Registration Dossier
Registration Dossier
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EC number: 276-763-0 | CAS number: 72676-55-2
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.29 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:
- 246.8 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Correction factor for differences in respiratory volume (rat/workers): 1/0.38
Correction factor for light activity at work : 6.7/10Correction factor for difference between human and experimental exposure conditions : 7/5 (In the study, animals were exposed 7 days per week, and workers work 5 days per week).
Oral absorption = 100 %
Inhalation absorption = 100%
NOAEC = NOAEL x (1/0.38) x (6.7/10) x 7/5= 100 x (1/0.38) x (6.7/10) x 7/5 = 246.8 mg/m3
- AF for dose response relationship:
- 1
- Justification:
- This factor is applied because the dose-descriptor starting point is a NOAEL.
- AF for differences in duration of exposure:
- 6
- Justification:
- DNEL is based on a subacute study (28-day).
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- AF not used for inhalation. Allometric scaling is implicitly taken into account in the factor for remaining differences.
- AF for other interspecies differences:
- 2.5
- Justification:
- A factor of 2.5 is applied for remaining difference.
- AF for intraspecies differences:
- 5
- Justification:
- A factor of 5 is applied for worker DNELs.
- AF for the quality of the whole database:
- 1
- Justification:
- The key study chosen for DNEL calculation is considered as a reliable study.
- AF for remaining uncertainties:
- 1
- Justification:
- No other assessment factor is applied.
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:
- 0.93 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:
- 280 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
Based on the TK assessment, a dermal absorption of 50% was used by default.
Correction factor for difference between human and experimental exposure conditions : 7/5 (In the study, animals were exposed 7 days per week, and workers work 5 days per week).Dermal NOAEL = oral NOAEL x 100/50 x 7/5= 100 x 100/50 x 7/5 = 280 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- This factor is applied because the dose-descriptor starting point is a NOAEL.
- AF for differences in duration of exposure:
- 6
- Justification:
- DNEL is based on a subacute study (28-day).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- An allometric scaling factor of 4 must be applied because the key study was performed on rats.
- AF for other interspecies differences:
- 2.5
- Justification:
- A factor of 2.5 is applied for remaining difference.
- AF for intraspecies differences:
- 5
- Justification:
- A factor of 5 is applied for worker DNELs.
- AF for the quality of the whole database:
- 1
- Justification:
- The key study chosen for DNEL calculation is considered as a reliable study.
- AF for remaining uncertainties:
- 1
- Justification:
- No other assessment factor is applied.
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:
- 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
- Reduction in bodyweight gain at 1000 mg/kg/day in males considered adverse.
- Higher thyroid gland weights, enlargement and increased incidences and severity of follicular cell hypertrophy/hyperplasia, including a possible related adenoma, and related changes in hormone levels (high TSH and low T3, T4).
- Combination of findings in the kidneys at 1000 mg/kg/day.
- Possible test material related diffuse hyperplasia in the urinary bladder and urethra of a single female.
- Reduction in bodyweight gain at 1000 mg/kg/day in males considered adverse.
- Microscopic changes observed for multiple organs at 300 and/or 1000 mg/kg/day (kidney, liver, thyroid) considered adverse, as it correlates with biochemical changes (lower alanine aminotransferase).
Several relevant repeated-dose toxicity studies conducted via the oral route are available on the registered substance.
During an OECD 408, it was concluded that the NOAEL was 300 mg/kg/day based on:
Reduction in alanine aminotransferase was not considered as adverse in the absence of clear histopathological correlation.
During an OECD 422, it was concluded that the NOAEL was 100 mg/kg/day based on:
Selecting results from the OECD 408 or the OECD 422 as the starting point for the calculation lead to different DNELs taking into account the difference in NOAEL and in Assessment Factor for study duration.
Starting point (NOAEL systemic, oral route) in mg/kg/day | 100 | 300 |
Study | OECD 422 | OECD 408 |
AF for duration | 6 | 2 |
DNEL (dermal route / workers) in mg/kg/day | 0.93 | 8.4 |
DNEL (inhalation / workers) in mg/m3 | 3.29 | 29.62 |
DNEL (dermal route / Gen pop) in mg/kg/day | 0.33 | 3 |
DNEL (inhalation / Gen Pop) in mg/m3 | 0.56 | 5.22 |
DNEL (oral route / Gen pop) in mg/kg/day | 0.17 | 1.5 |
Using the OECD 422 as the starting point results in lower DNELs and is therefore preferred as this is a more conservative approach.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.56 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:
- 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:
Correction factor for differences in respiratory volume (rat/general population): 1/1.15
Oral absorption = 100 %Inhalation absorption = 100%
NOAEC = NOAEL x (1/1.15) = 100 x (1/1.15) = 87 mg/m3
- AF for dose response relationship:
- 1
- Justification:
- This factor is applied because the dose-descriptor starting point is a NOAEL.
- AF for differences in duration of exposure:
- 6
- Justification:
- DNEL is based on a subacute study (28-day).
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- AF not used for inhalation. Allometric scaling is implicitly taken into account in the factor for remaining differences.
- AF for other interspecies differences:
- 2.5
- Justification:
- A factor of 2.5 is applied for remaining difference.
- AF for intraspecies differences:
- 10
- Justification:
- A factor of 10 is applied for the general population DNELs.
- AF for the quality of the whole database:
- 1
- Justification:
- The key study chosen for DNEL calculation is considered as a reliable study.
- AF for remaining uncertainties:
- 1
- Justification:
- No other assessment factor is applied.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.33 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:
- 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:
Based on the TK assessment, a dermal absorption of 50% was used by default.
Dermal NOAEL = oral NOAEL x 100/50 = 100 x 100/50 = 200 mg/kg bw/day.- AF for dose response relationship:
- 1
- Justification:
- This factor is applied because the dose-descriptor starting point is a NOAEL.
- AF for differences in duration of exposure:
- 6
- Justification:
- DNEL is based on a subacute study (28-day).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- An allometric scaling factor of 4 must be applied because the key study was performed on rats.
- AF for other interspecies differences:
- 2.5
- Justification:
- A factor of 2.5 is applied for remaining difference.
- AF for intraspecies differences:
- 10
- Justification:
- A factor of 10 is applied for the general population DNELs.
- AF for the quality of the whole database:
- 1
- Justification:
- The key study chosen for DNEL calculation is considered as a reliable study.
- AF for remaining uncertainties:
- 1
- Justification:
- No other assessment factor is applied.
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:
- 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:
- 0.17 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:
- 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:
Oral absorption is considered to be similar between rat and human, so no modification of the dose descriptor is needed.
- AF for dose response relationship:
- 1
- Justification:
- This factor is applied because the dose-descriptor starting point is a NOAEL.
- AF for differences in duration of exposure:
- 6
- Justification:
- DNEL is based on a subacute study (28-day).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- An allometric scaling factor of 4 must be applied because the key study was performed on rats.
- AF for other interspecies differences:
- 2.5
- Justification:
- A factor of 2.5 is applied for remaining difference.
- AF for intraspecies differences:
- 10
- Justification:
- A factor of 10 is applied for the general population DNELs.
- AF for the quality of the whole database:
- 1
- Justification:
- The key study chosen for DNEL calculation is considered as a reliable study.
- AF for remaining uncertainties:
- 1
- Justification:
- No other assessment factor is applied.
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
- Reduction in bodyweight gain at 1000 mg/kg/day in males considered adverse.
- Higher thyroid gland weights, enlargement and increased incidences and severity of follicular cell hypertrophy/hyperplasia, including a possible related adenoma, and related changes in hormone levels (high TSH and low T3, T4).
- Combination of findings in the kidneys at 1000 mg/kg/day.
- Possible test material related diffuse hyperplasia in the urinary bladder and urethra of a single female.
- Reduction in bodyweight gain at 1000 mg/kg/day in males considered adverse.
- Microscopic changes observed for multiple organs at 300 and/or 1000 mg/kg/day (kidney, liver, thyroid) considered adverse, as it correlates with biochemical changes (lower alanine aminotransferase).
Several relevant repeated-dose toxicity studies conducted via the oral route are available on the registered substance.
During an OECD 408, it was concluded that the NOAEL was 300 mg/kg/day based on:
Reduction in alanine aminotransferase was not considered as adverse in the absence of clear histopathological correlation.
During an OECD 422, it was concluded that the NOAEL was 100 mg/kg/day based on:
Selecting results from the OECD 408 or the OECD 422 as the starting point for the calculation lead to different DNELs taking into account the difference in NOAEL and in Assessment Factor for study duration.
Starting point (NOAEL systemic, oral route) in mg/kg/day | 100 | 300 |
Study | OECD 422 | OECD 408 |
AF for duration | 6 | 2 |
DNEL (dermal route / workers) in mg/kg/day | 0.93 | 8.4 |
DNEL (inhalation / workers) in mg/m3 | 3.29 | 29.62 |
DNEL (dermal route / Gen pop) in mg/kg/day | 0.33 | 3 |
DNEL (inhalation / Gen Pop) in mg/m3 | 0.56 | 5.22 |
DNEL (oral route / Gen pop) in mg/kg/day | 0.17 | 1.5 |
Using the OECD 422 as the starting point results in lower DNELs and is therefore preferred as this is a more conservative approach.
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.
