Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.6 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
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
441 mg/m³
Explanation for the modification of the dose descriptor starting point:
For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Regarding absorption, the available toxicokinetic data suggest rapid and nearly complete absorption by the oral route. Specifically, nearly 90% of an oral dose is excreted in the urine of mice within 12 hours of administration, and 92.6% of an oral dose is excreted in the urine of rats within 24 hours of administration. Since a maximal absorption already occurred by oral route, no additional factor was introduced for inhalation. To convert the oral NOAEL into inhalatory NOAEC, the following usual equation was applied: worker corrected inhalation NOAEC = oral NOAEL * (1/0.38 m3/kg/day)*0.67. Thus, the corrected dose descriptor for inhalation is: 250*(1/0.38)*0.67 = 441 mg/m3 for workers.
AF for dose response relationship:
1
Justification:
NOAEL determined in study
AF for differences in duration of exposure:
2
Justification:
DNEL is based on subacte study, but data available from other repeated dose toxicity study (up to 2-years) indicated that increasing the exposure duration does not increase the incidence of severity of adverse effects. For the purpose of conservatism, an AF of 2 was kept since all parameters were not evaluated in available repeated dose toxicity studies.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
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:
2.5 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
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.
AF for dose response relationship:
1
Justification:
NOAEL determined in study
AF for differences in duration of exposure:
2
Justification:
DNEL is based on subacte study, but data available from other repeated dose toxicity study (up to 2-years) indicated that increasing the exposure duration does not increase the incidence of severity of adverse effects. For the purpose of conservatism, an AF of 2 was kept since all parameters were not evaluated in available repeated dose toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.3 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):
50
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
other: NOAEL
Value:
217 mg/m³
Explanation for the modification of the dose descriptor starting point:
For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Regarding absorption, the available toxicokinetic data suggest rapid and nearly complete absorption by the oral route. Specifically, nearly 90% of an oral dose is excreted in the urine of mice within 12 hours of administration, and 92.6% of an oral dose is excreted in the urine of rats within 24 hours of administration. Since a maximal absorption already occurred by oral route, no additional factor was introduced for inhalation. To convert the oral NOAEL into inhalatory NOAEC, the following usual equation was applied: general population corrected inhalation NOAEC = oral NOAEL * (1/1.15 m3/kg/day). Thus, the corrected dose descriptor for inhalation is: 250*(1/1.15) = 217 mg/m3 for general population.
AF for dose response relationship:
1
Justification:
NOAEL determined in study
AF for differences in duration of exposure:
2
Justification:
DNEL is based on subacte study, but data available from other repeated dose toxicity study (up to 2-years) indicated that increasing the exposure duration does not increase the incidence of severity of adverse effects. For the purpose of conservatism, an AF of 2 was kept since all parameters were not evaluated in available repeated dose toxicity studies.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
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:
1.25 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):
200
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.
AF for dose response relationship:
1
Justification:
NOAEL determined in study
AF for differences in duration of exposure:
2
Justification:
DNEL is based on subacte study, but data available from other repeated dose toxicity study (up to 2-years) indicated that increasing the exposure duration does not increase the incidence of severity of adverse effects. For the purpose of conservatism, an AF of 2 was kept since all parameters were not evaluated in available repeated dose toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.25 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):
200
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable
AF for dose response relationship:
1
Justification:
NOAEL determined in study
AF for differences in duration of exposure:
2
Justification:
DNEL is based on subacte study, but data available from other repeated dose toxicity study (up to 2-years) indicated that increasing the exposure duration does not increase the incidence of severity of adverse effects. For the purpose of conservatism, an AF of 2 was kept since all parameters were not evaluated in available repeated dose toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
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