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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 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):
37.5
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
123.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in male animals in a combined oral repeated dose toxicity study with the reproductive/developmental toxicity screening test in rats (OECD 422). To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

 Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human) × (sRVhuman ÷ wRV) × (days of exposure in the study ÷ days of exposure worker)

= 100 mg/kg bw/day × (1 ÷ 0.38 m³/kg bw) × (1 ÷ 2) × (6.7 m³ ÷ 10 m³) × (7 days ÷ 5 days) = 123.4 mg/m³

sRV = standard respiratory volume; wRV = respiratory volume light activity for worker (8 h); ABS = absorption

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption. Exposure was 7 day/week in the combined oral repeated dose toxicity study with the reproductive/developmental toxicity screening test in rats while workers are exposed 5 days/week.

Thus, the corrected starting point for workers is 123.4 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
3
Justification:
The DNEL is based on a study with 56 days of exposure. The default assessment factor for duration extrapolation from subacute (28 days) to sub-chronic (90 days) of 3 can therefore be extrapolated to 1.6 similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The default assessment factor for duration extrapolation from sub-chronic to chronic is 2. Subsequently, the assessment factor for duration extrapolation from subacute to chronic is 2 × 1.6 = 3.2 rounded to 3.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.3 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):
150
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in male animals in a combined oral repeated dose toxicity study with the reproductive/developmental toxicity screening test in rats (OECD 422). To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

 Corrected dermal NOAEL = NOAEL(oral) × (ABSoral-rat ÷ ABSdermal-human) = 100 mg/kg bw/day × (1 ÷ 0.5) = 200 mg/kg bw/day

ABS = absorption

Based on the assessment of the toxicokinetic behavior according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) considering available substance specific data on physico-chemical and toxicological properties dermal absorption potential of the test substance is considered to be low. Thus, it is assumed that dermal absorption rate is 50% of that of oral absorption as worst case. 

Thus, the starting point for workers is 200 mg/kg bw/day for dermal exposure.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
3
Justification:
The DNEL is based on a study with 56 days of exposure. The default assessment factor for duration extrapolation from subacute (28 days) to sub-chronic (90 days) of 3 can therefore be extrapolated to 1.6 similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The default assessment factor for duration extrapolation from sub-chronic to chronic is 2. Subsequently, the assessment factor for duration extrapolation from subacute to chronic is 2 × 1.6 = 3.2 rounded to 3.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
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)
Most sensitive endpoint:
sensitisation (skin)

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:
0.6 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):
75
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in male animals in a combined oral repeated dose toxicity study with the reproductive/developmental toxicity screening test in rats (OECD 422). To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human) = 100 mg/kg bw/day × (1 ÷ 1.15 m³/kg bw) × (1 ÷ 2) = 43.5 mg/m³

ABS = absorption

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

Thus, the corrected starting point for the general population is 43.5 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
3
Justification:
The DNEL is based on a study with 56 days of exposure. The default assessment factor for duration extrapolation from subacute (28 days) to sub-chronic (90 days) of 3 can therefore be extrapolated to 1.6 similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The default assessment factor for duration extrapolation from sub-chronic to chronic is 2. Subsequently, the assessment factor for duration extrapolation from subacute to chronic is 2 × 1.6 = 3.2 rounded to 3.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in male animals in a combined oral repeated dose toxicity study with the reproductive/developmental toxicity screening test in rats (OECD 422). To correct the interspecies difference between rat and human the NOAEL has to be corrected as follows:

 Corrected dermal NOAEL = NOAEL(oral) × (ABSoral-rat ÷ ABSdermal-human) = 100 mg/kg bw/day × (1 ÷ 0.5) = 200 mg/kg bw/day

ABS = absorption

Based on the assessment of the toxicokinetic behavior according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) considering available substance specific data on physico-chemical and toxicological properties dermal absorption potential of the test substance is considered to be low. Thus, it is assumed that dermal absorption rate is 50% of that of oral absorption as worst case. 

Thus, the starting point for the general public is 200 mg/kg bw/day for dermal exposure.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
3
Justification:
The DNEL is based on a study with 56 days of exposure. The default assessment factor for duration extrapolation from subacute (28 days) to sub-chronic (90 days) of 3 can therefore be extrapolated to 1.6 similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The default assessment factor for duration extrapolation from sub-chronic to chronic is 2. Subsequently, the assessment factor for duration extrapolation from subacute to chronic is 2 × 1.6 = 3.2 rounded to 3.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
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:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation necessary.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
3
Justification:
The DNEL is based on a study with 56 days of exposure. The default assessment factor for duration extrapolation from subacute (28 days) to sub-chronic (90 days) of 3 can therefore be extrapolated to 1.6 similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The default assessment factor for duration extrapolation from sub-chronic to chronic is 2. Subsequently, the assessment factor for duration extrapolation from subacute to chronic is 2 × 1.6 = 3.2 rounded to 3.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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:
no hazard identified

Additional information - General Population