Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.47 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):
75
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
185.13 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; this has been included in this case due to a lack of data or the percentage of oral absorption. Therefore a factor of 2 was applied. 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.DNELs

AF for dose response relationship:
1
Justification:
There was a clear dose response in the study.
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 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 which for the males is a 28 day study (females for ca. 63 days) 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 NOAEL is from a new fully GLP compliant OECD422 study on the registered substance so a factor of 1 was used.
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:
0.7 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):
300
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
210 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. So the Oral NOAEL can be used also as the dermal repeat dose NOAEL as the basis for calculating Dermal DNELs,as dermal absorption is usually less than oral absorption this is a conservative approach.

An additional adjustment was made as recommended in ECHA guidance R8.4.3. The oral exposure for the rats was 7 days a week but dermal exposure of workers is considered to be 5 days a week. This is adjusted by dividing the NOAEL by 5/7 or 0.714286.

AF for dose response relationship:
1
Justification:
There was a clear dose response in the study.
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 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 which for the males is a 28 day study (females for ca. 63 days) 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 NOAEL is from a new fully GLP compliant OECD422 study on the registered substance.
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:
medium hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.37 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):
150
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
55.56 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:
There was a clear dose response in the study.
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 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 which for the males is a 28 day study (females for ca. 63 days) 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 NOAEL is from a new fully GLP compliant OECD422 study on the registered substance so a factor of 1 was used.
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:
0.25 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):
600
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 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. So the Oral NOAEL can be used also as the dermal repeat dose NOAEL as the basis for calculating Dermal DNELs, as dermal absorption is usually less than oral absorption this is a conservative approach.

AF for dose response relationship:
1
Justification:
There is a clear dose response so a factor of 1 is used.
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 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 which for the males is a 28 day study (females for ca. 63 days) 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 NOAEL is from a new fully GLP compliant OECD422 study on the registered substance so a factor of 1 was used.
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:
0.25 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):
600
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 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 and ECHA assumes equal absorption via the oral and dermal routes so no modification of the dose descriptor. This is a conservative approach.

AF for dose response relationship:
1
Justification:
There was a clear dose response so a factor of 1 is used.
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 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 which for the males is a 28 day study (females for ca. 63 days) 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 NOAEL is from a new fully GLP compliant OECD422 study on the registered substance so a factor of 1 was used.
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:
medium hazard (no threshold derived)

Additional information - General Population