Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.14 mg/m³
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 descriptor starting point:
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. 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 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-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.
AF for interspecies differences (allometric scaling):
1
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 REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
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.
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term 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:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
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.
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-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.
AF for interspecies differences (allometric scaling):
4
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:
5
Justification:
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.
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:
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

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.In 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 (PPARĪ±) 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 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).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
0.87 mg/m³
Explanation for the modification of the dose descriptor starting point:
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. 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 scaling):
1
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 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

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

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

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.01 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
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.
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 scaling):
4
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.In 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 (PPARĪ±) 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 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).