcentra-
tion
in scram IVz 111d be exp wed to coriverge with the curie d mi'lansource
sentedin Figure:: µ
' @@ �y �v��,�.t Xgr{�p }dyp �{�ik �^y� g ,�}� s'y �a R G y y�q y Sg9'y
K:,v-L:.� .:bare savr ej :�)�., -his Y"r4i.4�€5� .is > d 3°�T@ Y'�§,..�S�JY �`�"}'�''."o.�,�i Ord
I. this 3,To 'S b"IS Pfoven to be difficult u the- lael-, of regimial y
amd na - r-.l1y well -resolved data for KAM human s mm mid in. all
[ r � 3 .ru, media- Atthotime when this
DEQ-CFW 00079702

the origin. of PFOS and PFOA levels in serum prior to the phase out and their
exceptionally rapid decline since the early 2000's was still. poorly understood..
Some fluorochemicals, such as perfluoroalkylsulfonarDidoalcohols and
fluorotelorner alcohols, have been. found to undergo abiotic and biotic degrad-
tion into PFOS and PFOA."," This has led to a discussion of the presence of
PFOS and PFOA in the environment in terms of the relative contribution of
indirect (i.e. degraded precursors) versus direct emission sourceS.11, 16 A re-
lated debate has been ongoing concerning;thebody burden. of PFOS and
PFOA. Various species including rat, mice and trout have been found to me-
tabolise FT Hs and polyfluoroalkyl phosphoric acids into PFOA, as well as
perfluorooctanesulfonamide into PFOS, as the stable end-metaboliteS. 3711 Jn
vitro experiments also demonstrated the ability of human. microsomes and
hepatocytes to metabolise precursors.41,41,44 These findi n-gs suggest that the bi
otransformation of precursors subsequent to their absorption (i.e. "indirect"
exposure) could contribute to the total body burden of PFOS and PFOA in
humans. The relative importance of indirect and direct exposure has however
been widely debated in the scientific literature.","' Several total intake stud-
ies using concentrations in exposure media as a point of departure (i.e. bottom. -
up approach) combined with biotransformation factors estimated the contri-
bution of indirect exposure- Values ranged between <1 and 27% for PFOA
and 2-34% for PFOS, for low and intermediate exposure scenarios and up to
80% for PFOA and 55% for PFOS for high exposure scenario. 29,49,49 The dif-
ficulty in quantifying the indirect pathway for humans is partly due to the scar-
city of data on precursor concentration in exposure media, the interspecies
variability in metabolism rates (which increases uncertainty from extiapola-
tion to humans), the lack of knowledge on the pharinacoki netics of precursors
and, finally, the multiple exposure pathways that may contribute to the internal
exposure. Precursors can be found in various consumer products such as food
packaging, treated carpet and outdoor equipment '41., 11,11 and, as a consequence,
human exposure can. potentially occur. When this thesis work was initiated,
there was a need to quantify accurately the contribution of indirect exposure
in. order to, if non -negligible, address this ongoing source of legacy PFAAs.
By studying a highly exposed population with a well characterized external
exposure it would be possible to better constrain the metabolism yield of pre-
cursor in. hurnan.
1-2
DEQ-CFW-00079703

.3.3 Arc, fluorinated alternatives an i ltrovemertt on eg c�
F . .
!-historical e aa:xaples of chemical.substitution with structurally similar products
have der no strated that, by keeping, the similar desired functi o alities, the haz-
ardous and adverse properties are often taaairrtahied, leach..g to a " lockwiC
problem in the substitution processes' Because in.daastry- enerated data are of-
ten classified as "confidential business information", vital. inforta:ration cony
cercaing the identity- of fluorinated. alternatives, their properties, their tokico-
.logical profile, their production. and their emissions are oft n unavailable in.
tlae public, domain, ",hich hinders risk assessr enL 'I'lxoug their physicochem-
ical properties and production volur es are unknown., Wang et aio (2013) iden-
tified ed more than 20 novel and emerging fluorinated alternatives, aniotag which.,
functi.oraalizedperflaoropolyethers,." Despite the claim o.f'a lowerbioaccun.iu-
lati.on potential for many fluorinated alternatives, screening of 2930 chemicals
highlighted the general tendency of poly- and perflr orinated. structures to he
I'I T." Perfluoroalkyl. moieties are not expected to degrade in the environ-
ment, Furthermore, according to several toxicity steadies on rats, fluorinated
alternatives have a lower topic; potency-, al ')ara�.r�eter that allows the conipari-
sorr of substances according to their ability in triggering a specific effect, corn-
pared to their predecessors.5'-55 However, the potency rare is usually based
on the administered dose (he, the creed of a lower dose to trigger a, toxic effect
indicates a higher potency), which integrates the toxicoki et3cs of the sub-
stance within the toxic response. The affinity of P Ss to proteins,-51 which
appeared to increase with ehalrr-length,51s11 plays an important role, in. their
distribution and elimination. It is therefore not clear to -hart extent of the tox-
icity of short -chain alternatives is confounded. by their disir but on and .East
elir:nitaation. kinetics."'
Twee to this lack of transparency- and the limited knowledge about the environm
inert aed the human health .risk, the scientific community, through the Hel-
sin or and Madrid statement, brought attention to the potential issue.,-, Beaked
to the extensive use of fluorinated cheinicafs.6', Similar to long -chain PFCA,.s
and PFS s in tlae past, some of these alternatives have recently been detected
in American, Gennan and t::"l:rinese rivers, leading to a potential exposure
source. for hu manse1I-' As a result, it is argent to generate data and. properly
analyse theca to facilitate the assessment of the euvironrtt.ental fate and tonicity
of these alternatives and to evaluate if the hazaard has been. reduced compared
to the legacy PIFASs that they replace.
a . Objectives
This thesis is a model -based exposure assessment of PFASs that aims to con-
nect coinprehensivel.y the industrial production to the human body burden. of
13
DEQ-CFW 00079704

legacy.PFAAs. as well as to fill current knowledge gaps in the human expo-
sure of those legacy substancesand their replacements.
The following questions on human e.,<pos-iffe to PFA.Ss were addressed in four
studios, which directly reflect the knowledge gaps in the state of the science
outlined in section 13 -.
How did the li-anian exposure to legacy PFA-As globally and histod-
cally evolve? (Paper 1)
2) What is the relative contribution of direct and indirect (j.e. metabo-
lized precursors) exposure to the human body burden. for PFAAs?
(Paper.11)
3) Are the fluorinated alternatives less hazardous than their predeces-
sors? (Paper UJ)
4) Are PFOS and PFOA replacenients less potent than their predeces-
sors? (Paper IV)
The thesis explores various modelling methods, including quant urn-chenfistry
based models, linear free energy -based models mid pbarmacok-inctic (PK)
models to investigate the different questions. The speci.f.-Ic objectives of each
paper are listed below.
The main objective of this study was to recreate the historical intake of legacy.
PFAAs (PFOS, PFOA and. PFI-LxS) in the American and Australian population
by fitting a population PK model to cross -sectional. bionionitorhig data. The
secondary objectives were to estimate; their elirnination half-lives and investi-
gate the contribution of menstrwation as an additioDal elimination pathway.for
women,
Paper H
This paper aimed to investigate the contribution of direct (i.e. exposure to
PFOA) and indirect (i.e. exposure to 8',2 fluorotelomer alcohol (8-2 F"FOH)
-further metabolised fi-ito PFOA) exposme in occupationally exposed ski wax-
ers. The met6olisin yield, as a measure of the amount of PFOA originating
from. 8:2 FTOH, was. estimated using a dynamic otie-conipaitment PIC model.
The eliniination half-life of PFOA. was also estimated.
Paper -111
The primary obJective of this project was to predict the physicochemical prop-
erties of 16 emergingar.id novel fluorinated alternatives using in-sihro tools.
In. a second step, the likely environmental fate, characterised by the overall
14.
DEQ-CFW-00079705

persistence and. lor€ _ratx e transport potential, was predicted. uslra g a .l.nult media environmental fate modeL
—
Paper IV
The priirnar obJectiv Ways to assess the potex�.��r �f le acy PF, s ,� . the'
replacement;, by comparing dose -response curves from scab -chronic oral tox-
icity studies in male rats with the (loses expressed as 1) administered dose, 2
serum concentrations and 3) liver concentrations, A dynamic one -compart-
ment PK model was -eased to convert administered doses into the co Tmspondin
concentrations in sermn and measured liver-sermn concentration ratios were
used to convert the. e&drRtated concentration fi-I serum. fi to concentrations ixi
liver.
15
DEQ-CFW 00079706

2.1 Predicting physicochemical properties of organic
contaminants
Determinhi.g the physicochemical properties of contaminants is essential as a
preliminary step toward the identification of as potential hazard. In terms of
environmental fate, physicochemical properties control the partitioning be-
havio-ur mid thus the transport and. the degradation of the chemical once it is
released in the environment In this respect, tb.ey are often. used as input pa-
rameters in envirorunental fate models, In. addition, comparing chemicals on
the basis of their physicochemical properties allow the identification of poten-
tial. structural and Ruictional. similarities.This becomes crucial, when assessing
the reduction Of inherent hazard between legacy industrial contaminants and
their replacements. Because experimental data are often not available, espe-
cially far.noveland emerging contaminants, the physicochernical properties
have to be predicted using in sifico tools, Several quantitative or qualitative
structure -based predictive methods exist gush as quantitative structure—prop-
erty/activit-
y relationships (QSPR.s/QSARs),, linear ftee energy -relationships
(LFERs) as q " uantum-chemistry- based models. Selecting the pro. per method
depends on its applicability to the chemical considered butalso on the availa-
bility of predictive tools.
In Paper M., two predictive models were used to estirnate the physicocherni-
cal properties of legacy PFASs and their replacements. First, the quantum-
chel-nistty based model., COS MOther m, was used to estimate the air —water,
octanol—water, and octan.ol—air partition coefficients (KAw, Kow and Kc�A),
which. determine the preferential distribution of the chemical between two dif-
ferent phases, Briefly, energetically favoured confornaIels were predicted with
COSMOconf.ffom the chemical stracture of interest (Figure 3).Their surface
charge densides were then converted into chemical potential in different bulk
phases (i.e. octanol., water, gas) which were further -used to calculate the K.Aw,
K.)w and Karp of each conformer. The final coefficient value corresponded to
the weighted average of all con.flormers, based on. their .probability of occur-
rence. Second, the, LFER-based model SPARC, was -used to I iredict the acid
dissociation constant (pK,,) of PFOS, PFOA and the acidic fluorinated alter-
natives.
16
DEQ-CFW-00079707

F F
................ ................
Rgwe3; BramIde qfcM J,'] 1,7011pre-
dicled by C_ WSWOcm,�fmml used fo prt-uho air --water, and ac-
mmo[--�-fir Pcofflon coq'(fidenA (Xj m KmyRid Kad in CO3SM01herm- 1-he recl
(kmuI vellow zmd blue regions mdica� h&? cmd.1cm, ekwlron &mmir s rvspec�
Y
2.2 Environmental fate modelling
'nw- en-viromment is a complex dy"Hmnic system whem- contaminants can ua-
dergo diffi-isive and advective trmisport and transft-namions deponding on,
their intrinsic propertiand, 'thc physical and chemical constmints found in
the environment, Multimedia anvimmmental, nio dels givo the po y to t -,
I . - ssibili
simulate. thQ enviroaments) dmplif d, 6toofagivenehemica-linas - ne. reprosen-
tationof the, physsical world, in this respect, Me OECD 0%;,,erall Pers-istenco and
UngNRangc Transport potential Screening Too]." (hereafter referred as Ihe
OECD Tool') was used In Paper Ill to evaluatc the ctSriiueaad tote of
PFOS., PFOA, &2 FT0H and 16 fluorinated aftemalives, Thm OECD Took is
dable f fugacity-based muftimcdilza. num�s bahance lma-vvorld model avm br -free
on-line.
Figure 4: Scheme �!f the 01-_M imil, a intilameclia mamv hatancemod el (triken
1'rom J-Aqgmanr� e! aL (20, The air su'�Oco conmer IV Ith sail cuml seawater
-V mclit-ate'd in Ye emd the dcj�Ih qf'ewh' ccMIXWf Melly it? MePles_20.
of three bulk conipartmemm. mr, soil and seawmac, , inter-
connected with bidirectional diffusive and unidirectional advective fluxes, and
considers dogradation andadvectiara m; output fluxes (Figure 4 1 Me OECD
17
DEQ-CFW-00079708

Tool predicts the overall environmental persistence under steady-state condi-
tions (Pov, in days), which corresponds to the overall lifetime of the substance
Under consideration in the unit world, and two long range transport potential
indicators, namely, the characteristic travel distance (CTD, in kni) and the
transfer efficiency (TE, Mi CTD represents the distance at which the chem-
ical concentration at the source has dropped. by 63% and TE is the targeted.
transfer of the chemical from the air compartment into the soil or water com-
partment.
The input parameters required. were KAir and Kow, estimated with COS-
MOtherm (see section 2. 1), and the degradation half-life (ti/2, in hours) in air,
water and soil. The degradation parameters were estimated -using the EPISuite
package applying QSPR/QSAR methods. Because the deprotonated form of
acidic PFASs influences their environmental fate, KAw and Kow, which could
only be predicted for the neutral forms, were adapted to represent the air —wa-
ter and octanol—water distribution ratios of the corresponding anion. This ma-
nipulation could not be carried out for the estimated degradation half-lives.'
PK models describe in a relatively simple way complex physiological pro-
cesses that control the absorption, distribution, metabolism and excretion. of
exogenous chemicals in. an. organism. Initially developed to characterize the
fate of therapeutic drugs in animals and humans, this mathematical approach,
when combined with bionionitoring data, has been successfally used in the
exposure assessment of organic contaminants."" The type of bionionitoring
data, namely cross -sectional (i.e. various individuals are monitored at one
point in time) and longitudinal (i.e, the same individual is monitored over
time) determine the nature of information that can be assessed. With cross -
sectional data from various points in time, the past and contemporary intake
trends of PFASs within a population can be back -calculated by a PIC model,
that is, in this case, referred as "population -based PK model". In contrast, Ion---
gitudinal data give a better insight on the physiological response to a specific
exposure over time.
Two main categories of PK model exists: the one -compartment models, where
the organism. is described as one central, reservoir, and the multi -compartment
models (known as physiologically -based (PB)PK models), where the central
compartment is connected to one or several peripheral. compartments repre-
senting organs. Despite being more descriptive than one -compartment PK
models, PBPK models are more complex and require a proportionally larger
number of kinetic input parameters, which, if they are not well constrained,
increase the uncertainty of the predicted results. For Paper 1, H and IV, a
parsimonious one -compartment PK model. was favoured and its applicability
within the objectives of the papers was justified by, the following reasons:
DEQ-CFW-00079709

4, Qumtilafive infonamation on. the. inn is belhaviour -c- exch'ang ge
lit u arg s)o
sca.me, (Paper 1, 11 and XV),
2. ",ere too, low ro cxcocd,thc throshold ofsata-
rable Pix)cosg, (Pa. p er. I
3. lklultjm comparolient models available for PFASs are not able, to dy-
nanucally sinaulate- teas uptake- in .if Yunt fissuc-sas 1wyuw kii-stri-
bution canstults rather thwn: uptake raft'S."I
6-mue d1stribi uk-M was not nee -. a-n-since unly bloodlse-
rmm sampics, vcm- availabk-- for modal ov�duafion and fhrlug� pro-
ccs% S. (papel- 1. M-, 1 11)
'111C eltnii'llatiorl, balf-lik used to a plite the disappeanmer, of th��
Chemical In SWUM OVert = IS represcat have oaf tha, vpm-Al cliniina-
tion processus (Le, uninan!.. bile). md, dier fbm-Aces not raqw-'re a&
d1tional desai ffire clUninatim proce-s-Sus- tn thu. MGdGL (Paper 1, 11
and INFO
6.. Evaluate tho rnodeE -Simultmaeously with ooncentm-dons M -,;Cpdnl
m�ads aflo%cd t1k idanfifilcation of putontial axcecdc-d saturation
thre-sholds for ��acfi'PFAS- (Paper IV)
IFTIfur e 3 prcs�nt-,,, Lhe ganera-I conctpt of the unc-compannient PK model
adapted Bar ASs, The model preffict,S the conceranifian. in sculm as a funcm
Lion of invake, Olimination and volume of distribution, wbich is a proponibn�
--fl f - i, , n tbe body -mid
afin= eter bew cen the total m-nou f a a given chem Cal i
PU alffl-
its concekAm-non i . :n -seams, Mic:scruna is defined agflhe cumpaaftnent
since,FIRim,'a a. high affinity with blood proteins, such as ailbunain antund
to accumu Laic in suram-77
Intake Centra �. compa rtment SUMInatoo
n
1p,
F re ! Guru, schemaue qf die ane-conqpartmew FK nxdel used ir, t"aper i It
-I- -.4,1"On'ding an the ps"4h.-w w, h-v an -
and 1V Ifte n�odel �mes adapred in ealchpape e
sffwlered; Paper Ifiocused on. Me general, bjeo'Wrouiuf infah, Paper rev se 11fi , . . -xi &e
cawribumon haake emd Paper H'fibm-�wd on fl, �c ing"ornal dh-ardnIUMI O�f
11FII&F,
19
DEQ-CFW-0007971 0

Following this model definition, the mass balance of an. individual exposed to
a specific PFAS can be, generally expressed as a first -order differential equa-
tion (Eq. 1):
dCserum — I(t)*La— C (t) * ke
eft Vd*.Bw serum
13
Where C,,r.(ng/ml) is the concentration of PFAS in serum, I (ng/day) is the
intake of PFASs, E,,, (dimensionless) is the absorption efficiency dependent on
the uptake route considered (i.e. oral, inhalation, dermal), Vd (mllkg) is the
volume of distribution., Blfl (kg) is the body weight of the individual and k'.
(1/day) is the elimination- rate calculated ftom the elimination half-life (i.e. k,
= ln(2)/ti/2). For the three studies, the equation was solved under dynamic con-
ditions to integrate in the predictions the frequency (Papers H and IV) and
change in magnitude (Papers I and H) of intake over time. Depending on the
objective of the study, the model as presented in Eq. 1 required further para-
metrization and assumptions to improve the accuracy of the output results. In
Paper 1, modelling the exposure in a population required the implementation
of age- and gender -dependent factors influencing the body burden. of PFASs,
such as the intake from breast feeding, mother -to -foetus chemical transfer and
elimination fi-orn growth dilution and menstruation. Paper H dealt with lon-
gitudinal data obtained from an occupational exposure study that provided de-
tailed quantitative information about the exposure. Therefore, The PK model
included the working hours, to characterize the extent of exposure, as won as
the inhalation and ingestion exposure of dust. Paper IV differed from the two
other studies as the model was applied to rats and required to predict accu-
rately the concentrations in rat serum- under sub -chronic exposure conditions.
In this respect, biphasic trends in serum, where the decline of concentration in
serum after dosing is first attributable to the distribution of the chemical into
peripherical tissues, and second, when steady state is reached, to elimi- -nation,
had to be considered in the parametrization of the model.
After parametrization, the models were fitted to the biomonitoring data to ob-
tain., for Paper 1, the reference adult daily intake and the elimination half-life,
and, for Paper H, the metabolism yield of 8:2 FTOH and the elimination half-
life. The least -square optimization method 71 was used. to minimize the sum of
squared residual weighted (SS-RW), with. the best estimate corresponding to
the simulation with the closest coefficient of determination (= 1-SS . to 1.
In contrast with the two other studies, in Paper IV the model predicted the
concentration in serum with the objective to estimate the internal exposure in
in vivo subchronic experiments. The predicted results were expressed as area
under the serum concentration curve (AUC.) calculated at the interval be-
tween two doses when steady-state was reached. In addition, the internal ex-
posure in liver was also calculated from liver:serum. concentration. ratios. Ta-
ble 1. summarizes the type of biomonitoring data and model used in the three
studies as well as the PFASs and outputs that were assessed.
20
DEQ-CFW-00079711

Table 1: Summmy of the modellhkg approach in Paper I, Hand IV
Paper -1
Paper Ii
Piper T
P.FAS's
PFOS I Pta IY6 d PF'OA
PFO 18,2 FTOH
C_,-Q, Pl-0CAs /Ge.n
Data
Cross -sectional
Longitudinal
Longitudinal
Model.
Dynamic one -co part-
Dynamic one -comma t-
Dynamic ore -compart-
ment population -based
went ply. € odel
meat P m€adel
PK model.
Output
Pitted. adult daily intakc
Fitted metabolism yield
Preffloted !'RUC,, In se -
Fitted. elimination half—
P`imd €:linaination half-
rum.
life
lily
A Sensitivity and. :ncerk mty analysis
The sensitivity analysis of the inodel identifies which input parameter has the
highest impa.c,t on the predicted results. The uncertainty analysis qua nt -hies the
wic rta ftity propagated in the output results by the error in the input parai e-
t rso Conducting both analyses systeinatically is encouraged for a better un-
derstanding of model limitations and for a more transparent communi atio
of the resultso" Several methods were used in this thesis° In Paper I , due to
the nature of the predictive total used and the lack of validation data, the un-
certainty
. of the predictions was qualitatively evaluated and discussed lased
the potential application. doinain of the tools on perfluorinated chemical strurm
taar sa In leper I aid IV, the sensitivity. and uncertainty atial sis was carried
out by applying the Monte arlo t othnd. Briefly
fi, the technique consists in
running nurtierous simulations based on input data that are randomly varied
along ac defined distrihution.1:. paper ..:, the first -order analytical sensitivity
and error propagation method proposed ley :lvlacLeod et al. (2002) was used to
calculate the margin of error of the fitted result-&"
21.
DEQ-CFW 00079712

3 Results w.id discussion
3.1 Past and cunwe exposure, to PFAAs
The American -,wd.ArLstrahan adult daily intakes for PFOS estimated in Paper
I peaked in. the 1980's in both regionsand. reached levels of 4.5 and 4,0 DgAg-
bw/day, resl3ectively. The intakes started to decrease in the second half of
1990's with a halving -time of 2.3 years for USA and 4.5 years for Australia.
For PFOA, -ffie, peak occurred later, in 1992 (3. ng/kg-bw/day) for Australia
and 1.995 (1.. 1 ng/k-g-bw/day) in USA and started to decline in 1995 71th a
halving time of 5.9 years for Australia and in. 2000with a halving time of 5o8
years for USA.. Even. thaug.1i the predictive power for PFOA in USA was
weaker conipared to the other simulations, the similar time -trends; observed in
both regions for PFOS and PF)A suggest a common historical exposure
source. Since levels in the environment are higher in the Northern comparcd
to the Southern hemisphere,11,11 the results converge towards an exposure
linked to consurnerproducts rath-er than environmental exposure, In addition,
the decline of the fitted daily intakes in. the 1-9907s before the phase out coin-
cides with the drastic decrease in, concentrations of several POS15-derivatives
aromid year 1.998 measured in food packaging materials." These results cor-
roborate the hypothesis of Vestergren and Cowshis (�009)" stating the histor-
ical existence of an exposure pathway dominated by consumer products (see
Figure 2), While the model was successfully applied to IOS and PFOA, the
i.iaodel could not be fitted to PFIRS concentrations in senu-ii of both the.A.�.-ner-
ican. and Australian population. The bit nion-itoring data of HEM suggest a.
potential age -dependent exposure pattern, with a higher intake for individuals
below 20 years old. Specific age -dependent exposure such as dust intake for
toddlers and kids was not considered in the model. Furthennore, exposure to
HIM appears to still be ongoing at a sinailar niagnitude to the pre- hase out
P
exposure conditions, even. though, like PFOA and PFOS, it was phased -out by
the 3M Company iin 2000-2002.
Since the phase out, emissions of precursors may have become more im-
portant, S2 Exposure to precarsors, and subsequent metabolism. (i.e. indirect ex-
posure) has been hypothesised as a, potential exposure, route for PFO.A. and
PFOS, but has never been investigated on. a hunian cohort .41.13 In paper H,
the metabolism yield of 8.2 FTOH to PFOA was estimated as a quan.-
titative measure of indirect exposure on six ski wax technicians highly ex-
22
DEQ-CFW-00079713

posed to, PFOA and &-2 FTOcould wly- be estin-mied on the hvo teclrm.
nict"ins NVAll lawv Imernal CcAlceamattom, since-, tho-Ir body_ burdeft was sct--tson-
pac alh, Urited by the ongaitig expasure., as apposed to the techruclans w-Ah
high intemal. con.wntin. noms, Illa model r suits comfinned that the expostim
to 9,2 FFOH hal an-Mcmmot al effuct on flic PFOA body burden and can-
tributed bv, tip to 45% to Che'total PFOA conoentm fimnt In serum (Figure 6,
shadcd areaThe values estimated ws 0,0:027 and 0,002&v.vera close To
e, how -
over, 12-field hi er than, the oncs obtained in in vitro assays on bult.la hepaw-
9b W
cytes mul mic
Y'_ - 0,002?
�4
2W. 210
IN .. ..........
&I 4�
qN, qo 4'�' v"'
Figare 6z Pmdsaed rfineN) and measuere l e.YPFOA in se-
rum qf6ccupaslon-1114, extxixedski war wchmimamv- Me �*avd and Solid fia o� h-Onate
!oPF0,A omw Wturexposure io bodtPFOA and
,K2 FT011, respecfiwl�� The 4-� qTxienf e�f dele�minaaon ck) corre4wids to pit?.
Fe.mdid inc-luding horh expawre w PFDA awl 8:2 Mr011- ( wu Paver M-
The indirect exposwe, mpedenced by these, technic-ians was extremely. bigh.a
witb concentrations of 8�2 FT -OH in 'r as high as 890 m I -xr)os-
aU . - 1. 1- --sim Fhese 0 tire
cotiditions are, noit -.rya istic f6r the wx ral popul ation. Rc sidtal U F76H can
W- pm -scat err consu mer prod ucts such w texti 1 es, carpets and lb m itu m- that :re
treated with fluofinawd si&-chaiD polisiners to pmividc oil and water repek
lency"z. 8:2 F170H a. rrtr rt rs of up to 1300 gglm-� wery dctcctedin Out-
door mcar' I I As a consequence of its hibAl Vapour Pressum .2 FTOH migm-les
from consumer products tolndoof air where it is ii.dialed by hmmans.S'7311% The
concentrations a.fS.2 FFOH. m aff of resin arena homs and offices wcm, 'on
'50 n - "-." "'Ibc highest ivcre averagge, .ew imid 3.3 qymn-". respccfivcly,4
found ill outdoor equipmem shops, With concentration in sir as h�� -as '2186
q7!j`4u:,. but werestill 3 orders of maguitude lower thati in, the ski �&,ax wlmi-
c
1 12 an's -,wwking Cojubiried wit h the estimatee id isswuh�g a. I -
houv'dky exposure, these thr e firm oor environmem would vielda concentra-
fion of PFOA hi scramof 0,004 (housc)� 0,02 (office) and 0- 16 (shop) nglim I
13
DEQ-CFW-00079714

at steady state. Considering the current PFOA levels in serum of the back-
ground population, that average 2 ng/ml (range 0.95-3.48 ng/ml),11 the contri.-
bution of indirect exposure, in the case of 8:2 FTO H-, is likely negligible. It
should be however noted that Y.,,,, has been extrapolated on two individuals
only, which does not provide a high level of confidence in the estimated value.
As a result of their long elimination half-lives, the body burden of bioaccumu-
lative chemicals such as PFAAs keeps a "memory' of the past exposure con-
ditions and displays a slower response to changes in the magnitude of expo-
sure compared to more readily -excreted contaminants. Paper I and. II provide
good examples to illustrate the impact of exposure dynamics on. the human
body burden of PFAAs. As mentioned in section 3. 1, the six ski wax techni-
cians displayed different PFOA levels and sensitivity to the ongoing exposure:
while the PFOA body burden of technicians with low concentrations was
building up over time, technicians with high concentrations were depurating.
Simulating the past and. future concentration time trends in serum of both tech-
nician groups helps to understand the general connection between body bur-
den and exposure (Figure 7). When a sudden shift in exposure occurs, the
concentration in serum needs to readjust to reach steady state with the new
exposure conditions. For individuals who experience a reduced exposure,
which could be illustrated by the use of protective equipment for ski wax tech-
nicians or by a phase -out event for the general population (Paperl), the con-
centration in serum decreases over time. In turn., for individuals for which the
exposure levels shift upwards, the concentration in serum increases. As shown
in Figure 7, if the exposure level is constant over a certain period of time, the
concentration in serum at steady state will be the same in, all technicians.
Therefore, the duration of exposure combined with higher past occupational
exposure conditions likely lead to the discrepancies in PFOA body burden.","
24
DEQ-CFW-00079715

0
F�gure 7: MfAel simidafions (hhes) hjywhefically illnslrafit�g! fhe reftipwal
Mcwges qfTFOA Inserum qf/burAW ivar iechiiiei Me S ,,"Nds repi-VS0111
the niewmeed daw by Nikwin ey al
3.3 Tlieelimi.natio-ulialf-lifeasadeierniiiiatitfactoi-(ifbodv
burden
The chmivation half-IM., defined ky the aNcrotion processes� has a ducrulin-
Ing role In the- balance bm.%ven body burdian and ex-poqwre-, 11is toxiccAjac-tic
pamin oter is usual ly ostimawd on. dechning -
tions in h-uman blood or g concenno
untie, For bicaccunialative chenficals such a.- PFAAS it is imporlawto dif-
fle-rentiate the estinuited "apparmt" fmm the 1ntrinsic" elimination half -life -
sic efimimitioxf half-4ife and. specific eflinination processes such as gro-w-th dl-
In Paper I =d 11, the ongoingexpasair e was considered duling the
resenflag fitthfS processes and results were ftlefore rep I g the intrinsic dimil -a-
t boil half , In OCC U pational Ily c Np o scd Swedish men as w, c 11 as the Ane 6 can
and Australian mate polyulation, the elimination half-life of PFOA vvas con-
sia-ently estimated bawceo 2, and 21,8 years, 'A He the PFHxS simalatioos,
weic Overall the fitted elimination half4if for PFOS was 3JR
and 4,9 yea m in the Americaii and Australian men —respectively (Paper 1,),
`This duscre-pancy betuvoen both regions iv ws au-nbuted to the rumbcr Df vears
after phasc-out covered by the datawhich vvas hiigherin the
Anierican biomonkoring s-tudy, These fitted climination half-lives an,, wiflhin
the range of valucs reported for himnans in Floivevc--rz other
species sm-h as, redent -eys and dogs 1�-av c much f-19—or OliaLl. ination rates, nionk
wl ife, counted in hours to days-2' ilie reab., th 011.11ination haV sorpt-Oft Y r
ganiQ xfion transporters in the kidnikys and exte*sive uplake from caterolle-
pritic circulation for PFOS and PFOA- we beheved to be more active Processes
in huni ois, slowiing doi-vn the excretion of these substances,
25
DEQ-CFW-00079716

3.4 The lock -in problem of structurally similar
replacements
Since the desired. performance and properties of a chemical are obtained from
its chemical structure, replacing phased -out products with structurally similar
ones is a common, practice to maintain the requirements of industry. Never-
theless, hazardous properties are also inherent to the chemical structure and
substitution with similar products may, therefore, pose the same risk as their
predecessors. 111,11 Paper III and IV provide a preliminary assessment on the
similarity between PFOS, PFOA and 8:2 FTOH and their alternatives in terms
of physicochemical properties, environmental fate and toxicity.
NEW
1X 3' 1791 F 1111114111 � 11111 11111�111�1111111111 pill 11111111pgo 11 A OF
Despite some limitations, the modelling methods presented in Paper III al-
lowed a preliminary comparative assessment between PFOS, PFOA, 8:2
FTOH and their replacements based on their predicted physicochemical prop-
erties, persistence and long-range transport. Overall, estimated log K,,w values
differed by less than 1.6 log unit. Estimated log K.", values between PFOS and
its replacements were less.than 0.6 log units apart, while for PFOA, four of
the six replacement had log K,,, within less than 2 log units. For 8:2 FT0H
replacements as well as two PFOA replacements, log &,w values were differ-
ent by 4 log units compared to the legacy PFASs. hydrophobicity is likely
linked to the molecular sizes since bigger molecules require higher energy to
create a cavity among strongly -bonded water molecules. The inclusion of
ether linkage(s) appeared to have a steric effect on the perfluorinated mole-
cules, but had a negligible impact on its polarity. Concerning their behaviour
in the environment, only two replacements were predicted to be less persistent
(Pov<103 0 days) and mobile (CTD <1 700km) than PFOS and PFOA and 8:2
FT OH replacements were estimated to be less persistent (Pov<350days) but
more mobile (CTD>1900km) than 8:2 FT` Ile These results suggest similar
properties and environmental fate between the alternatives and their predeces-
sors.
The rationale behind the use of shorter chain hornologues and other fluori-
nated alternatives to replace PFOA is based on a lower B and VO' In terms of
potency, the following ranking has been established based on administered
dose and its effect on the liver weight of male rats: PFNA>PFOA>GenX>
PFBA>PFHxA (see Figure 8). Paper IV investigated. to what extent this rank-
ing is attributed to differences in pharmacokinetics among the substances. As
shown in. Figure 8, the ranking changes to
PFNA'zGenX>PF0A>PF11xA>PFBA when considering scram A:UC,, and
26
DEQ-CFW-00079717

when considenns, liver AUC-,,,, 111C
msults were correlated ivith the serain mid liver distribution and the
chinination half -fife_ Due to the, high b-loaccumulatiors potential of PFNAInd.
to a lesser exetent, A. the- dose quire to rcqich certain leval "i-I Se-ruln or
liver is kwv carm-d to short -chain PFCAs, PFOS and PFBS wene also
as-sessed but r�sults were inconclus] ve sl n Ce no sign-&C"Int eff'W on tile I ii ver
w6glit Nvas observed for PFBS:" Tlwse findings Indleato that toxkokinutics.N
is an important paimmetter in fhe toxicit-y- of PFAAs and, that -abornativv, to
Iqga PFAAs could likely be intrinsically a s po
Nlore ancrition should I b-pedoil Geri was asosudiednx r
1.11. According to both studie GenX is as persistent and mobile, as PFO-A and
could posqiblv be more intd.imically poterA than PFOA-
Figure 8: Lowev ahwmed qftci levcls (WLJ-'�) ofthe mcrease in Uttw
U-TigMt III male rals cTpr av aderr nystered &s pm&cmlsentfil AUC"
cend pre&acd fiver , LORLs awreW spand I re to the rArrs
W �-'-fjzmq reparted by 1he 311afies, ftldkyne�l Iri Me legend, '5' 17he tire?
%eighr�Wos - are ctko reporml W file, leg"end
27
DEQ-CFW-00079718

This work provides an insight on different aspects of the broad field of human
exposure to PFASs. The past and current exposure to legacy PFASs as well as
the propensity of novel and emerging PFASs to be hazardous were investi-
gated.
In Paper 1, the daily intakes of PFOS and PFOA. were successfully estimated
from cross -sectional data of two geographically distant populations. The time -
trends in exposure were, within the uncertainty range, similar in both regions,
suggesting a common historical exposure dominated by consumer products
and, upon removal, replaced nowadays by a lower but dominating diet expo-
sure. Furthermore, the declining daily intake prior to 2000 suggests that the
industry phase out could have been initiated earlier than the official announce-
ment in, 2002. Finally, the relatively fast response to the shift in production
reinforces the idea of a direct correlation between the industrial phase -out ac-
tions and the decline in serum concentrations.
In Paper H, the metabolism yield, representing the amount of 8:2 FTOH ab-
sorbed that is metabolised to PFOA, was successfully fitted to longitudinal
biomonitoring data of occupationally exposed ski wax technicians. However,
while the contribution of indirect exposure to the body burden of PFOA was
important for ski waxers, it is probably a negligible exposure pathway for the
general population. Nevertheless, this study could only investigate the expo-
sure to 8:2 FrOH and, therefore, the same conclusions might not stand for
other precursors.
In Paper HI, the physicochemical properties including the persistence and
long-range transport of fluorinated alternatives were predicted using different
in sitico tools, and compared with the legacy PFASs they are currently replac-
ing. Despite different molecular structures (e.g. inclusions of new atomic moi-
eties), a majority of fluorinated alternatives displayed similar properties, per-
sistence and long-range transport as their predecessors. This implies that the
hazardous characteristics of legacy PFASs could also be inherent to some
fluorinated alternatives.
In. Paper IV, the potency ranking among the legacy PFAAs and their alterna-
tives was gradually disappearing as when concentrations closer to the target
tissues were used for the assessment. This indicated that toxicokinetics are an
important factor in. determining the toxicity of PFAAs.
28
DEQ-CFW-00079719

5 Future perspectives
Despite the decrease in, production of legacy PEA -Ss, (bi)srrrrual. bi.orxrorritorin
offthe population should be maintained in the fature, especially for long -chain
PFCAs, for which serum concentrations are still increasing despite the recent
regulation. Every additional year farther away fi-om the phase -out brings new
insights on the exposure and dcpuration trends (e.g. estimated. elimination
half-lives). Frrxtlrcrr or , be able to l'icrifon popidation-scale PK—
rmodelling on. the longer-chainI�FCAs in the. future, Wb.ich could not be studied.
in this thesis since population7basod model are suited for declining chemica].
body burden. If possible in the. -future, it wo-uld be an opportunity to estimate
the elimination half-lives of long -chain PFCA.s, which are currently unknown
but expected to be lout„, Furthermore, .fiat re research. should investigate the
potential age_depeudency in exposure to PF:H S, especially for toddlers and
ki&& To date, the apparent elimination half-life of PFHx.S in. hu nans has been
estimated only once.".ddi.tional bion orritorirr , cross -sections in the future
couldhelp establishing the intrinsic elimination half-life of PFRx . Overall,
every thong . the long -chain PFASs are now regulated, research towards €rr.�fcs-
figating the link between their emissions and their bode burden should con-
tinue with the objective to identify the effectiveness of chemical phase —outs
and production..shifts. Recent biomonitoring studies have shown that huni s
are being exposed to a wide range of or anofhrorme eorrrpoun.ds, with increas-
ing ratios of unidentified ones. As non -target, analytical method,,, identify
novel PFAs in human serwn there may be farther candidates for lon -te-n: .
human biomonitoring."4
The exposure study on exposed. ski waxers was rr unique opportunity to study
the relative contribution. of indirect versus direct exposure. Because occupa-
tional exposure studies raise awareness of working conditions and promote
the use of protective eyrripr:r�ent, future work on ski waxer exposure is likely
to be of limited value. Ski waxers now wear protective face masks and work, -
in highly ventilated. workspaces, which has likely reducedtheir e-posure,
Evers though precursors are being regulated along with their predecessors in
Europe and USA., high exposure to precursors could still occur regionally in
other production centres such as China and Brazil."' Occupational cohorts in
these regions could provide elevated exposure conditions to further sftrdy the
indirect exposure to other volatile precursors. Where can, however, be political
29
DEQ-CFW 00079720

and industry resistance to conduct such studies in these emerging economic
regions where chemical regulation is currently lower than in Europe.
One of the niakjor findings of this thesis was, despite some uncertainties, the
similarities between- legacy PFAAs and their fluorinated alternatives in terms
of properties, environmental fate and potency (albeit only for one toxic end-
point). These preliminary hazard assessments should be refined in the future
as more information and monitoring data become available. Nevertheless, fu-
ture research should be efficiently structured and organised to first prioritise
the important data gaps and provide comparable data. A more precautionary
approach that would limit the necessity of further research on the >3000
PFASs in society would be to follow the recommendation of the Madrid State-
ment, and eliminate PFASs from non -essential uses. In parallel to such strict
regulation of PFASs, sustainable non-PFAS alternatives that are both func-
tional and. non -hazardous should be developed. Regardless of how strictly
PFAS are regulated in the future, resource -effective methods to regulate the
large number of PFASs are needed. Society cannot afford to continue
ontinue to re-
search and regulate each PFAS individually and therefore grouping PFASs
according to their similarities (e.g. toxic mode of action)"' may be.a feasible
alternative that deserves future consideration.
30
DEQ-CFW-00079721

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DEQ-CFW 00079730

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40
DEQ-CFW-00079731

Acknowledgments
This piece of work could not have been achieved without the. direct or indirect
support. f s. sigi:facant nun.i er of individuals. And because this thesis tags
me roughly ld d days to write, I will. take the necessary aaaaaraaarat ofl ages t
express my gratitude to each one of them (haters gonna hate).
First of all, thanks- to airy. two maim. supervisors, Ian and Robin, who provided.
me with. the toads to ,get through the world of scientific research. Together, we
have achieved interesting Trglects even. though. the path was sometimes sinu-
ous. I leaarn. t to be wrong and. less stubborn Hello, Paper It.. a which is asgood
thin& T guess. Robin, , you were of as great m rrtal support during the char est
periods of this entire process. Thanks to Matt, thepatience ou bad towards
my I000+ questions on the mathematical suspect of my models and the uncer-
tainty analyses is laudable. 'Thanks also to wry co-authors and theirvaluable
inputs.
Then, part of the credit gages to my friends and colleagues, ftom -f r and close.
Starting with my all-time favourite ofliceiate, Stathis.The amount of shared
stories and adventures would. reqjiire an entire book to be told. So, for now- 1.
will just mention our Fridaay's da ce-libe.-- o-on.e-i.s-waat lxiu, sessions i flae
office to release the tiusLTation from our code errors and this: "Oh! Get me
away from here I9m (ling / Play me aa. song to set awe fee".. A gigantic thank:
to Kim., any life coach, you made it possible in the most gen. ui e ways, count-
less times. Another huge one to Kerstin, iny partner in crime for acne illion
things" you know which Draw. Also to Usa, for your listening, your coolness
but above aa.11 for your cafes. food. for the soaud and farad for the brain. Credit
goes also to Berit, Lara and Maria, by my side for the farn and less far .mo-
ments. Thank you girls! To than former and cinTent cesO gang, 'Who made
parties, gatherings and 1-unch. discussions memorable- Dimi, Jana.. Steffen,
.Anton, Lukas, Dfimie , U, Matte, Marko, Giannis, Anne,, Raed, Bra. Clau-
dia, , Stella. Thanks to Fiona, for her scientific input in Paper I and Wouter
for haying aa�y. PFA s informer (Gen: algid not escape Paper AT, thanks to you).
ces "s Joao, Ellen., Maf lda and Zandra. To ..,.vita and her bimonthly
massages, attempting as, best as one can to remove the muscle trots caused
by my science. To the ..- E.W rs, Luraa" Andreia, : ate(rina ), Sornru, dra
Hui, Fenix, GG, Ana, Ulaa., Juan, Gopal and. Claudio. Mary unforgettable
moments, especially in. Madrid. I mghaarn, mdarn and S-heal . Special thaw
41
DEQ-CFW 00079732

to Thuy, for be the, only PhD colleague at ACES with whorn I could
cuss PK niodel issues but also piano niter :mid tab4Q teauls. trick serves. To
Cath and Nrefs: iv e can do this., I did it wid you'l) do it! Enormous diank.-s to
both of you for these last few months, dic morning bus challongy cs. th--IK � daily
motivational Whatsapp chats, rile icc skaing commauto. e-N',', etc, And bc)Klnd
cvcn�thhig, thanks for proo-f4cading my ackilowledSoatents, We don't want
them to be too chcesy, do vw? To the Swedish French. Connecoon. E-flenne.
Alex, Clifford, Quentin et vatre Pai-sksive gouaillc fianchouiljar&, qui VaC
went a manquer dwis le Nord, Etienne, sp4clal big tip pour to Kerguelen
rt,,Ues- Hagen, your philosophy saved my sanity more than once, and also you
saved Gustav so you deserve my eternal grautude, My flatuiate Patrik, we
in.ade a prct�y good team, at K53A, Sadly, all good dfinggs, some to an end,
Piatr,. your "alivays took at, the bright side of life" motto was luckily %,e*,
mu eh contagious. Le i e, Waides being"nay personal Madab Help You, have
been a precio�L5 support duning- these lam,
months and bevond, Tenz, thanks
for ywr enlightening. Whatsaipp sketches on ho-tv a 3D matrix works, T'he rest
of the ETH-Crew who re gnai n s. untouchod despite t is years- Marti n, Bri
g
chrigi, mle missing ten rM n ns of dw T ' undal- -Sebi & Fro 6, You trained me
to function with few hours of sleep. To the unbreakable Posifs,, Ju', Ca s,
Kiks, Valoux Minish, Annelou and Luluponce, Gregoir, I hanks for dqo
sky�_% and for cbecking my � look -lost fonnal french writing, Harris, you cnµ
couraged me to strt tens Pell) 165-9 krn away from comfort zwic and kept
on screamalng "aflez le Chat!". Higglcdy�pigglody T ims. Adriana, Fvi obi
Luis, Pim. Jonathan, Fran , Erally,. ien, Alex, Mandy, OrvLex,
Ricky, Alema. I`hanks,for your motivati woks w %
mg alo, the nd R_ ay
I vvould like to take the tinic to thank my teacher from secondaA! kh6ol, Mr.
S_ who. by not be,)ie�ing in my Qapacities in, Scincea gave me the uffirmatc
motivation to provc him wrong, 1 would probably not be herea -without his m-
consideration, And, while we, an at uncry nvrenaonal acknowled-gemeats, I
should thank my plan ti, nky bike G u stav and P hil Collins' Sus-
5u,dio
for keeping me,cool when. dining the wall,
Ilugge big up to my parents and their unconditional sup
port-E - Eve a though you
did not fully understood what -my rusearch was exacd about, 1will neverget
tired to explwin it to vou over and over ag wn, S is los 11%anks to
Rom a* nay belo�, ed brother, mid hi s abi lity -to make me take it c,-;jsN! wid1just
,a few words, Now that you hav-e a soon -to -be Doetoras alittle Sister you
nally, Owe BrIc some rc-spe'eta you too, Caro.
Finally, the last sentences traditionally left for the life par -ill go to n1v
soulniatc, Aurklie, And forthat sake, hi sivitch to fimmb,Wesh ma pd-am
pour tutnes les videos de R, Zorn que tip m'as envoy endard les noni I breux
coups de mou, Tu sais toug",ours agir pcndant les Poriodes, de erilse-.et lant
42
DEQ-CFW-00079733

Contents lists availaWu at it ierlcnLlir£ nt
Science of the Total. Environment
jou -naal hornepage: vuv va. lvavlar.00rriiloa ata soltntar?v
modeling ant of the physicochemical properties and ,..,' CYossM
uk
environmental fete of emerging and novel per- and
polyfluoroalkyl substances
Melissa Ines Gs7mis', Zbanyu l Wang b, Martin Scheringer by [an T. Consuls ,£.*
" ra?>lintrst??>?ar afAp�Iied Earrdrontnentrti Seca??r.?> �'TrTuf). Sfc?e��hr�im iln9rers3ty, �'�'-20£r'w'3 ,Brat?;.1`w:?i???. ����f?>n
a Institute_fur €'1??>rnlcttl?rrul 13kaa>rr,�laxeernr, ;;??f tnriGi£ t'FI-ti0:1:3.Zt?rleit, SudtFtttf.€te?d
1-1iGHLiGHTS
COSle Others and SPARC. ;are used to estimate physicocberniuil properties.
w The properties of PFECAs and PFESAs are similar to PFCAs and PFSAs, respe t'vely.
The OECD Tnol is used to estimate the envirouineaatai fate.
Many fluorinated alternatives have similar environmental fate to legacy; PFA Ss.
b Urgently needed experimental studies are luFNightc.d,
Ai R T I C I. E I IS F 0 A B S T ti A C `f'
Article hb5€e V:
L —chain Nerd mroaikyl carborryiic acids yPPCI%s} and j�erfiR?rtriD Yll{aE%e si11f43rE1£ dC1e�S (PFSAs) are j}£rs151er t,
Received 4 Augtst 2014
bioaccumulative, and toxic contaminants that are globally present in the erivirCF?aFr3ent, wildlife and humans.
Received in revised four? 9 October 2014
Accepted 20 toolbar 2014
Phase -taut actions ;anti use restrictions to reduces the environmental release of long -chairs PFCAs, PFSAs and
Available online g hint°enxter aoa4
their precursors have been taken since 1G001 In particular, long -chain Poly_ and perfluoroalkyl substances
(FIFA_' s) are being replaced vv ith shorter-d hain lanai ologues or other fluorinated or non -fluorinated atternanves.
Editor: Adrian covad
A key question is: are these altematives, pa£tinAirly the structurally similar fluorinated ahernames, less h aza?rd.
ous to humans and the environment tuna the substances they replace'? Several fluorinated alternatives including
f. 3nverds:
I.yerlluu£uether carboxyl( acids (PFECAs) and PctllurrGetll€ r st if nl acids 1,PFESAs) have been recently identi-
Hazard asse2wneat
fled. However, the scarcity of experimental data, prevents hazard ;anti risk assessments for these substances. In
Environmental fate
this study, we use state-of-the-art in silko trials to estimate key properties ofthese newly idendfled fluoriaaated
FluorE?ra°ed a ttema rave
alternatives, [i] CCS,'1f.Itherni and SPARC are used to estimate physicuchernfcal propene& The US EPA EPISuite
la si4£o to,31
fIR)s
software packafr e is used to pr'ediLt degradation half-lives in air, neater and soil, [ll] In combination with estimated.
PMA
chemical properties, a fugacat�v-based nndtimedda mass -balance unit -world rnodel - the OECD Overall Persis..
tence (Pov) and Long -flange Transport Potential M'M Screening; Tool ... is used to asses the likely envirmimen-
tal taste of these alternatives. Even though the fluorinated Aternatives a:ontain some studctoral differences, their
physicochemical properties are. not significantly different front those of their Predecessors. Enrtlaerrnore, ratust
of the alternatives are estunaied to be similarly persistent and mobile in the environmem as tfFe long-chaain
PFASs. The models therefore predict that the fluorinated aItern anves :Pill become giolmlly distributed in the en-
vtronnient sirmlar to their predecessors. Although such in sdico methods are coupled with uncertainties, this pre-
linnnay assessment provides enough cause for concern to warrant experimental work to better" determine the.
Properties of these fluorinated ;alternatives.
�D 2G14 El.if. pier B,VL All rights reserved,
10 Introduction
In the last decade, perflu£aroalk�l carbtrxlFiit ad ids (PP£ As) and
perf uoroalkane sulfonie. acids (PFSAs) were recognized as
'" £:tar?�sp?xnd"any aeFiixnr. Tel.. -t� a6 #i 16 d01".?.
E-mail oddressr ia::?.,:+a ?xeuirr Prase (I.T. Cousins),
h :i'^?. ,ili1t ;:l.:;iiWmV2U14,1ii.i?i�x
004P 1)697 0 2014 Elsevier ON. All rights reseTved€.
persistent (Penult and Debris, 1666; Key et al., 199S) and those
with "long' perflnnroallryl chains were shown to be bioaccurnulative
(H€ ode ct aL, 2606) and toxic. (Kennedy et al., 2004:.6orR et al,. 21113).
Our definition of " long''chain .referrs to PFCAs with 7 or more fluorinated
carbons (including PrOA, which is designated as bioaccurnulative under
REACH; ECHA, 26B) and their precursors as well as PFSAs with 6 or
more fluorinated carbons a -Ind their precursors (Buck et al, 2011).
DEQ-CFW 00079734

DEQ-CFW 00079735

992 AU GonL ek drt I (2015) .981 -991
Long -chain PFCAs and 11PSAs are globally present„ including m the
abiocic environment (Yamashita et al- 2005; young et al„ 2007), and
wildlife (kannan et al.„ 20021 in remote regions, indicating the long-
range transport potential of these substances. Furthermore, humans in
industrialized countries contain relatively high levels of long -chain
PFCAs and PESAs in their serum (ltannan et A,, 2304; O31 en et al.,
2003), suggested to be due to the historical presence of these substances
and their precursors in a wide range. of consumer products (Vestergren
and Cousins, 2009). Due to concern regarding their hazardous proper-
ties, there have been a number of actions by industry and regulatory aar-
thorities to reduce the environmental release of long; -chain PFCAs,
PFSAs and their precursors. In the period 2000-2002, 3NI phased out
its global production of perffuorooctaue sufPoanic acid (PFOS) and rebated
chemicals derived. from perfluorooctane stdfonyl fluoride (Pt1SF, Q
i.e., POSF-based chemicals) and replaced their use in certain key prod
nets with perfluorobtuane dsulfonyl fluoride (PB`31', C4)-based chemicals,
In 2009, PrOS and related POSF-baser! chemicals were added to Annex B
(restriction of production and use) of the Stockholm Convention on
Persistent Organic Pollutants (liNEP, 2009). Similar actions have also
taken place: for perfluorooctanoic acid (PFt3A) and other long -chain
PFtA homologues,. For example, the US Environmental Protection
Agency (US EPA) and eight major global fluoropoly order and fluorotelomer
manufacturers have agreed to work toward the elimination of long -chain
PFCAs and their precursors from point -source emissions and products by
201T g US EI'A, 2006). In addition, PFOA and its ammonium salt (APFO) as
well as C3, -t`,a PFCAs have been listed in the Candidate list of Substances
of Very High Concern under the European chemicals regulation, REACH
(ECHA 2I1I3).
A common feature of all the above actions is an on -going industrial
transition to replace long -chain PFCAs, PFSAs and their precursors
with alternatives, particularly other poly- and perfluoroalkyl. substances
(PFASs) such as shorter -chain homologues and functionalixed
perfluorapolyethers (PFPEs) in applications where. extremely low
surface tension and/or durable oil- and water -repellency is needed
(Molt, 2011). Although the identity of fluorinated substances used
in industrial processes and consumer products is often cfai€ned as
"confidential business information" (Cfll) by the manufacturers, a ruun-
her of fluorinated alternatives used in different: industrial branches and
consumer products were identified by Wang; rt al. 201310 A, fc'eyr ques-
tion fs are these fluorinated. alternatives less hazardous for hu-mans
and the environment than their predecessors;' There have been other
historical examples showing the Iorolnld`nns oassnc:iated with removing as
chemical from the market and replacing it with other structurally simi-
lar chemicals from the same. class of substances (Stremp€ i €=t A., 2012:
Col dswin et: al._ 2€11:3). Wang. et al_ (2£113) reviewed available knowl-
edge on the identifier! .fluorinated alternations and highlighted the
scarcityof information, on their production volumes, emissions, (bier)
degradability, bfoaccumnulatfve potential and. (eco)to,'icity. Conducting
experiments to generate missing data for all these fluorinated altema.
tives is expensive and tinge -consuming. However, a preliminary assess-
ment using in silica mne.tbods including quantitative structure-•propemr;
activity relationships (Q$PRsrQSARs) can provide valuable insights and
help to prioritize future research needs (3trempel et A,, 2€12, i.,awOr
and Wania, 2013; Howard and Fhderiz, 010),
The ,afar of this work is to provide a preliminary assessment of
emerging and novel fluorinated alternatives with state-of-the-art in
silica tools. We use the terminology of "emerging" and "novel" that
has previously been applied to bro€nfnated flame retardants (Bergman
et al., 20I 2). Emerging fluorinated alternatives are defined as alterma•-
tines have been recently ideandfded in the. environment, wildlife, flood
or humans (e.g;'. Adona). Most of the alternatives included in this study
are novel alternatives, i.e. those are known to be present in maanufacnir-
irg processes, mnaterfals nand products, but have not yet been identified in
environmental samples, avildlife„ food or humans, First, CDSSvltltherma
and SPARC are: used to predict physicochemical properties and EPISuite
is used to predict degradation half-lives in air, water and soil,
COSIn Otherr n and SPARC were previously used. to estimate, the physico-
chemfcal properties of long -chain PFA.Ss, including partition coefffcfents
(.tirgn et al., 2006, Wl ng et al., 'NI 1) and acid dissociation constants
(p&s) (t err, 200S). The US EPA FPtSuitd=a soflvaare package is a well -
established Q.5PRj:'QISAR tool used to estimate physicochemical proper-
ties and degradation faalf-fives in hazard assessments (Strempel et. al.,
2€112; 2ar'f3 et. al., 2I112). It has, however, been shown to be in acLurate.
for e 6niatingF the physicochemical properties of PFA3s (Atp et al.,
21 06) and is therefore only used here for esfimating the environmental
degradation half-lives.'Ibe structural differences of the fluorinated after -
names and Chef; estimated physfcocheannfcal properties, are analyzed to
provide insights alto the impact of structural changes on physicocherni-
cal properties. -Second, based on the estimated physicochemical proper-
ties and degradation half-lives„ the environmental fate of the fluorinated
alternatives, more specifically the overall persistence (Pov) and long.
range transport potential "TP), is assessed by using the OECD Overall
Persistence ,and long-Range'Iransport Potential Screening Tool (hereaf-
ter "the OECD Tom"), The OECD Total was developed as a "consensus
model', combining the essential aspects of nine multimedia fate and
transport models'Wegn-aann et al., 2009). It should be noted that this
study focuses or the physicochemical properties and passible environ-
mental fate PM1 and LRTP) of the selected fluorinated alternatives.
The pteddicdon of bioaccumulatiod potential (R) and (eco)toxicity (T) is
not included m this study because. there is a lack of mechanis is under-
standing about the possible oleo- and proteinophilic bloacc mndanon.
behavnor as well as tine toxic: mole -era' -anion of these fluorinated alterma-
tives. However, a discussion of possible strategies for assessing if is in-
cluded in the Discussion section.
2, metfrods
2J. Selectedfluorinated altematfves
A total of 16 ernerg;inga' and novel fluorinated alternatives, were in-
vestigated, including five perfluoroether carboxylic. acids (I'FECAs)
and two perfluotoether sulfonic acids (PFESAs) identified by y`t=ang;
et al. (2013) and for which the chemical structures were known ( see
Taabfe 1). 'flat, selection of the fluorinated alternatives for this study
was limited by the large amount of unknown fluorinated chemical
structures in the products identified by Wang; et ai, (2013)Further-
more, some fluorinated alternatives (namely "CF2=CFOCF CF(CFa)
CF2CF2SO2F (CAS no. 15093 14- 5) and CFat1CF(CF3)COF') were not con-
sidered due to their use in closed industrial processes. These substances
are likely used as intermediates to produce monomers for certain
polymer. they are not expected to be present in significant quantities
in the environment because they are chemically bound an the
polymers resulting in a limited fraction of them in industrial waste
streams (US EPA, 2012), The plausible degradation products of two
alternatives were, on the other hand, included in the analysis, since
they could possibly he long-lived chemicals and more toxic than their
pare' at .nrnpnr€nds as observed for rather contaminants (Farrel et at..
22 vq).
The 16 fluorinated alternatives and B degradation products were. di-
vided into fourgroups. l) fluorinated alternatives replacingPFOA; 2) fluo-
rinated alternatives replacing PFOS; 3) fluorinated alternatives replacing
8:2 fluorotelomer alcohol (8:2 FTOH); and 4) fluorinated alternatives
replacing certain POSF- and/or fluorotelomer-based substances.
For practical purposes, each compound was renamed with a
specific abbreviation (based on its acronym, commercial name, etc,.) as in-
dicated it Table I and will be referred to by this abbreviation throughout
the paper.
22. Estimation oftkysieocheminat properties
For fluorinated alternatives and their predecessors (PFOA,. PFOS
and 8.2 FI'OH), physicochemical properties were predicted using
DEQ-CFW 00079736

DEQ-CFW 00079737

AV. Gxaail� or, al. ; . Bence¢ etf the r uta 1. C'M"arrarraCo. a 505, If 2015) q&1-39a
COSMOtherm and SPAP.C. Ct3SMOtherm (v. C3.0 release t1 A3,
COSl`ultllogic GmbH & Cu, KG) is a quantum-chermstry-based inkidel
that was developed according to tine: 'Conductor-lil e Scree ring Model
for Peal Solvents' (C£1SMO-RS) theory; details about the model and
background theory can be: found in the review by Mar,rt. (2003), De-
tailed property estimation work has been described by Wang et al,
(20I1), who reported re:seutts for physicoc:hemlcal properties of legac y
PPASs, In briefs the estimation of physicochemical properties using
Cf'):liMOtherin follows several steps: 1) COSllrlticaonf (v, 21, COSMOlogic
GmbH & Co. KG) is used to search for the lowest energy conformer(s) of
the compound of interest in the gas phase, which includes geometry
optuni:zation or, the quantum cbemistry level, calculation of the surface
charge density of the molecule and cluster analysis; 2) the surface. -
charge density of the conformer is further converted into the chemical
potential to the molecule in solutions of water and octanol as well as
ira the gas and pure liquid phases bared on statistical thermodynamic
equations that fare built in CC€Sa°wrltltberrn (II ;Nit i aL MNXY € {, The
physicochemical properties of each conformer are then estimated
from its chemical potential in the givers phase(s), 3) the final physi-
cochemical properties of each chemical are the weighted average,
based on the Boltzmann distribution, of the properties of individual
conformers. The conformers that require higher energy costs for .for-
mation have a lower probabiliq of occurrence and thus these con-
formers have a smaller contribution to the: final averaged property
than the energetically more favorable conformers. The following
properties were predicted by using Ct1SMOtherm: the air -seater,
octanol--water, and octanol-air partition coef" ciesus (.lw;AW, Ko, ,A,
and KOA), the sub -cooled liquid phase vapor pressure (Pa,), aand the
solubilities in aster (,SN) and octanol (.S'r.3)o flue to the absence of ex-
perimental data, external comparison of estimated properties, was
not feasible, internal consistency among e.stfrnat.ed properties was
controlled by ushig the "three solubility" approach proposed by
Cone: and Mackay _!€ 00)
The: add -dissociation constants (pK,.$) of acidic. fluorinated altema-
tive.s (e,g,, PFEC.As and PFESAs) wrere predicted using SPARC (October
2011, re.le.a,,e w4.6,l691-sd.ti,1t38 ). Briefly, SPARC is a linear free ener-
gy (LPEii.)-based inodel that adjusts the experimental pit,, value of the
ionizable anxiety in the molecaule as a function of the perturbation
exerted by the rest of the structure (Hilal et al., 1996)o MA et al,
i1SSS) used SPARC to estimate the phi for 35E5 organic compounds
(detailed. list not provided by the atithors) and SPARC has also been
used to estimate the. pK, of PFOA and other fluorinated carboxylic
acids (Coss. 2008) and in another study C?....C9 PTCAs and Ca --Cs Pr-SAs
(Rayne and Purest, 2009).
23. Estimation ofdegradation fool -.lives in air (ta,z_r, water 1`tar2av > and
soil (tjj )
The US EPA EPISuite ( version d.l 1) was used to estimate the degra-
dation half-lives in air, water and soil. The degradation half-life in
air ;tj,2A) was predicted by AOPWIN. A01"Arll'1 considers only reactions
with hydroxyl (OH) radicals and dines not consider other processes such
as direct photolysis. It predicts a second -order rate constant that can be
converted to a pseudo first -order rate constant by multiplying; the sec-
ond -order rate constant with the atmospheric OH radical concentration
(i.e, 105.1W,6 molecules;`cm'). The biodegradation Half-lives in water
and soil (tr,a.,v and ter;z) under aerobic conditions were: predicted
using BID9ArfIw13. The BIDWIN3 model is built on estimated scores of
the biodegradability of 200 substances for which the molecular stra.ac-
tures are divided into fragment descriptors. The model analyzes the oc-
currence of certain fragments in the molecular structure of a
chemical and then rases the corresponding descriptors to estimate
the likely biodegradation half-lives with a score: system (Le. 5 =
hours; 4 = days.; 3 m weeks; 2 = months: 1 = years)- MWIN3
outputs were converted into half -fives (in hours) with the conver-
sion scheme proposed by Aronson et al. (2€€06). Degradation half
`183
lives from ACll"WfN and BMW wore estimated for the substances
in their neutral form, Experimental half -laves, whenever available,
were preferred ogre: EPISuite estimates, For example, the exper;n-een..
taal OH radical reaction rate constants of 3:1 PTDI-I (Bravo et ai„ 20 A 0)
and 5:1 FTOH (Hurley et al., 2e004) were used instead of AOP€A1IH
estimates.
2A, Straacmre prgpea-ty relationships: coinpazrlson with PF0S, PFOA and 8:2
FFOH and non fluariiaotad analogues
The chemical partition space defined by log Kow and log .Krww was
,used to assess the: impact of stnictural differences, such as the inserdon
of ether linl£ages into pertluoroallryl chains, between PFOS, PFOA and
8:2 t"rOH and their respective alternatives (Le.., PFFSAs, PPECAs and
ar:1 t lfPl-is) on physicochemical properties. Even tl-anugli PF'MaPA is all
ai ernative to PFOS in metal plating, this coinjxjund was not considered
at this stage of the: analysis .since. its chernical structure shared few sim-
ilaritic:s with PrOS. In addition, we conducted cornparisous between es-
timated properties of the PPEC,2s, PFESAs and PFOS, as a reference for
the fully fluorinated carbon chain, and their corresponding hypothetical
non-ftuorn aated analogues (i.e., all fluorine atoms in these fluorinated
alternatives were replaced with hydrogen atoms), to gain insight
into how (per)fluorination of the molecules influences their physico-
chemical properties, In order to verifv the molecular viatbfhty of
the non -fluorinated analogues, the experimental information on non -
fluorinated analogues of PFECAs and PFESAs was collected; whenever
the rntarn-faroninated compound was not found in the ChemSpider data-
base (Le., morn -fluorinated analogues of PFrECA,, PTTEC.A,, P-53, P-53E),
EPI4uite and CDSMfltherrn were used to assess the likely degradability
of the structure and to identify potential reaction centers (i,e„ polar
moieties). For acidic compounds (such as PFOS, PFOA, PF'ECAs and
PFESAs), the properties of the substances in their neutral form, were
compared,
2.,5, Prediction ofenvirt nnaentxi lute
The OECD Tool (version 2.2), available for free for download at
h'ttp:oecd,crg t:.il.i%1/£.?£'.n3 /
oecdpuvandlr Tuscre e r it gtuol.-is€ran, was used to assess the eniviron-
Mental fate of the Ifs fluorinated alternative:, and ll € egradat.ion
products. The environmental fate of PFOS, PFOA and 8:2 FTOH was
also estimated for c:otnpa.rison, The OP'M Tool is a fug,aclty-based
multimedia mass balance unit -world rnodel, containing three bulk
conipartinents representing soil surface laver, seawater surface
layer, and the troposphere (Wegnnann et a-1- 2€.09). Details on the
toch.nical background and design of the mode:l are provided by
i' egataann er ale N=tl£ ). The model input parameters are l'og KAW,
tag Ko,v. t .2,,�, f1 ,, _, and ta v,s. It should. be noted that in this study
the physic:ochemdcal properties were estimated for the neutral
form of the substances. Because anionic species have substantially
different environmental fate and bebavior From neutral species
(e,g., anionic spec es partition much araore into alu.eou,, phases rath-
er than into ai.r and; or lipid phases, in comparison to neutral spe-
cies), it is necessary to ac€:ount for the extent of dissociation and
make adjustaaae:nts in the modeling. Therefore, we made the follow -
hag assumptions and adjustment of estimated physitochenaical prop-
emes: if SPARC pre€ ,c teed the pf<r value to be higher than 6, a substance
was assumed to be mainly in the n£uetral form under assumed environ-
rnental pH conditions and I-lae estiniaated log Kp aarad log Kx v atiere da-
rectly used as input para.n,aeters for the model; for substances with as
predicted py",, lower than G, the estimated log Ko J and Iug KA'Pv were
cone cred according to the ionized fraction of the chemical. To this end,
the air-ivater and uctatiol-water distribution ratios, Dpw and ,Doti,, as
suggested by Wang et al. 23yC)11), were calnalated as featlows
DEQ—CFW 00079738

DEQ-CFW 00079739

U
0
TaMe I
Ustof,N° 16 fluonna"p-d. aftemativesand 6degyadadon pmdhxtaOlosen in 10 13is.%kY, log-Eherwith 3;be4 i:ommeal na rdme. Aie), abbfevia` n,CWS :ndustna: applkaUor, are
ladiczI.e': 4E boU
C Cornmerc; a � name
Abhre,,4aOom
CAS number
Structure
lOdustlial appkation.
Nuvrimm-0 ahemcinves
rppl�nng PFOA
------------------------------------
Adona
Ado§la
958445-44-8
ak
Nuoropol nun-pfocessingaids
y
GeILX
Genx
62,037- 80-3
F
FluompoiYmel. pwCeF,,Mng aids
Unknown
PFFECA, (�,e, PeffluoS .o trio -,her
3292M-24 6
FluoroWymer pracessing aids
Carboxyl : acie..)
uo,koown
PFFECA, (A;e. perfluom trie-hu
FIVLMP*i"q'ner pruceainr aids
cal boxyk' add)
v
F, T% A
FEE
908020-52-0
m
Fluoropolymer processing aids
6:2 ITCA
6,2 MA
53826-12-3
Fluoropolyrner processing aids
Fh"wina"e"! alto naCves
repig6zg 11,I35'
F-53
F-i3
7�4925-�A--,
fvleW pWioy,
X,
P-53B
F-5.39
73 C, 0 r, - 19 -
f r s
Metal pW ing
Unknown
PFBSaPA (Le.
E20945-47-3
Mpeai Pa':iog
hosph,,rk acid
Muonnutrd aheimadves
rcpiadng 8:2 PIOR
Rv-.610
3:1 F1,0H
3?5-()1-9
"BuMng 'or Sobotarmus to 1Fe used in
suifacpIreatmen, oiiexl:He,ieatheraud carpct9,
RM620
5; I FTOH
423-46-1
'Building Nucks" fot aiEi3staiACeS to iX, Used in
F i 3 "face t ea M:wn of tex E oe, l,.a Oher and carlas

DEQ-CFW 00079741

Muorin a I ed a!, ern a dves i-epiadng cenain POST- ana,%nr f'nurnPcio ier- 3 s d substances
EF-N441 I-T) FF-N
Novec 1230 Novec
Forafac 1183 Forafac
ijAnov4i
PFOTS;-"I(m)
PFOTSi-(OH).?,
IpFmi-(OH)3
12 M720 RM720
6
n
C)
C)
C)
N)
39847-39-7
756-13-8
30475-32-7
85?157-1&5
Degradation product
Degradation pioduct
Degradation product
Raw material for ionic liquids
Fire Suppression of
Fluorinated surfactants used in AFFTs
Unknown
.Surface treatmc-nt
rnptaK
,md
r•

DEQ-CFW 00079743

986 MI Gomis et al, the Tatc)r E3z3,rrt,n33Aent 505 t'2015, 9-3r-991
(SchwarZenbach et al., 2QP5; and used as input. parameters.
1
D,w,vl:,Qoevy :::: 1 _. 1 {yr.€- h,.; KA ,Elrraui(l)
In Eq. t )„ partition coefficients and pK,, values estimated by
t:C3SMOtherm and SPAPC were used and the erwiroinne:ntal pH value
was assumed to be 7. The pK,, values used for the calculation of D,,e ns
and Df,rq for PFOA and PFOS were 0.5 (Vie:rke et al., 2€111b) and 127
(Broolte et ai., 200), respectively. While it is pos aible to convert partf-
don coefficients of neutral species to da`st3 ibution ratios cif bath charged
and neutral species, a similar adjustment: cannot be carried out for the
degradation half-lives, as there is little empirical information available
are the impact ofionization on degradation. Became the anionic species
of acidic organic chemicals (T€i.lp et al., 20l19) including PFOS and
1)E A (Higgins and l.uth, 2t?06! sorb to organic matter, the hypothetical
organic carbon -water partition coefficient (Kc�), which is a well
established parameter to quantify sorption to sediments, soil and
suspended/volatile panicles, -was calculated for each of the anionic fluori-
nated alternatives and spe=c ified in the OECD occ l's code, The details of the
calculations are presented below 'fable A2 of the: Supplementary data.
Three emission sc marlins wore considered, in which emissions occur
either to air, water or soil, respectively. For each emission scenario„ the
OECD Too[ Calculates 1) the overall persistence (Prv) in days, 2) the
characteristic travel distance (CTD) in kilometers and 3) tile
transfer efficiency (TE) in percent, l'av describes the overall lifetime of
a chemical in a inutt.i-compartment environment consisting of air,
water, and staid, CID and TE are both LRTP indicators. CTD represents
the ddstarice in Ism at which the initial chemical concentration at the
sources point has dropped to lie (i.e., 37%) (lie>ratamat et al, 1 :1:13), It
should be noted that in the CTD calculations water ant air cornpart-
ments are considered to be mobile. TE quantifies the transfer of the.
chemical from the atmosphere into the soil or water cornpartint-gut in
a target region (MacLeod and Mackay. 2004). The final outputs of the.
f1Et'I.1'Tool are the highest Pov, CTD and TE from. time three„ emission
sceraarios rand are shown in two graphs with l.Ii'I"1D indicators versus
N PFO A
T Mona A GYS X
�
PFrECA,
* PFTECA2 �t, EE3a
6:: FICA
�
0 PFos
13 F-53 OF --sal
t t 8,2 FTOM
.... 3.1 F'MH -�.�- 5d FroH
_10%i"„
Q
i0
i
a
2 4, s
s
Pov, respec ively, A Monte Carley analysis was carried out for each the ml
ical in order to identify the influence of the variability and uncertainty of
each input parameter on the key model outlauts.
33, Physicochemical properties offluorinated ealteyrr=h„es
Fig, 1A shoes estimated lag K,kw and lug Kow for PFOS, PFOA, and 8:2
1TCrf•I together with PFECAs, PFFSAs, 6.2 FTt A and n,I i I't3l`ls that are
replacing these substances. Estimated values of log and log tie'A,
for the fluorinated alternatives replacing curtain POSF- and/or
fluor-otelomer-based substances (i.e., Fcarafac, PFli apA, EF-N, Novec,
PFC€TSi„ RM720) and the six degradation products are presented in
Table A2 of the Supplementary data.
Log Kow and log gaw of the two IaFI:¢.SAs (Le., I^-53 and F-5:3111) are
similar to those of PFOS, differing by less than one dog troika Concerning
the fluorinated altt,aYnat3ves to PFCIA, these display similar lag Kew
values (i.e„., <2 log unit: ranee 1, as their common predecessor, Their
Jog Kcw values, however, are: rraore variable (teen, lie within ;.a mange
of --4 log units). On the l.og KQ)av a,cis„ two distinct groups are diffe.renti-
ated, with EF..A, GenX, 6:2 FICA and Adonaa on one side and PHECAs,
F-53 and F-53B together with PFOS can the ether side, S:2 FTOH is
more hydrophobic. (higher log Kow) than its replacements, 3.1 and
5:1 Ff'(,lhlso Furthermore, 5� 1 1 IOH has a higher log I aW and lag Kow
than .3:1 MOH. Compared to PFt1A and FFOS, their respective fluorinat-
ed alternatives presented in Fig, lA have almost identical polarization
surface charge densities„ o ,see (r-profiles in Figure A7 of the
`supplementary data),
HECAs, PFESAs and PFOS are more hydrophobic than their hypo-
thetical non -fluorinated analogues, v0th log K,v,, and lag l(a,,,v values
that are lower by 3• 5 and 2 6 log units, respectively ,k I13). In addi-
tion, Adona and EEA, which have one and two ether linkages between
perfluoroaldcyt chains„ display similar lag Kaw with 0.13 log unit differ-
ence, whereas their corresponding non -fluorinated analogues have log
Kaav values that differ by 2.6 log units,
A ;> V & 13 * tr McAsnQ ¢r-€) a€ ¢'F•Eat�Qi 1r E€Q1� e
Log K..
Fir, I. Chemical spte map ti[`.p33ling kQ g KAkv Ver('us log K�)w mrAl t4 MA, Pt•a5 and 8:2 F70r j 3r0 W hypothetical riE73A-�€E337tiitc33;PE) d3A�Ugti�s Q,a PrE�'r�s, PFFSA's
af331 1I'e'1 a. a�t<tyi7(S;3) ;1E1C.S C4F7-e5PtSt1Gt t� i 7'�n,.,. r v fluoe7nated a i:e,313iS4'PS 811d the E' CCSETd SDOE363A7 E7fft341UGrInated 3'.33rE3gues ate lridicatcd by the same syiE bolo .
DEQ-CFW 00079744

DEQ-CFW 00079745

AIL Gamhi, e? aI ; .SrJetcc 4 thr Ra tcl t'73;4nniYa3?ertt Saw (:?015) 9331 ­9.91
32 Persisrence and long-range transport potential
In Fig, 2A, estimated Pov and CTD for PFOS, PFOA and Pot HUH and
their fluorinated alternative s are presented, Besides Adona and HA,
which have a C'D and 130v of 592 krn anti 346 days, respectively, , the al-
ternatives to PFOS and PFOA are estimated to be similarly persistent as
their predecessors with a common estimated residence time of
1038 days in the whole model environmental system and similar
CDs between 1736 and 1745 learn, Furthermore, even though their
persistence is less than 3110 days, 3;1 and 5;1 Pl't7Fis have C"fts
(>40000 km) more than sire banes longer than the C"d1 of 8.2 FrOH.
Fig. 313 shows the estimated Pov and CID of fluorinated alternatives re-
placing certain Pa3SF- and/or fluorotel€ mer-based substances, Fide of
these alternatives are estimated to he less persistent than most of the
alternatives as well as the legacy PFASs presented in Fig. 2A with an av-
erage Pr
av of 326 daVs for PF0'5i-10H)2 and P.M720, and 131 days for
Novec, PFO Si and PFOTSi-(01-1), The averaged CTft of PFOTSi-(OH)l '
and Itd 720 is 800 kin, while for PFOT5i and Novec, the CTDs are 1.3
and 23 timers higher than for PFOS and PPf1A, respectively. Foaafa ; FF-
N, PFOTSi-(OH), 13Tf11'Si.-( 1111, arid the other degradation products
have sirr3ilar O'fts as PFOA and PPOS. Except for 31 1°EOH and 5.1
P'TOd-1, which display valuers € xceeding Q7 )% Pared 1 fit %, respectively, the
TE values f€ar• the: other substances in Fig, tf' and D vary from below
0.001% to 6.87%, depending €3n they transport media {i.e., air or fester)
a.nd log PO a.'17re. trnajarity of die fluoriaiate:d alternatives h ave a liiglaer
TE compared to the substances they replace.,
The contribution of each input parameter to the model outputs is
assessed through a Monte Carlo uncertainty analysis (results are provided
in Figure A6 of the Supplementary data), 'Three different cases are:
observed, [I] for all ionic and for highly hydrophilic (i.e„ logKnw1; - —Pp
log K®.a > 9) neutral alternatives, the degradation half-life in water is the
1E+d�z <, �tayr'£313,a;=47s, ���u➢to €�F"fr�R,•;, Pr.���3rA,, �-s3,�-,�3�. r�F�Sa�a
3 d FIM 3:l MKM 5;1 E"r3`'9d
:IF.ga r .
987
par;amete-�r comiihuting the most to the output variance of bath CT9
and P€ v since inns and hydiDph.ilic compounds are mainly distributed
in the. wvater• phase. P3 notion coefficients are the mast infiuentdal input pa-
raotete:ra affeetiraf, tfae v al3.te of lE. An elrcepnoo is PMSaPA .for wvh.ich CM
>ararl Pov ;are sensitive to la€at.fa ley; :��q and deg
radatioo half-life in water
while TE' is m aioly affected by half-life. in air. [ii] For (semi -)volatile alter-
natives Ni C.' lag Kpau,, _ 35log R' A <: 73 5), Pluq is .sensitive to the degra-
daton half-lives in water, air or soil, while the degradation half-life in air
affects the values of CfD ind 'FE, [Hi] For alternatives with moderate hy-
drophilicity (i,e., lag KA,,v : — 3.5 and log KOA > 7.5), Pour and CfD aae ;af-
fected by the degradation half-life in water and 3'k is sensitive to
degradation half-life in air.
4� Discussion
4.1, Influence of stru tural variability on pk sicochemicol proper -des
this study provides a prehmiraary assessmentofernerging and novel
finorinated altt-miadves that replace long -chain ands and
their precursors. Fven though PFECAs and PFES..As, which are alternatives
to PFOA and PFOS, respectively, contain some structural differences such
as ether llnkage(s) between perfluorinaterl carbon chains and reptace-
merat of fluorine atom with chlorine atom at the end of perf€ua nether
chain, their physicochemical properties are not significantly changed
compared to those of the: predecess€3m Among PPI Ols, the differences
drn physictpche:rnical prvportles can Relybe explained her difFerent molec-
ular sizes (i.e., P1 ITCAs versus H'.A, Adona and R se nX, which have similar
er-profiles but different molecular sizes). Also, while. the Insertion of
ether linkage(s) does not. signihe:antly ;affect the electron withdrawing
effects of the perfluorinated carbon chain on the acidic: functional
group at the rather end of the carbon chain, the presence of a methyl
�.E4e87 - Ei�v', Kaeaia ; 3'NtXtSi :e7Hr,, FtA4%24;tS�t}oz.:
jj' ,�.a'repiSd ��firSk€a6tS � errdr5i•r€asta,
333o-97.e"a
Y.E-t ad
:B.E•a.Y73
1Er03
y�,
B
at3xI .... ..... ......... ........ .........
..
---
a.E-raa IE+€ 2
1E+03
IE+CA aF-cl AE407 3E-103
:.E+04
€&r{. �r
& rG'3iE'05 'W` rY+€'�b3'Si.i€:?9i �IXt�it?3•Ge 6D3-0i7
�a'rrE�a�x.r-5i
�rtP�72A 9�4pA.".ies";aFd3, �fi-oratac
FYtrH ... x:r Si0p9 ..a,S:3 €fora
tdrnec �E��^d
gE-43�
1E-a5
�
3FJ7
:3.F_ai3 v , „••...... ................................... .. ........ ..... .............
..
IE+00 IE+02
2.E+04 IE+€aa IE+02
1E+04
a eta- 2. t pig i t)ESdY?SY?: -- C l<t3 Yt.t3.' 3?33zi' YI'<F0.' distance (crn) 713) YEi ;3SB? t3'<E3S3fY F' S
ti7S:i£ 3kS;y (pP, in - aE a fimctT'on of 37V£ all persistence b days for fluorinated aite3nat€ves to trMp,
PFOS and u; 7 p•ii H� ; (A and C, respectivel%,) and thm7t33.ted 3ltC73Y7tIveo replacing
itr'. jl POST- 33'i? ,;br f orotelomer-baseia subs3ai3us (B and D, rospECEl.Yfaqtt}.'Me. 131r3.rk 1193E
the 3mmifd fun CID or .11 rota e ivet3 a'e,V.
DEQ-CFW 00079746

DEQ-CFW 00079747

988 AU Ga rnk eYcl j Smut ? nj' & Tmact Fnvi=atrad;5w 505 421O1S 9SI-991
moiety separating the acid group from the pe:rflunri# aced carbon chain
(Le„ in the case of 6,2 FTt A) or a par Bally fluorinated car}kiss
(l,e., Adona) enhances the polarity of the carboxylic group, as depicted
in the es -profiles (see Figtwe A i of the Supplementary data). Further-
more, while the substitution of rigid -C'F2- groups with ether groups
decreases the molecular size of PFFC"As compared to the compounds
they replace for a siniilar chain length, the addition of da chlorine: x tom
increases the molecular size (see~ Adona, EEA and PFOA for ether and
F-53 and r- s3B for chlorine in the Supplementary date., Table A2), A
smaller molecular size requires less energy to create a cavity among
strongly -bonded water molecules. For example, Adora and Genf,
which have. a. similar polarity as PFOA, but a smaller molecular size
than PFOA (see or profiles in Figure A7 of the Supplementary data, dis-
play a slightly more hydrophilic behavior than Pr€3A. On the contrary,
clue to a higher chemical potential in grater caused by the: higher energy
costs of cavity formation, larger molecules such as PIFTECAa and FF'I`Et:.A
have a higpher &w than PFOA The numerous factors involved in cenack
ling Kg iv make it difficult to accurately assess the thermodynamic origins.
behind this partition process, which considers the costs of cx sty forma-
tion of the solute and solute -solvent interactions in both water and
cactanol phases, Unlike in air, the solute can have. Van -der- ails and
H-brand interactions with octanol„ as it is, to a lesser e:.uant than. water,
a bipolar solvent
Replacing hydrogen with fluorine: clearly hrarirogeniae.s the sul,,c.tur-
al variability among different molecules by deloca.lizing the polarity of
the acidic functional group (seen €-T-proiales, Figure. A2 in the Supplemen-
tary data). Unlike hydrogen, the, strongly eiect.ronegl'ative fluorine atoms
minimize the global polarity of the inoiecule by polling the electrons, of
partially charged poles toward they fluorinated carbon chain, As a conse-
gueoce_, the presence of ether-linkage(s) and chlorine atom in the mol-
ecule increases the polarity of the rrun-fluuriatatecl analogues more
strongly than for they PFECAs and PFESAs. In addition, all conformers of
the non -fluorinated analogues contain intrimolecular H-beard interac...
Lions, whereas no intrafriolecular H-honding; is observed for conformers
of PFEC.As and PMSAs. Intramolecular H-bonding competes with inter-
molecular H-bond interaction resulting in a decrease of polarity at the
compound grid increase of its chemical potential within polar solvents
(Warm et. al, 2011), A lower KAw and Kow would therefore be
observed without such internal H-bonds, The rigidity: of the skeletal
structure of PFECAs and PFESAs, which impedes irtramcie,-War interac-
tion, is induced by the presence of fluorine atoms, In addition, the
ir.=olecu.l;ar volume of 111'ECAs and PFESAs is 30% larger than that of the
non -fluorinated analogises (see Tamale A2 in the Supplementary data)
and sire variability among PFECAs and PFESAs is higher. (Le., 240 A
for PFECAs and PFESAs versus 1:50 it for non.- fluorinated analogues).
Together, these factors can likely explain the higher variability of.lfjvN,
respectively, among the tuns -fluorinated analogues than the FrECAs,
PFBAs and their predecessors,
42 Assessment of the environmentalfate of alternatives
Both P,ov and LRTP reflect the overall fate and behavior of the
chemical it the environment that results horn the combination of
degradation processes in different media, intermediate excha'nh'e and
thermodynamic force -driven phase partitioning. According to our
study, the Poi, and 1.RTP of the fluorinated alternatives to PFOA ,and
PFOS are similar to those of their predecessors, Moreover; some. of the
fluorinated alternatives replacing certain POSF- and/or fluoroteloaner-
based substances are as persistent and mobile as PFt2S and PFDA. It is,
therefore, likely that these alternatives can be globally d so1buted
in the environment and reach remote regions far from the primary
emission sources, similarly to the legacy PFASs (MacDonald eat ah,
2000, g, aria, 2€ f ; Scock et al„ 2007 .The 16 fluorinated alternatives
;arid 6 degradation products presented in this study can likely be consid-
ered as very persistent under the El~. REACH guidelines, since their
estimated degradation half-hves in water and soil are >60 days and
> 180 days, respectively ;pCM, 2012). In addition, the extremely per-
sistent perfluorinated fractions (the C-F bond is the strongest brand in
chemistry; Krafft, 2001) may well be the ultimite degradations products
of the fluorinated alternatives and accumulate in the environment,
Transfer from the atmosphere to the Earth's surface, depicted by TE, is
estimated to be more efficient for PFTECAr, PFTECA2, E.2 FICA, F-55,
F -538, 3.1 PTOH and 5;1 FTC}li compared to the compounds they
replace and also for most of the fluorinated alternatives replacing cer-
tairi POSF- andtar fluorotelorner-based substances. However, although
TE estir-aates are higher for these alternatives than for Prt3S and rrOA,
the absolute values are still low and do not necessarily imply enhanced
atmospheric transport. HydropUic alternatives display low TE and
will mostly reach rernore regions via ocean currents (ZArfl e: ai„ 2012)
rather than by atmospheric transport. Furthermore, a high TF value
°-> I GOV indicates that the compound (e.f;., alt-arnatlwts_ to 8:2 FTOR)
cycles several times ae„tsveen soil avail air due to its relatively long deg-
radation. half-life in air, high vapor pressure. and low hydrophobicity
(t4i ; ariarui eail; 2il09).
4_ o Assessment potential
C»,rc= 4; o'c<<l-estahlislrec} assessment of the biciaccumulative potential of
cheiracals is -by nieans of KOw as an indicator of the ability of a netural
compound to partition from water into lipid -rich tissues within an
raga€ isni..Aw coMmg to this screening; criterion that has been adopted
by the REACH guidefines (ECHA, 2012), some of the alternatives such
as :Mover and IIFOI'3i are likely bioaccumulative, since their estimated
log Kc,w is above 43, Furthermore, neutral alternatives with intermedi-
arylog fE0-A and hiEh log Kos � -5 may have the tendency to biomagnily
in air•-breathfng animals (Kelly or al. 2007). Recently, the membrane-
,, titer partition coefficient (ICi,e,,; has been proposed to be a more accu-
rate descriptor of bioaccmulation than. Kow for conventional organic
substances (Gobas et al., 1393), more specifically for H-bond donor
compounds and undissociated acids (Endo et afro 201 I), A first approx-
imation of K, gyp, using the simple regression equation proposed in
Endo et al, (N! 1) slows that the difference between lCrar,,,,,. and Kc,vv
for the oeutradak.ernadve:s and the protonated species of the acidic al-
ternatives is ;root signlficant ( f1.2 log units) (see. Table A2 fn the Siipple:-
mematy, data). It should be noted that for highly acidic PrCAs and PFSAs,
the: ionic species is likely predominant except at very low pH values
(<2) (Vierke et al., 2013a). The ionic state of PFAA.s prevents them
from accumulating in adipose tissues and induces rather a
irrote,inophilic behavior, especially with pla.srna albunun (,)ogres rut Al ,
2003, Chtm and f uo, 2£1M l.ebert. and .;a€: ,afar-es-Spc:€.c:ci; 2010), As
a re:suit of d e strr. aural similarities to PrC..As and PFA`1s, it is possible
that nary NECAS and PF�,S s might also have: high affinity to proteins,
Therefore, assessing the: Iri€aac:ctraratil rt'%crag of these acidic fl=mated al-
ternatives with a pK;, <6 $,C:€arader et al, 2C1C18) according;' to the. regrilato-
ry criteria that are solely iris£: l an fCuw or Kea,A, (i.e., chemical partitions
into adipose tissues) could possibly result in significant und.erestima-
bon. Therefore, in order to assess the bioaccumulation potential of
these acidic: fluorinated alternatives, much of the empirical work to un-
derstand tires protein -binding niechanisnis and kinetics of PFAAs and
their alternatives is stall needed (Ng and Hungea•buhler, 20 z)o
44, ,Fur, Mueatltln Luid unc.e.rinimies
For a preliminary assessment of the environmental fate. cif lluorinated
alternatives ;on a g lcriral scale), the: tyl.C'I.1'."00l is h. e:ly saaificient How-
ever, the accuracy of estimated results depends strongly on 1) the can-
sistency and accuracy, of input parameters and 2) the environmental
processes consiete red in, the rnridel,
4AAL Unr:ertax nn s it the inputparameter esdrnution
For pl ysicoclrearrical prcrlse=rti£as, t.}eea aiiplicabihtya of COS.yICltherni
foe• Pa 1Ss in their -,corral form has been demonstrated in two studies
DEQ-CFW 00079748

DEQ-CFW 00079749

AU G'V72Iis et at"Science. elf the'iaraa nVironnump.. 50,5 f2f)I S 9R 1 ­9191
,%;yang, et Ai, 2011', AT et al- 2W5), whereas the applicability of
HF.X-NR sPu' N, KOVsJWIN and NIMP131" IN in the EPISuite package, which
predict E;;.,r, Kow and PL, respectively, is questionable for PFASs, givt=ra
that they performed poorly for legad:y PFASs as shown iaa a previous
scurfy (Arp et al., 2006), SPARC is a well -established tool that has
been extensively used by regulators and scleutists to predict the
ptfb of chemicals (US EPA, 2003), However, the. p.l ,,s of fluorin au, -A al-
ternatives are likely a anderestir€iated by Sig RC— As shown in the vase
of GenX, its experimental ff, of18 (E€.HA, is muclr higher
than the estimated one ( 0.06), There are large uncertainties re-
garding the p ,,s of the fluorinated ,Ot:e.imtives, which was also
true for the PKAs (Coss, 20081 clue to difficulties, in measuring pKx
fur highly fluorinated substances. For some acidic aalte.ruaatives, the
value ofpKa used in talc lations of I, v and ari, can have a large ire..
pact on the results €.af CTI) and TE, as shown in Table Ali of the Supple-
mentary data, Reducing, the uncertainty in pKas of fluorinated
alternatives that have pP, values in the environmental pH range is
therefore a lesejrch priority,
For degrac•Iation half-lives, the FP1Suite. models used, ADPWIx l and
MOWN, apply Q$Pk methods (Kwok and M ffison, I P, 5. Boedbling
;al., 13: A'. Evaluating the predictive power of these Q5PPs for fluori-
nated compounds is hmited by the scarcity of empirical values. Some
studies already corroborate the accuracy of AOP`vt IN predictions when
it: conies to r ea:ction of organic chemicals emicails with Oil radicals in the atmo-
sphere (�'tOsten et al- 1995. Sabl)ic and Peijnenburg. 2001). Measured
second -carder rate constants for atmospherdc OH radical-rriediated detg-
radation are available for three fluorinated alternatives and four legacy
PPASs, Lallowi g a limited evaluation ofAOP` INN =;see Table A.4 of the
Saappieinentary dara). Even though its training and test seas contain sev-
eral fluorinated substances, AOPWlNN has a tendency to ovev predlcd
second -order rate constants. For example., the predicted rate constant
of N.-ethyl perfluorobutane suffonarude ErFBSA) is 24 bores higher
than the experimental one ( Martin et aL„ 2006). hi addition, At1PWIN
slightly ov„erpred cts the second -order rate constants by loss than a
factor of 2 for 3:1. FTOH (Bravo etal., 2010) and 5:1 F'TOH (Hurley
et al., 2004), by a factor of 3 for N-niethyfl perfluorvbutane
sulfonamidoetbatiol (lvleMSF) (D'E€ira e:t al., 2d� ,1i) and by a factor of 4
for 8:2 F"FDH (Ellis et al_, 2 33) and PFi1A ( tarley et A., 20t ). As a con-
sequence, the fluorinated alternatives presented in this work are likely
to be even more persisten', in air (and have greater t"1D) than shown
in Fig. 2. In addition, it is noted that. A01WIli, which only encompasses
reaction with 01-1 radicals. (iod ,, 4idirect photolysis), recognizes when a
molecule cann€.t undergo Indirect photolysis. For instance, the half-life
of No4>ec could riot be predicted, since this molecule is degraded
through dit---c t photolysis only (Jackson et al., 2011, Taniguchi et al,.
Several starches evaluated the accuracy of the BIOWIN program for
organic compoun dsoWhile it is an effective tool for binary classification
of chemicals (i.e., readily- biodegradable or not). Fl101r'i!IN has limited,
quantitadve predictive power (Gouin et al., 2004, Amnsou et ad., 2€ 06,
lt.;dne et al., ''€3tT , f.irri and Fox, 2012), Due to the lack of experimental
data on ultinaate. €ricrubial degradation of fluorinated alternatives,
assessing the accuracy of 131L1WI'y3 estimated for these compounds is
currently riot. possible. Nevertheless, experimental primary biodegr•ada..
tion half-lives ofseveral fluuroodomzer;based substances (Liu and Meiia
Avendafao, 202) allow an assessment of BIOVVIN4, which is an expert
survey moduie based on the same estimation method as MOWIN3 but
designated for pri€nary rather than; ultimate degradation. Assessing
BlMAON-4 can thus provide insight into the predictive power of
BIMNIN1 BIOWd.l A uncle.restlmates the primary degradation half-life
of 6:2 fl£iorotelorner sulfenic acid (602 F TSA) by a factor of more than
2.5 and overesthrsates the primary degradation half-life of 8.2 FTDH
into PFOA by up to 17 times, The poor predictive power of BIOWIN d
indicate,, tba: the estima ions of BltiWIN3 are also Inaccurate, As a con-
sequence, the predictive power of MOWIN3 for PFASs is expected to be
limited.
989
4.4.2 ,I;DT v33'd5iti7df'ntri!fine r€ oidei aild € utput p+€arametErs
The Monte Carlo analysis revealed that the degradation half-lives in
wader and air are the. major contributors to the uncertainty of Po%, and
011. Both estimated input parameters also depend on the environmen-
tal processes considered in the OECD Tool"s calculations. Sonic possibly
significant processes that may influence the Pov and LBTP of fluorinated
alternatives are not represented in the OKD Tool. Among them is the
possible transfer of fluorinated alternatives from the seawater surface
to the atmosphere via marine aerosol generation„ due to their
surfactant- like properties, This phenomenon is already rather well doc-
umented for PFO/PFOA (Websmr and Ellis, 2310, Peth et al., 2011,
McMurdo et ai„ 2008) as well as for other tong -chain PFCA,s and PFSAs
(Reth et al., 2011). Briefly, the strong surfactant-hl€e properties of
long -drain PrCAs and PFSAs cause Chem to acrumudate. in the surface
microlayer of the ocean and thus also in. the. marine aerosols formed
from the microlayer of ocean surface: water caused by the waves.1"he
pli of marine aerosols is between 3.2 and 5.4 (Psteran di°ral., 121334) on
average. T1tus, if a flu£aririatd4ci alternative has a pKa in this pH range, a
large fraction of protoriatard form of the substance rna,y well be present
in the madne� aerosols, lu this case, if the proto€3LatLd fluorinated alterna-
tives have a high vapor pressure, a significant amoum of protouated
species may volatilize from the marine aerosol into the atmosphere
and thus be transported long distances. Since such euvlrvnmentaal pro-
cesses are fiat included in the OECDTool, the crD outputs might be
underestimated for sonic: of the fluorinated alternatives,
de Outlook
To date, the absence of experimental data on degradation half-lives
and physicochemical properties is a major drawback for carrying out
hazard and risk assessments of emerging chemicals such as fluorinated
alterr itives. At this stage, the use of in silica methods remains the only
time- and resource -saving tool for the Identification of potential hazard-
ous chemicals. Despite the inherent uncertainties, our study provides
qualitative evidence that most of the alternatives do not differ signifi-
cantly from PFOA, PFOS and their precursors regarding the physico-
chemical properties and likely environmental fate. These alternatives
are GeuX, PFTECA 1, PET a, 6:2 FTCA, (alternatives to PFOA) F-53, F-
53B, PFBSaPa (alternatives to PFDS), 6.1, 3:1 FTOT-Is (alternatives to
8.2 FTDH), Forafac, EF-N, Novec, the degradation products of tit Ul72dl,
PFOTSi and its degradation products (alternatives to certain PtTSF-
andfor fhmrotelomer-based substances) and further investigations
should focus on them. Faartherfriore, irtilar€over€cent: of the data quality
and information on production volurnes and envitomnrital cinission
estimates are required for further, more cluantitative risk asser.ssinent.
The experiments that are urgently needed to improve: the hazard
assessment of the afore.listed fluorinated alternatives and to determine
if they are safe for humans and biota area 1) (blo)degradabon experi-
ments in relevant environmental media for Individual substances;
2) pK, measurements of the acidic: fluorinate€l akernatives, in particular
PFECAs and PFESAs-, 3) bioaccumulation experiments, including
protein -binding experiments for the, acidic fluorinated alternatives
and f £?VJ experiments for the neutral ones; and 4) toxicity test,, to iden-
tify their erode-of-acdlon and toxicity, which can be further used to
develop i_SAR models that caul be reliably used to predict the toxicity
of PFASs. A summary table showlfag a comparison of fluorinated alterna-
tives to legacy PFASs and hicrhbgliting experimental priorities for each
fluorinated alternative,, is available in Table A9 of the. Supplementary
data.
Aolr;t owl lgments
European Union's Seventh Fra.awwork.. Progrannn£. for research,
technological development and rlerraotfst.rataori under grant agreerilent
no, 316665 (A-UAN1 project) and the Swiss Federal Office for the. Envi-
ronment (MEN) for their financial support..
DEQ-CFW 00079750

DEQ-CFW 00079751

s90
Appendix A, Sax plf,:a nitary tMt.a
X- P Cnrrtls et at I Srierre of the Total Envlror net#t 3fxS z2t11 S, 3_a }?
Sapplei1•YettUW data to this article can be found online at http ''/dx,
z$i3Ux, s = 0A M 6,, j.-citotenv,20 t it,10,062,
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