Registration Dossier
Registration Dossier
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EC number: 276-770-9 | CAS number: 72705-24-9
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 16.5 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:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1 234.2 mg/m³
- Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).
- AF for dose response relationship:
- 1
- Justification:
- The dose response relationship is considered unremarkable, therefore no additional factor is used.
- AF for differences in duration of exposure:
- 6
- Justification:
- The default assessment factor for subacute to chronic duration extrapolation is used.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
- AF for other interspecies differences:
- 2.5
- Justification:
- Recommended AF for other interspecies differences.
- AF for intraspecies differences:
- 5
- Justification:
- The default value for the relatively homogenous group "worker" is used.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole data base is considered to be sufficient and uncritical.
- AF for remaining uncertainties:
- 1
- Justification:
- The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
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:
- 46.7 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:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 14 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is limited. Although water solubility and log Pow may allow dermal absorption, the size of the molecule lies above the cut-off point of 500 g/mol (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”) and hydrolysis upon skin contact is not expected. Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of the oral absorption was taken for calculation.
- AF for dose response relationship:
- 1
- Justification:
- The dose response relationship is considered unremarkable, therefore no additional factor is used.
- AF for differences in duration of exposure:
- 6
- Justification:
- The default assessment factor for subacute to chronic duration extrapolation is used.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The default allometric scaling factor for the differences between rats and humans is used.
- AF for other interspecies differences:
- 2.5
- Justification:
- Recommended AF for other interspecies differences.
- AF for intraspecies differences:
- 5
- Justification:
- The default value for the relatively homogenous group "worker" is used.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole data base is considered to be sufficient and uncritical.
- AF for remaining uncertainties:
- 1
- Justification:
- The approach used for DNEL derivation is conservative. No further assessment factors are required.
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
General
DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.
Workers – Hazard via inhalation route
Long term systemic inhalation DNEL, worker
The DNEL long term, systemic (inhalation) is derived by route-to route extrapolation from the repeated dose oral toxicity study.
Step 1: Selection of the relevant dose descriptor (starting point):
The combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening (OECD 422) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 1000 mg/kg bw/day.
Step 2: Modification into a correct starting point:
Using a conservative approach, a worker DNEL (long term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.
Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day
Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d
Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5
Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³
Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³
Frequency of exposure in study: 7 days/week
Frequency of worker exposure: 5 days/week
Corrected inhalatory NOAEC for workers
= 1000 mg/kg bw/day* 0.5 * (1 / 0.38 m³/kg bw/day) * (6.7 m³/10 m³) * (7/5)
= 1234.2 mg/m³
Step 3: Use of assessment factors: 75
Interspecies: (allometric scaling): 1
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 6
Remaining uncertainties AF: 1
In conclusion, long term systemic inhalation DNEL, workers = 16.5 mg/m3
Short term systemic inhalation DNEL, worker
No data for the classification and labelling of the test substance for acute systemic toxicity (inhalation) is available. The substance is not classified for acute oral toxicity and acute dermal toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL is required.
Short and long term local inhalation DNEL, worker
No data on respiratory irritation is available. However, the test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). This implies that no potential damage to mucosal tissue may occur due to inhalation exposure.
Workers – Hazard via dermal route
Long term systemic dermal DNEL, worker
The DNEL long term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study (OECD 422).
Step 1: Selection of the relevant dose descriptor (starting point):
The combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening (OECD 422) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 1000 mg/kg bw/day.
Step 2: Modification of the starting point:
There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is limited. Although water solubility and log Pow may allow dermal absorption, the size of the molecule lies above the cut-off point of 500 g/mol (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”) and hydrolysis upon skin contact is not expected. Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of the oral absorption was taken for calculation.
Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day
Frequency of exposure in study: 7 days/week
Frequency of worker exposure: 5 days/week
Oral absorption of the rat / dermal absorption of humans (ABSoral-rat / ABSinh-human): 100/10
Corrected dermal NOAEL for workers:
1000 mg/kg bw/day * (100%/10%) * (7/5) = 14000 mg/kg bw/day
Step 3: Use of assessment factors: 300
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 6
Remaining uncertainties AF: 1
In conclusion, long term systemic dermal DNEL, workers = 46.7 mg/kg bw/day
Short term systemic dermal DNEL, worker
The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Long term and short term local dermal DNEL, worker
The test item is not classified for skin sensitization or skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment has to be conducted.
Worker – Hazard for the eyes
The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.
References
(not included as endpoint study record)
- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.
- ECHA (2016). Guidance on information requirements and chemical safety assessment.Part E: Risk Characterisation, Version 3.0, May 2016.
- ECHA (2017). Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance, June 2017.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2.5 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):
- 150
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 370.37 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Using a conservative approach, a general population DNEL (long term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.
- AF for dose response relationship:
- 1
- Justification:
- The dose response relationship is considered unremarkable, therefore no additional factor is used.
- AF for differences in duration of exposure:
- 6
- Justification:
- The default assessment factor for subacute to chronic duration extrapolation is used.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
- AF for other interspecies differences:
- 2.5
- Justification:
- Recommended AF for other interspecies differences.
- AF for intraspecies differences:
- 10
- Justification:
- The default value for the relatively homogenous group "general population" is used.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole data base is considered to be sufficient and uncritical.
- AF for remaining uncertainties:
- 1
- Justification:
- The approach used for DNEL derivation is conservative. No further assessment factors are required
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:
- 16.7 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):
- 600
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 10 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is limited. Although water solubility and log Pow may allow dermal absorption, the size of the molecule lies above the cut-off point of 500 g/mol (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”) and hydrolysis upon skin contact is not expected. Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of the oral absorption was taken for calculation.
- AF for dose response relationship:
- 1
- Justification:
- The dose response relationship is considered unremarkable, therefore no additional factor is used.
- AF for differences in duration of exposure:
- 6
- Justification:
- The default assessment factor for subacute to chronic duration extrapolation is used.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The default allometric scaling factor for the differences between rats and humans is used.
- AF for other interspecies differences:
- 2.5
- Justification:
- Recommended AF for other interspecies differences.
- AF for intraspecies differences:
- 10
- Justification:
- The default value for the relatively homogenous group "general population" is used.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole data base is considered to be sufficient and uncritical.
- AF for remaining uncertainties:
- 1
- Justification:
- The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
- 1.7 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):
- 600
- Dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
No modification is done as the same exposure route is considered.
- AF for dose response relationship:
- 1
- Justification:
- The dose response relationship is considered unremarkable, therefore no additional factor is used.
- AF for differences in duration of exposure:
- 6
- Justification:
- The default assessment factor for subacute to chronic duration extrapolation is used.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- The default allometric scaling factor for the differences between rats and humans is used.
- AF for other interspecies differences:
- 2.5
- Justification:
- Recommended AF for other interspecies differences.
- AF for intraspecies differences:
- 10
- Justification:
- The default value for the relatively homogenous group "general population" is used.
- AF for the quality of the whole database:
- 1
- Justification:
- The quality of the whole data base is considered to be sufficient and uncritical.
- AF for remaining uncertainties:
- 1
- Justification:
- The approach used for DNEL derivation is conservative. No further assessment factors are required.
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
General
DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.
General population – Hazard via inhalation route
Long term systemic inhalation DNEL, general population
The DNEL long term, systemic (inhalation) is derived by route-to route extrapolation from the repeated dose oral toxicity study.
Step 1: Selection of the relevant dose descriptor (starting point):
The combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening (OECD 422) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 1000 mg/kg bw/day.
Step 2: Modification into a correct starting point:
Using a conservative approach, a general population DNEL (long term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.
Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day
Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw/d
Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5
Frequency of exposure in study: 7 days/week
Frequency of general population exposure: 7 days/week
Corrected inhalatory NOAEC for workers
= 1000 mg/kg bw/day* 0.5 * (1 / 1.35 m³/kg bw/day) * (7/7)
= 370.37 mg/m³
Step 3: Use of assessment factors: 150
Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
Interspecies AF, remaining differences: 2.5
Intraspecies AF (general population): 10
Exposure duration AF: 6
Remaining uncertainties AF: 1
In conclusion, long term systemic inhalation DNEL, general population = 2.5 mg/m3
Short term systemic inhalation DNEL, general population
No data for the classification and labelling of the test substance for acute systemic toxicity (inhalation) is available. The substance is not classified for acute oral toxicity and acute dermal toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL is required.
Short and long term local inhalation DNEL, general population
No data on respiratory irritation is available. However, the test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). This implies that no potential damage to mucosal tissue may occur due to inhalation exposure.
General population – Hazard via dermal route
Long term systemic dermal DNEL, general population
The DNEL long term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study (OECD 422).
Step 1: Selection of the relevant dose descriptor (starting point):
The combined repeated dose toxicity study with the reproduction/developmental toxicity screening (OECD 422) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 1000 mg/kg bw/day.
Step 2: Modification of the starting point:
There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is limited. Although water solubility and log Pow may allow dermal absorption, the size of the molecule lies above the cut-off point of 500 g/mol (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”) and hydrolysis upon skin contact is not expected. Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of the oral absorption was taken for calculation.
Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day
Frequency of exposure in study: 7 days/week
Frequency of general population exposure: 7 days/week
Corrected dermal NOAEL for general population:
1000 mg/kg bw/day * (100%/10%) * (7/7) = 10000 mg/kg bw/day
Step 3: Use of assessment factors: 600
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 10
Exposure duration AF: 6
Remaining uncertainties AF: 1
In conclusion, long term systemic dermal DNEL, general population = 16.7 mg/kg bw/day
Short term systemic dermal DNEL, general population
The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Long term and short term local dermal DNEL, general population
The test item is not classified for skin sensitization or skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment has to be conducted.
General population – Hazard via oral route
Long term systemic oral DNEL, general population
The DNEL long term, systemic (oral) is derived from the combined repeated dose oral toxicity study (OECD 422).
Step 1: Selection of the relevant dose descriptor (starting point):
The combined repeated dose toxicity study with the reproduction/developmental toxicity screening (OECD 422) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 1000 mg/kg bw/day.
Step 2: Modification of the starting point:
No modification is done as the same exposure route is considered.
Step 3: Use of assessment factors: 600
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (general population): 10
Exposure duration AF: 6
Remaining uncertainties AF: 1
In conclusion, long term systemic oral DNEL, general population = 1.7 mg/kg bw/day
Short term systemic oral DNEL, General population
The test item is not classified for acute oral toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
General population – Hazard for the eyes
The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.
References
(not included as endpoint study record)
- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.
- ECHA (2017). Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance, June 2017.
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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