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DEQ-CFW 00000590
ammonium... - Registration Dossier - ECHA
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ammonium , ,,-t r flu r -(htlr r )
propanoate
EC number: 700-242-3 CAS number: 62037-80-3
Toxicological information
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Longterm exposure
Hazard assessment conclusion: DNEL (Derived No Effect Level)
0.14 mg/m'
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
1.76 mg/m3
Explanation for the modification of the dose
The key study for DNEL calculation is an OECD 453 rat chronic toxicity study via oral
descriptor starting point:
administration. The NOAEL was determined to be 1 mg/kg bw/day, based on adverse effects in
females at 500 mg/kg bw/day, and males at 50 mg/kg bw/day. Factors of 1/0.38 m3 and 0.67
were applied to the starting point to account for standard respiratory volume, and increased
respiratory volume in active workers as compared to individuals at rest, respectively, per REACH
guidance R.8.4.2. Since the substance was determined to be completely absorbed from the
gastrointestinal tract, no modification of the starting point was needed to correct for oral
administration as compared to inhalation.
AF for dose response relationship:
1
Justification:
The starting point is a NOAEL from a robust OECD 453 guideline chronic toxicity/carcinogenicity
study. An assessment factor of I is appropriate per REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
1
Justification: The starting point is from a robust OECD 453 guideline chronic toxicity/carcinogenicity study. The
study was a 2-yr dosing study, and included a 1-year interim sacrifice. An assessment factor of 1
is appropriate per REACH guidance R.8.4.3.1.
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AF for interspecies differences (allometric
scaling):
Justification:
AF for other interspecies differences
Justification:
AF for intraspecies differences
Justification:
AF for the quality of the whole database:
Justification:
Acute/short term exposure
Hazard assessment conclusion:
DNEL related information
Local effects
Longterm exposure
Hazard assessment conclusion:
Acute/short term exposure
Hazard assessment conclusion:
DNEL related information
III
A factor of 1 is appropriate since the adjusted start point was via inhalation (mg/m3), per REACH
guidance Appendix R. 8-2.
2.5
Since there are no data to justify a reduction or increase in the interspecies default assessment
factor, a default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
5
Since there are no data to justify a reduction or increase in the intraspecies default assessment
factor, a default factor of 5 is appropriate per REACH guidance R.8.4.3.1.
1
A high quality, robust toxicity database exists for this substance. An assessment factor of 1 is
appropriate per REACH guidance R.8.4.3.1.
no hazard identified
no hazard identified
no hazard identified
Workers - Hazard via dermal route
Systemic effects
Longterm exposure
Hazard assessment conclusion: DNEL (Derived No Effect Level)
0.02 mg/kg bw/day
Most sensitive endpoint: repeated dose toxicity
Route of original study: Oral
DNEL related information
DNEL derivation method:
Overall assessment factor (AF):
Modified dose descriptor starting point:
ECHA REACH Guidance
50
NOAEL
1 mg/kg bw/day
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Explanation for the modification of the dose
descriptor starting point:
AF for dose response relationship:
Justification:
AF for differences in duration of exposure:
Justification:
AF for interspecies differences (allometric
scaling):
Justification:
AF for other interspecies differences:
Justification:
AF for intraspecies differences:
Justification:
AF for the quality of the whole database:
Justification:
The key study for DNEL calculation is an OECD 453 rat chronic toxicity study via oral
administration. The NOAEL was determined to be 1 mg/kg bw/day, based on adverse effects in
females at 500 mg/kg bw/day, and males at 50 mg/kg bw/day. Since the substance was
completely absorbed via the gastrointestinal tract following oral administration, no adjustment is
needed to compensate for the dermal route,
1
The starting point is a NOAEL from a robust OECD 453 guideline chronic toxicity/carcinogenicity
study. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
1
The starting point is from a robust OECD 453 guideline chronic toxicity/carcinogenicity study. The
study was a 2-yr dosing study, and included a 1-year interim sacrifice. An assessment factor of 1
is appropriate per REACH guidance R.8.4.3.1.
4
A factor of 4 is appropriate to extrapolate between rats and humans, per REACH guidance
Appendix R. 8-2.
2.5
Since there are no data to justify a reduction or increase in the interspecies default assessment
factor, a default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
5
Since there are no data to justify a reduction or increase in the intraspecies default assessment
factor, a default factor of 5 is appropriate per REACH guidance R.8.4.3.1.
1
A high quality, robust toxicity database exists for this substance. An assessment factor of 1 is
appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion: no hazard identified
DNEL related information
Local effects
Longterm exposure
Hazard assessment conclusion: no hazard identified
Acute/short term exposure
Hazard assessment conclusion: no hazard identified
Workers - Hazard for the eyes
Local effects
Hazard assessment conclusion: high hazard (no threshold derived)
Additional information - workers
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This substance is a solid powder, and workers could potentially be exposed via the inhalation and dermal
routes. Therefore, no DNELs for the oral route for workers were derived. The substance is an eye irritant, but no other
local effects were observed in acute or repeated exposure studies; therefore no DNELs for local effects were derived.
DNELs for long-term exposure systemic effects via the inhalation and dermal routes were derived.
Based on an oral LD50 of 1750 mg/kg in male rats, the substance is classified as acute toxicity Category 4 toxic
according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no.
1272/2008. The male and female rat 4-hour inhalation LC50 was greater than 5000 mg/m3, and is not classified as
acutely toxic by the inhalation route according to the EU Classification, Labelling and Packaging of Substances and
Mixtures (CLP) regulation (EC) no. 1272/2008. The substance is classified for eye irritation category I according to the
EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. The
substance did not produce skin irritation or corrosion or skin sensitization in laboratory animals. The substance has
been extensively tested for effects on genetic material and no classification for mutagenicity is required according to
the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. The
substance has been tested, and is not classified as a developmental or reproductive toxicant according to the EU
Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. Multiple
repeated exposure studies have been conducted. The key study for repeated inhalation study was an OECD 453
(Combined Chronic Toxicity/Carcinogenicity Study) guideline study in rats.ln the chronic toxicity/carcinogenicity study
in rats, test substance -related neoplastic changes were limited to the high dose groups (50 and 500 mg/kg/day in
males and females), and were consistent with the known effects of peroxisome proliferator alpha (PPARa) in rodents.
Neoplastic effects included hepatocellular tumours in 500 mg/kg/day females and, equivocally, pancreatic acinar cell
tumours and testicular interstitial cell tumours in 50 mg/kg/day males. All tumours occurred with a clear threshold in
both males and females. In females, liver tumours in the 500 mg/kg/day dose group occurred in association with
marked systemic toxicity, as well as liver toxicity, and no hepatocellular tumours were observed in females at lower
doses where no liver toxicity was observed. The induction of liver tumours in female rats at 500 mg/kg/day, and the
equivocal increase in pancreatic acinar and testicular interstitial cell tumours in male rats at 50 mg/kg/day are likely not
relevant to humans based on the following: most research indicates that induction of these specific tumours in rats by
non-genotoxic peroxisome proliferators likely has little or no relevance to humans, especially in plausible human
exposure scenarios; the test material was determined to be non-genotoxic based on a battery of in vivo and in
vitro genotoxicity studies; liver tumours were produced only in females and only at doses associated with marked
hepatic and systemic toxicity (including lethality); and thresholds were established for all tumour types in both males
and females. Based on these considerations, the test substance is not classified for carcinogenicity in humans,but
based on non-neoplastic effects the substance is classified as a STOT RE Category 2 (liver, blood) according to the EU
Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no, 1272/2008.
All REACH Annex IX and X type studies, i.e., carcinogenicity, developmental, reproductive and chronic toxicity studies
were conducted to comply with a U.S. EPA consent order, or for product stewardship purposes. They were not
conducted to meet REACH registration requirements.
The key study for the DNEL calculation is an OECD 453 rat chronic toxicity study via oral administration. The NOAEL
was determined to be 'I mg/kg bw/day, based on adverse effects in females at 500 mg/kg bw/day, and males at 50
mg/kg bw/day (for details see repeated exposure section).
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
Hazard assessment conclusion:
Most sensitive endpoint:
Route of original study:
DNEL related information
DNEL derivation method:
Overall assessment factor (AF)
DNEL (Derived No Effect Level)
0.04 mg/m'
repeated dose toxicity
Oral
ECHA REACH Guidance
25
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Modified dose descriptor starting point: NOAEC
0.87 mg/m'
Explanation for the modification of the dose
The key study for DNEL calculation is an OECD 453 rat chronic toxicity study via oral
descriptor starting point:
administration. The NOAEL was determined to be 1 mg/kg bw/day, based on adverse effects in
females at 500 mg/kg bw/day, and males at 50 mg/kg bw/day. A factor of 1 /1.15 m3 was
applied to the starting point to account for standard respiratory volume per REACH guidance
R.8.4.2. Since the substance was determined to be completely absorbed from the
gastrointestinal tract, no modification of the starting point was needed to correct for oral
administration as compared to inhalation.
AF for dose response relationship:
1
Justification:
The starting point is a NOAEL from a robust OECD 453 guideline chronic toxicity/carcinogenicity
study. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
1
Justification: The starting point is from a robust OECD 453 guideline chronic toxicity/carcinogenicity study. The
study was a 2-year dosing study, and included a 1-year interim sacrifice. An assessment factor of
1 is appropriate per REACH guidance R.8.4.3.1.
AF for interspecies differences (allometric 1
scaling):
Justification: A factor of 1 is appropriate since the adjusted start point was via inhalation (mg/m3), per REACH
guidance Appendix R. 8-2.
AF for other interspecies differences: 2.5
Justification: Since there are no data to justify a reduction or increase in the interspecies default assessment
factor, a default factor of 2.5 is appropriate per REACI i guidance R.8.4.3.1.
AF for intraspecies differences: 10
Justification: Since there are no data to justify a reduction or increase in the intraspecies default assessment
factor, a default factor of 10 is appropriate per REACH guidance R.8.4.3.1.
AF for the quality of the whole database: 1
Justification: A high quality, robust toxicity database exists for this substance. An assessment factor of 1 is
appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion: no hazard identified
DNEL related information
Local effects
Long term exposure
Hazard assessment conclusion
Acute/short term exposure
Hazard assessment conclusion:
DNEL related information
no hazard identified
no hazard identified
General Population - Hazard via dermal route
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Systemic effects
Long term exposure
Hazard assessment conclusion: no hazard identified
Acute/short term exposure
Hazard assessment conclusion: no hazard identified
DNEL related information
Local effects
Long term exposure
Hazard assessment conclusion: no hazard identified
Acute/short term exposure
Hazard assessment conclusion: no hazard identified
General Population - Hazard via oral route
Systemic effects
Longterm exposure
Hazard assessment conclusion:
Most sensitive endpoint:
Route of original study:
DNEL related information
DNEL derivation method:
Overall assessment factor (AF):
Modified dose descriptor starting point:
Explanation for the modification of the dose
descriptor starting point:
AF for dose response relationship:
Justification:
AF for differences in duration of exposure:
Justification:
DNEL (Derived No Effect Level)
0.01 mg/kg bw/day
repeated dose toxicity
Oral
ECHA REACH Guidance
100
NOAEL
1 mg/kg bw/day
The key study for DNEL calculation is an OECD 453 rat chronic toxicity study via oral
administration. The NOAEL was determined to be 1 mg/kg bw/day, based on adverse effects in
females at 500 mg/kg bw/day, and males at 50 mg/kg bw/day. The human exposure route and
the experimental exposure route are both oral, and it is assumed that the substance is completely
absorbed.
1
The starting point is a NOAEL from a robust OECD 453 guideline chronic toxicity/carcinogenicity
study. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
1
The starting point is from a robust OECD 453 guideline chronic toxicity/carcinogenicity study. The
study was a 2-year dosing study, and included a 1-year interim sacrifice. An assessment factor of
1 is appropriate per REACH guidance R.8.4.3.1.
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AF for interspecies differences (allometric 4
scaling):
Justification: A factor of 4 is appropriate to extrapolate between rats and humans, per REACH guidance
Appendix R. 8-2.
AF for other interspecies differences:
2.5
Justification:
Since there are no data to justify a reduction or increase in the interspecies default assessment
factor, a default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
Since there are no data to justify a reduction or increase in the intraspecies default assessment
factor, a default factor of 10 is appropriate per REACH guidance R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance. An assessment factor of 1 is
appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
Hazard assessment conclusion: high hazard (no threshold derived)
Additional information - General Population
This substance is a solid powder, and exposure to the general population is unlikely. Nevertheless, inhalation and oral
exposure are plausible so DNELs were derived for these exposure scenarios. No DNELs for the dermal route in the
general population were derived. The substance is an eye irritant, but no other local effects were observed in acute or
repeated exposure studies; therefore no DNELs for local effects were derived.
Based on an oral LD50 of 1750 mg/kg in male rats, the substance is classified as acute toxicity Category 4 toxic
according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no.
1272/2008. The male and female rat 4-hour inhalation LC50 was greater than 5000 mg/m3, and is not classified as
acutely toxic by the inhalation route according to the EU Classification, Labelling and Packaging of Substances and
Mixtures (CLP) regulation (EC) no. 1272/2008. The substance is classified for eye irritation category I according to the
EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. The
substance did not produce skin irritation or corrosion or skin sensitization in laboratory animals. The substance has
been extensively tested for effects on genetic material and no classification for mutagenicity is required according to
the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. The
substance has been tested, and is not classified as a developmental or reproductive toxicant according to the EU
Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) no. 1272/2008. Multiple
repeated exposure studies have been conducted. The key study for repeated inhalation study was an OECD 453
(Combined Chronic Toxicity/Carcinogenicity Study) guideline study in rats.ln the chronic toxicity/carcinogenicity study
in rats, test substance -related neoplastic changes were limited to the high dose groups (50 and 500 mg/kg/day in
males and females), and were consistent with the known effects of peroxisome proliferator alpha (PPARa) in rodents.
Neoplastic effects included hepatocellular tumours in 500 mg/kg/day females and, equivocally, pancreatic acinar cell
tumours and testicular interstitial cell tumours in 50 mg/kg/day males. All tumours occurred with a clear threshold in
both males and females. In females, liver tumours in the 500 mg/kg/day dose group occurred in association with
marked systemic toxicity, as well as liver toxicity, and no hepatocellular tumours were observed in females at lower
doses where no liver toxicity was observed. The induction of liver tumours in female rats at 500 mg/kg/day, and the
equivocal increase in pancreatic acinar and testicular interstitial cell tumours in male rats at 50 mg/kg/day are likely not
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relevant to humans based on the following: most research indicates that induction of these specific tumours in rats by
non-genotoxic peroxisome proliferators likely has little or no relevance to humans, especially in plausible human
exposure scenarios; the test material was determined to be non-genotoxic based on a battery of in vivoand in
vitro genotoxicity studies; liver tumours were produced. only in females and only at doses associated with marked
hepatic and systemic toxicity (including lethality); and thresholds were established for all tumour types in both males
and females. Based on these considerations, the test substance is not classified for carcinogenicity in humans,but is
classified as a STOT RE Category 2 (liver, blood) according to the EU Classification, Labelling and Packaging of
Substances and Mixtures (CLP) regulation (EC) no. 1272/2008.
All REACH Annex IX and X type studies, i.e., carcinogenicity, developmental, reproductive and chronic toxicity studies
were conducted to comply with a U.S. EPA consent order, or for product stewardship purposes. They were not
conducted to meet REACH registration requirements.
The key study for DNEL calculation is an OECD 453 rat chronic toxicity study via oral administration. The NOAEL was
determined to be 1 mg/kg bw/day, based on adverse effects in females at 500 mg/kg bw/day, and males at 50 mg/kg
bw/day (for details see repeated exposure section).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. E C H A
The assignment of a registration number does however not guarantee that the information in the dossier is correct or that •YSC NAM CNIMICA Lt AC CNCY
the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been
reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information
without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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