Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.11 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):
75
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
308.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs.  Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = mg/m3 inhalation NOAEC for workers. An additional adjust was made as recommended in ECHA guidance R8.4.3. The oral exposure for the rats was 7 days a week but inhalation exposure of workers is considered to be 5 days a week. This is adjusted by dividing the NOEC by 5/7 or 0.714286.

AF for dose response relationship:
1
Justification:
The top dose 250mg/kg was the NOAEL for reproduction.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from an OECD422 study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure. As the NOAEL is from an OECD422 study the factor of 6 was used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.
AF for other interspecies differences:
2.5
Justification:
ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.
AF for intraspecies differences:
5
Justification:
ECHA guidance recommends a factor of 5 for intraspecies differences for workers
AF for the quality of the whole database:
1
Justification:
The DNEL is based on testing the registered substance in a modern full GLP compliant guideline study
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
developmental toxicity / teratogenicity
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:

ECHA guidance assumes that absorption for dermal exposure is the same as for oral exposure, which is a worst case assumption.

AF for dose response relationship:
1
Justification:
No adverse effects were seeen art the top dose of 250mg/kg.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a OECD422 / 28 day study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure. As the NOAEL is from an OECD422 study the factor of 6 was used.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.
AF for other interspecies differences:
2.5
Justification:
ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.
AF for intraspecies differences:
5
Justification:
ECHA guidance recommends a factor of 5 for intraspecies differences for workers.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on testing the registered substance in a modern full GLP compliant guideline study
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in IUCLID Calculator the oral NOAEL in the rat mg/kg/day *1/1.35 mg/m3 inhalation NOAEC for the general population (based on 60 kg bodyweight rather than 70 kg for workers).

The point of departure is the NOAEL from the OECD442 study, 250 mg/kg on the registered substance a currnet guideline study fully GLP compliant, including the new endocrine disruption end points

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.23 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):
150
Dose descriptor starting point:
NOAEL
Value:
250 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
185.18 mg/m³
Explanation for the modification of the dose descriptor starting point:

ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs (oral absorption assumed to default to 50% and inhalation to 100%). Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in IUCLID Calculator the oral NOAEL in the rat mg/kg/day *1/1.35 mg/m3 inhalation NOAEC for the general population (based on 60 kg bodyweight rather than 70 kg for workers).

AF for dose response relationship:
1
Justification:
The NOAEL 250 mg/kg/day is the top dose.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day / OECD422 study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure. As the NOAEL is from an OECD422 study the factor of 6 was used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.
AF for other interspecies differences:
2.5
Justification:
ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.
AF for intraspecies differences:
10
Justification:
ECHA guidance recommends a factor of 10 for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on testing the registered substance in a modern full GLP compliant guideline study
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
developmental toxicity / teratogenicity
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:

ECHA guidance assumes that absorption for dermal exposure is the same as for oral exposure, which is a worst case assumption.

AF for dose response relationship:
1
Justification:
The NOAEL is the top dose 250mg/kg.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day / OECD422 study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure. As the NOAEL is from an OECD422 study the factor of 6 was used.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.
AF for other interspecies differences:
2.5
Justification:
ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.
AF for intraspecies differences:
10
Justification:
ECHA guidance recommends a factor of 10 for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a NOAEL for a new guideline study on the registered substance which is fully GLP compliant
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low 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:
developmental toxicity / teratogenicity
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:

There is no route to route extrapolation as the NOAEL is from an oral study in rats so no modification of the dose descriptior.

AF for dose response relationship:
1
Justification:
The NOAEL 250mg/kg is the top dose.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day / OECD422 study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure. As the NOAEL is from an OECD422 study the factor of 6 was used.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.
AF for other interspecies differences:
2.5
Justification:
ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.
AF for intraspecies differences:
10
Justification:
ECHA guidance recommends a factor of 10 for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a NOAEL for a new guideline study on the registered substance which is fully GLP compliant
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/1.35 = mg/m3for a 60 kg member of the general population as include in the IUCLID calculator.

The point of departure is the NOAEL from the OECD442 study, 250 mg/kg on the registered substance a currnet guideline study fully GLP compliant, including the new endocrine disruption end points.