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Registration Dossier
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EC number: 222-852-4 | CAS number: 3634-83-1
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2.45 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 18
- Dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 44.1 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Considering no effects were observed at the highest dose tested in the semi-chronic inhalation toxicity study in rats, and no indication is present at what dose level systemic effects can be expected, the oral NOAEL is more relevant to use as starting point.
Starting point: NOAEL of 50 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.
Conversion of an oral NOAEL into a corrected NOAEC:
For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV
= 50 mg/kg bw/day * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3(8h)/10 m3(8h)
= 50 mg/kg bw/day * 1/0.38 m3/kg/8h * 0.5 * 6.7 m3 (8h)/10 m3(8h)
= 50 mg/kg bw/day /0.38 * 0.5 * (6.7/10) = 44.1 mg/m3.
With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume; ABSoral-rat /ABSinhal-human= 50/100= 0.5, assuming no differences in inhalation absorption between rats and humans.
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEL
- AF for differences in duration of exposure:
- 6
- Justification:
- Extrapolation from subacute study to chronic exposure worker
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation; is included in dose descriptor starting point
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 3
- Justification:
- Difference in sensitivity among workers
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 32.8 mg/m³
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 3
- Dose descriptor starting point:
- NOAEC
- Value:
- 58.3 mg/m³
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 98.5 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Starting point: NOAEC of 58.3 mg/m3 in an acute inhalation toxicity study in rats (4 hour exposure).
For the acute exposure duration, timescaling seems to be appropriate (Table R.8-20). Haber’s law: Cn * t = k 58.33 * 4 = 7.93x105, so C = 3√7.93 x105/0.25 (15 min) = 147 mg/m3.
Corrected inhalatory NAEC based on the inhalation starting point =
147 mg/m3* 6.7/10 a = 98.5 mg/m3
a: 8 hour respiration rate human/respiratory volume light activity worker
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEC
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation; is included in dose descriptor starting point
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 3
- Justification:
- Difference in sensitivity among workers
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6.5 mg/m³
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 9
- Dose descriptor starting point:
- LOAEC
- Value:
- 58.3 mg/m³
- AF for dose response relationship:
- 3
- Justification:
- Extrapolation of LOAEC to NAEC as there was a clear dose response and lowest tested dose level causes respiratory damage/irritation without macroscopic abnormalities while these effects were noted at the next higher dose level
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation; is included in dose descriptor starting point
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 3
- Justification:
- Difference in sensitivity among workers
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.35 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 72
- Dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 25 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
Either the oral or inhalation study could be used as starting point to derive a dermal DNEL. As in the inhalation studies local effects were leading, resulting in a NOAEC of greater or equal than value for systemic effects, the oral study seems to be more reliable as starting point.
Starting point: NOAEL of 50 mg/kg bw/day in a sub-acute oral toxicity study in rats.Oral absorption is considered to be 50% and dermal absorption is considered to be 100%:
50 mg/kg bw/d * 50/100 = 25 mg/kg bw/d
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEL
- AF for differences in duration of exposure:
- 6
- Justification:
- Extrapolation from subacute study to chronic exposure worker
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Correction for caloric demand from rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 3
- Justification:
- Difference in sensitivity among workers
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Additional information - workers
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.72 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 30
- Dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 21.7 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Considering no effects were observed at the highest dose tested in the semi-chronic inhalation toxicity study in rats, and no indication is present at what dose level systemic effects can be expected, the oral NOAEL is more relevant to use as starting point.
Oral absorption is considered to be 50% and inhalation absorption is considered to be 100%:
Corrected inhalatory NAEC based on the oral starting point=
50 mg/kg bw/d * 1/1.15a * 50/100b = 21.7 mg/m3
a: 24 hour ventilation rate rat
b: oral/inhalation absorption
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEC
- AF for differences in duration of exposure:
- 6
- Justification:
- Extrapolation from subacute study to chronic exposure general population
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation; is included in dose descriptor starting point
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- Difference in sensitivity within general population
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 29.4 mg/m³
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 5
- Dose descriptor starting point:
- NOAEC
- Value:
- 58.3 mg/m³
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 147 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Starting point: NOAEC of 58.3 mg/m3in an acute inhalation toxicity study in rats 4 hour exposure).
For the acute exposure duration, time-scaling seems to be appropriate (Table R.8-20). Haber’s law: Cn * t = k 58.3WE3 * 4 = 7.93x10E5, so C = 3√7.93 x10E5 /0.25 (15 min) = 147 mg/m3.
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEC
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation; is included in dose descriptor starting point
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- Difference in sensitivity within general population
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.9 mg/m³
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 15
- Dose descriptor starting point:
- LOAEC
- Value:
- 58.3 mg/m³
- AF for dose response relationship:
- 3
- Justification:
- Extrapolation of LOAEC to NOAEC as there was a clear dose response and lowest tested dose level causes respiratory damage/irritation without macroscopic abnormalities while these effects were noted at the next higher dose level.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No correction for caloric demand for inhalation
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- Difference in sensitivity within general population
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.21 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 120
- Dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 25 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
Starting point: NOAEL of 50 mg/kg bw/day in a sub-acute oral toxicity study in rats. Oral absorption is considered to be 50% and dermal absorption is considered to be 100%: 50 mg/kg bw/d * 50/100 = 25 mg/kg bw/d
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEL
- AF for differences in duration of exposure:
- 6
- Justification:
- Extrapolation from subacute study to chronic exposure worker
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Correction for caloric demand from rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- Difference in sensitivity within general population
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.42 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC guidance (Technical Report No. 110, October 2010)
- Overall assessment factor (AF):
- 120
- Dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Value is NOAEL
- AF for differences in duration of exposure:
- 6
- Justification:
- Extrapolation from subacute study to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Correction for caloric demand from rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- Difference in sensitivity among general population
- AF for the quality of the whole database:
- 1
- Justification:
- Reliable studies used
- AF for remaining uncertainties:
- 1
- Justification:
- No remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- high hazard (no threshold derived)
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.
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.
