Registration Dossier
Registration Dossier
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EC number: 214-189-4 | CAS number: 1112-39-6
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 19.7 mg/m³
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 12.5
- Dose descriptor starting point:
- NOAEL
- Value:
- 100 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 246.8 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the OECD 421 DRF oral NOAEL on the registration substance itself.
To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:
Corrected starting point for the inhalative route for workers:
= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)* (7 days exposure rat/5 days exposure worker)
= 100 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ * 1.4 = 246.8 mg/m³
In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.
(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)
- AF for dose response relationship:
- 1
- Justification:
- The dose descriptor starting point is based on a NOAEC.
- AF for differences in duration of exposure:
- 1
- Justification:
- relevant period is covered (males: 17 weeks starting from 10 weeks prior to mating; females: from 10 weeks prior to mating, then continuing until the day prior to termination on LD 21)
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- AF not used for inhalation route
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA default
- AF for intraspecies differences:
- 5
- Justification:
- ECHA default
- 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:
- By inhalation
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:
- 2.8 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- 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:
- 100 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 140 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The long-term DNEL for systemic effects via the dermal route is determined on the basis of the OECD 421 DRF oral NOAEL on the registration substance itself.
Corrected starting point for the dermal route for workers:
Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat / 5 days exposure worker) = 100 mg/kg bw/day *(1/1) * (7/5) = 140 mg/kg bw/day. It is assumed that oral and dermal absorption rates are equal.
- AF for dose response relationship:
- 1
- Justification:
- The dose descriptor starting point is based on a NOAEL.
- AF for differences in duration of exposure:
- 1
- Justification:
- relevant period is covered (males: 17 weeks starting from 10 weeks prior to mating; females: from 10 weeks prior to mating, then continuing until the day prior to termination on LD 21)
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The experimental animal was a rat.
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA default
- AF for intraspecies differences:
- 5
- Justification:
- ECHA default
- 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:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
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:
- 3.5 mg/m³
- Most sensitive endpoint:
- effect on fertility
- 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:
- 100 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 87 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the OECD 421 DRF NOAEL on the registration substance itself.
Corrected starting point for the inhalative route for general population:
= NOAELoral * (1/1.15 m³/kg bw/day (24h)) * (ABSoral-rat / ABSinh-human)
= 100 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 87 mg/m³
In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.
(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)
Thus, the corrected starting point for general population was 87 mg/m³ for inhalation.
- AF for dose response relationship:
- 1
- Justification:
- The dose descriptor starting point is based on a NOAEC.
- AF for differences in duration of exposure:
- 1
- Justification:
- relevant period is covered (males: 17 weeks starting from 10 weeks prior to mating; females: from 10 weeks prior to mating, then continuing until the day prior to termination on LD 21)
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- AF not used for inhalation route
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA default
- AF for intraspecies differences:
- 10
- Justification:
- ECHA default
- 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:
- By inhalation
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 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- 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:
- 100 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 100 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The long-term DNEL for systemic effects via the dermal route is determined on the basis of the OECD 421 DRF oral NOAEL on the registration substance itself.
It is assumed that oral and dermal absorption rates are equal.
- AF for dose response relationship:
- 1
- Justification:
- The dose descriptor starting point is based on a NOAEL.
- AF for differences in duration of exposure:
- 1
- Justification:
- relevant period is covered (males: 17 weeks starting from 10 weeks prior to mating; females: from 10 weeks prior to mating, then continuing until the day prior to termination on LD 21)
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The experimental animal was a rat.
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA default
- AF for intraspecies differences:
- 10
- Justification:
- ECHA default
- 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:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- 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:
- 100 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
No route-to-route extrapolation is needed as the long-term DNEL for systemic effects via the oral route is deteremined on the basis of the OECD 421 DRF oral NOAEL on the registration substance itself.
- AF for dose response relationship:
- 1
- Justification:
- The dose descriptor starting point is based on a NOAEL.
- AF for differences in duration of exposure:
- 1
- Justification:
- relevant period is covered (males: 17 weeks starting from 10 weeks prior to mating; females: from 10 weeks prior to mating, then continuing until the day prior to termination on LD 21)
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The experimental animal was a rat.
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA default
- AF for intraspecies differences:
- 10
- Justification:
- ECHA default
- 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.
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