Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.7 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):
36
Modified dose descriptor starting point:
NOAEC
Value:
529 mg/m³
Explanation for the modification of the dose descriptor starting point:
No long term inhalation study is available. The oral OECD 422 study is the longest test giving the most reliable results and was therefore used for the route to route extrapolation. Following ECHA guidance R.8 the inhalation point of departure was calculated using a factor of 6.7/10/0.38
AF for dose response relationship:
1
Justification:
100% inhalative absorption assumed
AF for differences in duration of exposure:
6
Justification:
ECHA guidance R.8 default
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA guidance R.8 default
AF for other interspecies differences:
1
Justification:
A factor of 1 instead of the ECHA default factor of 2.5 is justified. Two acute oral rat toxicity studies are available which show lethal effects at similar doses (8g/kg). The approach of ECETOC, Technical report No. 110 (2010) is conservative enough to cover remaining differences.
AF for intraspecies differences:
3
Justification:
The ECETOC Technical report No. 110 (2010) assessment factor of Intraspecies Extrapolation of 3 for workers is justified in accordance with the following reasons:
• Given that both oral and inhalation exposure studies show a similar critical effect (i.e., kidney and liver weight increase), and given the fast excretion of MPD identified in the toxicokinetic study, the metabolism of the substance is sufficiently well understood. Therefore, no difference in sensitivity (toxicokinetics) between test animals and humans is to be expected besides aspects already covered by allometric scaling.
• The ECHA default intraspecies AF of 5 for workers can be broken down into equal factors for toxicodynamic and toxicokinetic differences, respectively. As toxicokinetic differences can be eliminated based on the above study results, the ECETOC factor of 3 is used as reasonable values for intraspecies extrapolation.
AF for the quality of the whole database:
2
Justification:
assessment is based on a single long term study only. A quality factor of 2 was therefore applied to account for missing chronic studies.
AF for remaining uncertainties:
1
Justification:
ECHA guidance R.8 default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 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):
144
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For both oral and dermal absorption an assessment factor of 1 was used based on the toxicokinetic results discussed above
AF for dose response relationship:
1
Justification:
100% dermal absorption assumed
AF for differences in duration of exposure:
6
Justification:
ECHA guidance R.8 default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance R.8 default
AF for other interspecies differences:
1
Justification:
A factor of 1 instead of the ECHA default factor of 2.5 is justified. Two acute oral rat toxicity studies are available which show lethal effects at similar doses (8g/kg). The approach of ECETOC, Technical report No. 110 (2010) is conservative enough to cover remaining differences.
AF for intraspecies differences:
3
Justification:
ECETOC 2010, see justification at inhalation systemic above
AF for the quality of the whole database:
2
Justification:
assessment is based on a single long term study only. A quality factor of 2 was therefore applied to account for missing chronic studies.
AF for remaining uncertainties:
1
Justification:
ECHA guidance R.8 default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Ambiguous results were otained from eye irritation studies with rabbits. A worst case approach has been adopted and eye irritation is concluded which also warrants the classification of the substance as hazardous.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 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):
60
Modified dose descriptor starting point:
NOAEC
Value:
260 mg/m³
Explanation for the modification of the dose descriptor starting point:
oral OECD 422 study is the longest test giving the most relaible results. Route to route extrapolation following ECHA guidance example R.8-1 for general population AF = 1.15 m³* d/kg bw.
AF for dose response relationship:
1
Justification:
ECHA guidance R.8 default
AF for differences in duration of exposure:
6
Justification:
ECHA guidance R.8 default
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA guidance R.8 default
AF for other interspecies differences:
1
Justification:
A factor of 1 instead of the ECHA default factor of 2.5 is justified. Two acute oral rat toxicity studies are available which show lethal effects at similar doses (8g/kg). The approach of ECETOC, Technical report No. 110 (2010) is conservative enough to cover remaining differences.
AF for intraspecies differences:
5
Justification:
The ECETOC Technical report No. 110 (2010) assessment factor of Intraspecies Extrapolation of 5 for general public is justified in accordance with the following reasons:
• Given that both oral and inhalation exposure studies show a similar critical effect (i.e., kidney and liver weight increase), and given the fast excretion of MPD identified in the toxicokinetic study, the metabolism of the substance is sufficiently well understood. Therefore, no difference in sensitivity (toxicokinetics) between test animals and humans is to be expected besides aspects already covered by allometric scaling.
• The ECHA default intraspecies AF of 10 for the general public can be broken down into equal factors for toxicodynamic and toxicokinetic differences, respectively. As toxicokinetic differences can be eliminated based on the above study results, the ECETOC factor of 5 is used as reasonable values for intraspecies extrapolation.
AF for the quality of the whole database:
2
Justification:
assessment is based on a single long term study only. A quality factor of 2 was therefore applied to account for missing chronic studies.
AF for remaining uncertainties:
1
Justification:
ECHA guidance R.8 default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
for both oral and dermal absorption an assessment factor of 1 was used.
AF for dose response relationship:
1
Justification:
ECHA guidance R.8 default
AF for differences in duration of exposure:
6
Justification:
ECHA guidance R.8 default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance R.8 default
AF for other interspecies differences:
1
Justification:
A factor of 1 instead of the ECHA default factor of 2.5 is justified. Two acute oral rat toxicity studies are available which show lethal effects at similar doses (8g/kg). The approach of ECETOC, Technical report No. 110 (2010) is conservative enough to cover remaining differences.
AF for intraspecies differences:
5
Justification:
ECETOC 2010, see justification at inhalation systemic above
AF for the quality of the whole database:
2
Justification:
assessment is based on a single long term study only. A quality factor of 2 was therefore applied to account for missing chronic studies.
AF for remaining uncertainties:
1
Justification:
ECHA guidance R.8 default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA guidance R.8 default
AF for differences in duration of exposure:
6
Justification:
ECHA guidance R.8 default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance R.8 default
AF for other interspecies differences:
1
Justification:
A factor of 1 instead of the ECHA default factor of 2.5 is justified. Two acute oral rat toxicity studies are available which show lethal effects at similar doses (8g/kg). The approach of ECETOC, Technical report No. 110 (2010) is conservative enough to cover remaining differences.
AF for intraspecies differences:
5
Justification:
ECETOC 2010, see justification at inhalation systemic above
AF for the quality of the whole database:
2
Justification:
assessment is based on a single long term study only. A quality factor of 2 was therefore applied to account for missing chronic studies.
AF for remaining uncertainties:
1
Justification:
ECHA guidance R.8 default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Ambiguous results were otained from eye irritation studies with rabbits. A worst case approach has been adopted and eye irritation is concluded which also warrants the classification of the substance as hazardous.