Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
other: NOEC
Value:
25 mg/m³
Explanation for the modification of the dose descriptor starting point:
28 mg/kg bw/day x (1/0.38) x (50 oral abs/100 inhal abs) x (6.7/10)
AF for dose response relationship:
1
Justification:
NOAELs established in repeat dose tox studies. Carcinogenicity via peroxisome proliferation not relevant to man
AF for differences in duration of exposure:
1
Justification:
Duration appropriate to delayed ossification in pregnancy: chronic NOAELs considerably higher than starting point selected, and carcinogenicity observed not relevant to man
AF for interspecies differences (allometric scaling):
1
Justification:
Already taken into account during the correction of starting point
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
2
Justification:
Database appropriate for tonnage. 2 assigned because of readacross, although readacross material likely to be the worse of the two materials.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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)
Value:
0.56 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
other: NOEL
Value:
56 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
28 x (50% oral abs / 25% dermal abs)
AF for dose response relationship:
1
Justification:
NOAELs established in repeat dose tox studies. Carcinogenicity via peroxisome proliferation not relevant to man
AF for differences in duration of exposure:
1
Justification:
Duration appropriate to delayed ossification in pregnancy: chronic NOAELs considerably higher than starting point selected, and carcinogenicity observed not relevant to man
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for extrapolating toxicokinetics from Rat to Human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
2
Justification:
Database appropriate for tonnage. 2 assigned because of readacross, although readacross material likely to be the worse of the two materials.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
no hazard identified

Additional information - workers

The substance, or the read-across substance, were not considered mutagenic in studies that were adequately conducted. In reliable 90 day and chronic/carc dietary studies in the rat and the mouse for a near identical read-across substance, clear NOAELs were established. Only a LOAEL was established in mice based on tumours, however these were via a mechanism not relevant to man (peroxisome proliferation). A NOEL of 28 mg/kg bw/day was established in the teratogenicity study for the read across material, based on a slight "non-adverse" increase in delayed ossification and skeletal variations, and this value drives the DNELs. No correction for duration of exposure was applied as the NOEL is already considerably lower than the chronic NOAELs established (even when the 90 day mouse NOAEL of 200 mg/kg bw/day is corrected for duration by a factor of 2). An additional AF of 2 was applied under "Quality of Database" given that the DNELs are based on read -across although the readacross material likely to be the worse of the two materials. In acute oral, dermal and inhalation toxicity studies no adverse effects were observed at the limit dose in the dermal toxicity study, at 2000 mg/kg in the oral study or at 200 mg/kg in the dermal study. No local tolerance issues were identified from skin irritation, skin sensitisation, or eye irritation studies. The NOAEL for paternal and foetal effects in the OECD 415 reproduction study conducted was 170 mg/kg bw/day. There was no effect on reproduction.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.24 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
other: NOEC
Value:
12 mg/m³
Explanation for the modification of the dose descriptor starting point:
28 mg/kg bw/day x (1/1.15) x (50 oral abs/100 inhal abs)
AF for dose response relationship:
1
Justification:
NOAELs established in repeat dose tox studies. Carcinogenicity via peroxisome proliferation not relevant to man
AF for differences in duration of exposure:
1
Justification:
Duration appropriate to delayed ossification in pregnancy: chronic NOAELs considerably higher than starting point selected, and carcinogenicity observed not relevant to man
AF for interspecies differences (allometric scaling):
1
Justification:
Already taken into account during the correction of starting point
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
2
Justification:
Database appropriate for tonnage. 2 assigned because of readacross, although readacross material likely to be the worse of the two materials.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
DNEL (Derived No Effect Level)
Value:
0.28 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
other: NOEL
Value:
56 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
28 x (50 oral abs/25% derm abs)
AF for dose response relationship:
1
Justification:
NOAELs established in repeat dose tox studies. Carcinogenicity via peroxisome proliferation not relevant to man
AF for differences in duration of exposure:
1
Justification:
Duration appropriate to delayed ossification in pregnancy: chronic NOAELs considerably higher than starting point selected, and carcinogenicity observed not relevant to man
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for extrapolating toxicokinetics from Rat to Human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
2
Justification:
Database appropriate for tonnage. 2 assigned because of readacross, although readacross material likely to be the worse of the two materials.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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)
Value:
0.56 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
other: NOEL
Value:
28 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAELs established in repeat dose tox studies. Carcinogenicity via peroxisome proliferation not relevant to man
AF for differences in duration of exposure:
1
Justification:
Duration appropriate to delayed ossification in pregnancy: chronic NOAELs considerably higher than starting point selected, and carcinogenicity observed not relevant to man
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for extrapolating toxicokinetics from Rat to Human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
2
Justification:
Database appropriate for tonnage. 2 assigned because of readacross, although readacross material likely to be the worse of the two materials.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The substance, or the read-across substance, are not considered mutagenic in studies that were adequately conducted. In reliable 90 day and chronic/carc dietary studies in the rat and the mouse for a near identical read-across substance, clear NOAELs were established. Only a LOAEL was established in mice based on tumours, however these were via a mechanism not relevant to man (peroxisome proliferation). A NOEL of 28 mg/kg bw/day was established in the teratogenicity study for the read across material, based on a slight "non-adverse" increase in delayed ossification and skeletal variations, and this value drives the DNELs. No correction for duration of exposure was applied as the NOEL is already considerably lower than the chronic NOAELs established (even when the 90 day mouse NOAEL of 200 mg/kg bw/day is corrected for duration by a factor of 2). An additional AF of 2 was applied under "Quality of Database" given that the DNELs are based on read -across although the readacross material likely to be the worse of the two materials. In acute oral, dermal and inhalation toxicity studies no adverse effects were observed at the limit dose in the dermal toxicity study, at 2000 mg/kg in the oral study or at 2000 mg/kg in the dermal study. No local tolerance issues were identified from skin irritation, skin sensitisation, or eye irritation studies. The NOAEL for paternal and foetal effects in the OECD 415 reproduction study conducted was 170 mg/kg bw/day. There was no effect on reproduction.