Registration Dossier
Registration Dossier
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EC number: 701-314-7 | CAS number: -
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 76.9 mg/m³
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 30
- Dose descriptor starting point:
- other: Annex XI Section 3.2(a) adaptation substance-tailored exposure-driven testing is appropriate for fulfilling the second species information requirement based on QSAR model.
- Value:
- 2 305 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The DNELs derived from the QSAR model were compared against DNELs derived by applying well accepted default adjustment factors for allometric scaling from rat to rabbit (ref ECHA guidance). The DNEL derived from the QSAR model was more conservative for exposure prediction compared to application of adjustment factors alone. This provides some perspective on reasonability of the value derived from the QSAR approach. However considering the QSAR derived DNEL is based on extensive PNDT datasets and is more conservative; these DNELs were relied upon in the exposure assessment. There are two particularly noteworthy aspects for regulatory interpretation of the model: (1) that the prediction uses the lower 95th percentile, making it a conservative estimation method for a point of departure, and (2) it is derived using data from developmental toxicity studies, hence the studies are from the endpoint of interest.
- AF for dose response relationship:
- 1
- Justification:
- QSAR PoD was based on No Effect Level
- AF for differences in duration of exposure:
- 1
- Justification:
- Exposure duration is for the relevant time period.
- AF for interspecies differences (allometric scaling):
- 2.4
- Justification:
- Default AF for rabbit to human.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default AF for interspecies (other).
- AF for intraspecies differences:
- 5
- Justification:
- Default AF for workers.
- AF for the quality of the whole database:
- 1
- Justification:
- Quality of database deemed as sufficient.
- AF for remaining uncertainties:
- 1
- Justification:
- Any remaining uncertainties are already incorporated into the QSAR model.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 16.75 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 3
- Dose descriptor:
- NOAEC
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:
- 137.7 mg/kg bw/day
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 30
- Dose descriptor starting point:
- other: Annex XI Section 3.2(a) adaptation substance-tailored exposure-driven testing is appropriate for fulfilling the second species information requirement based on QSAR model.
- Value:
- 413 mg/kg bw/day
- Modified dose descriptor starting point:
- other: DNEL derived from oral QSAR modified for dermal exposure (route-to-route extrapolation). Original starting point multiplied by 10 for differences in absorption.
- Value:
- 4 130 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The DNELs derived from the QSAR model were compared against DNELs derived by applying well accepted default adjustment factors for allometric scaling from rat to rabbit (ref ECHA guidance). The DNEL derived from the QSAR model was more conservative for exposure prediction compared to application of adjustment factors alone. This provides some perspective on reasonability of the value derived from the QSAR approach. However considering the QSAR derived DNEL is based on extensive PNDT datasets and is more conservative; these DNELs were relied upon in the exposure assessment.There are two particularly noteworthy aspects for regulatory interpretation of the model: (1) that the prediction uses the lower 95th percentile, making it a conservative estimation method for a point of departure, and (2) it is derived using data from developmental toxicity studies, hence the studies are from the endpoint of interest.
- AF for dose response relationship:
- 1
- Justification:
- QSAR PoD was based on No Effect Level
- AF for differences in duration of exposure:
- 1
- Justification:
- Exposure duration is for the relevant time period.
- AF for interspecies differences (allometric scaling):
- 2.4
- Justification:
- Default AF for rabbit to human.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default AF for interspecies (other).
- AF for intraspecies differences:
- 5
- Justification:
- Default AF for workers.
- AF for the quality of the whole database:
- 1
- Justification:
- Quality of database deemed as sufficient.
- AF for remaining uncertainties:
- 1
- Justification:
- Any remaining uncertainties are already incorporated into the QSAR model.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
- Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.
- Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.
The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL.
The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:
Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor.
In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs. |
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.57 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 5
- Dose descriptor:
- NOAEC
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:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic 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 for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
- Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.
- Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.
The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL.
The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:
Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor.
In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs. |
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