Registration Dossier
Registration Dossier
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EC number: 276-957-5 | CAS number: 72869-86-4
Toxicological Summary
Administrative data
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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
