Registration Dossier
Registration Dossier
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EC number: 921-910-2 | 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:
- 69.1 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA REACH Guidance in combination with publications and the ERASM project evaluation
- Overall assessment factor (AF):
- 25.5
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1 763 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:
The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 1763 mg/m³.
- AF for dose response relationship:
- 1
- Justification:
- No adverse effects were observed up to the limit concentration.
- AF for differences in duration of exposure:
- 3.4
- Justification:
- Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- The allometric scaling is already taken into account in the starting point correction.
- AF for other interspecies differences:
- 1
- Justification:
- Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006).
- AF for intraspecies differences:
- 3
- Justification:
- There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 3 is considered to be sufficient.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the database is of high quality. The DNEL derivation is based on reliable guideline studies.
- AF for remaining uncertainties:
- 2.5
- Justification:
- An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
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
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 9.8 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA REACH Guidance in combination with publications and the ERASM project evaluation
- Overall assessment factor (AF):
- 102
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.
- AF for dose response relationship:
- 1
- Justification:
- No adverse effects were observed up to the limit concentration.
- AF for differences in duration of exposure:
- 3.4
- Justification:
- Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 3
- Justification:
- There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 3 is considered to be sufficient.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole database is considered of high quality.
- AF for remaining uncertainties:
- 2.5
- Justification:
- An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
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
Worker:
Based on the available data, there is no need for classification and labeling of 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2-Propanediol, monocarbamate.
The primary routes of anticipated industrial and professional exposure for 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2-Propanediol, monocarbamate, are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).
Inhalation long-term exposure – systemic effects:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:
The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 1763 mg/m³.
For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:
- Interspecies factor: 1
Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006).
- Intraspecies factor: 3
There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 3 is considered to be sufficient.
- Exposure duration: 3.4 (Batke et.al., 2011)
Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- Dose-response: 1
- Remaining uncertainties: 2.5
An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
Total AF = 1 x 3 x 3.4 x 1 x 2.5 = 25.5
Based on this calculation the resulting DNEL is 69.1 mg/m³.
Dermal long-term exposure – systemic effects:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.
For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:
- Interspecies factor: 4
Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- Intraspecies factor: 3
There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 3 is considered to be sufficient.
- Exposure duration: 3.4 (Batke et.al., 2011)
Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- Dose-response: 1
- Remaining differences: 2.5
An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
Total AF = 4 x 3 x 3.4 x 1 x 2.5 = 102
Based on this calculation the resulting DNEL is 9.8 mg/kg bw/day.
- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.
- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.
- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.
-ECHA (2008). REACh Guidance document R.8
-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.
-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 20.5 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA REACH Guidance in combination with publications and the ERASM project evaluation
- Overall assessment factor (AF):
- 42.5
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 870 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 870 mg/m³.
- AF for dose response relationship:
- 1
- Justification:
- No adverse effects were observed up to the limit concentration.
- AF for differences in duration of exposure:
- 3.4
- Justification:
- Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- The allometric scaling was already taken into account in the starting point correction.
- AF for other interspecies differences:
- 1
- Justification:
- Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006).
- AF for intraspecies differences:
- 5
- Justification:
- There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole database is of high quality.
- AF for remaining uncertainties:
- 2.5
- Justification:
- An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
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
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 5.9 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA REACH Guidance in combination with publications and the ERASM project evaluation
- Overall assessment factor (AF):
- 170
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.
- AF for dose response relationship:
- 1
- Justification:
- No adverse effects were observed up to the limit concentration.
- AF for differences in duration of exposure:
- 3.4
- Justification:
- Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 5
- Justification:
- There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole database is considered of high quality.
- AF for remaining uncertainties:
- 2.5
- Justification:
- An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
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:
- DNEL (Derived No Effect Level)
- Value:
- 5.9 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA REACH Guidance in combination with publications and the ERASM project evaluation
- Overall assessment factor (AF):
- 170
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
The NOAEL of 1000 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation.
- AF for dose response relationship:
- 1
- Justification:
- No adverse effects were observed up to the limit concentration.
- AF for differences in duration of exposure:
- 3.4
- Justification:
- Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 5
- Justification:
- There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the database is considered of high quality.
- AF for remaining uncertainties:
- 2.5
- Justification:
- An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
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
Consumer
Based on the available data, there is no need for classification and labeling of 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2-Propanediol, monocarbamate.
For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.
Inhalation long-term exposure – systemic effects:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:
The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 870 mg/m³.
For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:
- Interspecies factor: 1
Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account. Within the ERASM project, studies in rats and mice are being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006).
- Intraspecies factor: 5
There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- Exposure duration: 3.4 (Batke et.al., 2011)
Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- Dose-response: 1
No adverse effects were observed up to the limit concentration.
- Remaining differences: 2.5
An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
Total AF = 1 x 5 x 3.4 x 1 x 2.5 = 42.5
Based on this calculation the resulting DNEL is 20.5 mg/m³.
Dermal long-term exposure – systemic effects:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF 2019) with the registered substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 1200 mg/kg bw/d for rats, corresponding to 1007 mg/kg bw/d of 3 -Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate, oligomers, reaction products with 1,2 -Propanediol, monocarbamate.
There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.
For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:
- Interspecies factor: 4
Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- Intraspecies factor: 5
There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- Exposure duration: 3.4 (Batke et.al., 2011)
Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- Dose-response: 1
No adverse effects were observed up to the limit concentration.
- Remaining differences: 2.5
An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
Total AF = 4 x 5 x 3.4 x 1 x 2.5 = 170
Based on this calculation the resulting DNEL is 5.9 mg/kg bw/day.
Oral long-term exposure – systemic effects:
The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for rats.
The NOAEL of 1000 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation.
For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:
- Interspecies factor: 4
Recommended for the rat in REACh Guidance document R.8 for allometric scaling
- Intraspecies factor: 5
There were no systemic effects observed in the repeated dose study with rats. Therefore an intraspecies factor of 5 is considered to be sufficient.
- Exposure duration: 3.4 (Batke et.al., 2011)
Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). Furthermore, female rats were exposed for 42-56 days instead of 28 days as requested in a regular 28-day study.
- Dose-response: 1
- Remaining differences: 2.5
An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.
Total AF = 4 x 5 x 3.4 x 1 x 2.5 = 170
Based on this calculation the resulting DNEL is 5.9 mg/kg bw/day.
- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.
- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.
- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.
-ECHA (2008). REACh Guidance document R.8
-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.
-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.
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