Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.16 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEC
Value:
77 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
54 mg/m³
Explanation for the modification of the dose descriptor starting point:

The weight of evidence suggests a NOAEC for systemic toxicity of 20 ppm (77 mg/m3) from 13-week toxicity studies (Collins, 1992; Kim et al., 2006; Nemec, 2006). After correction for the exposure duration in study (6 hrs/day, 7 days/week) to default worker exposure (8 hrs/day, 5 days/ week) and for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3), the NOAEC for workers is 54 mg/m3.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15.5 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
Value:
385 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
193 mg/m³
Explanation for the modification of the dose descriptor starting point:

For rats the NOAEC for systemic toxicity was 100 ppm (385 mg/m3) in an acute (6-hour) neurotoxicity study (Nemec, 2005). After correction for the exposure duration in study (6 hrs/day) to default worker exposure (8 hrs/day) and for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3), the NAEC for workers is 193 mg/m3.

AF for dose response relationship:
1
Justification:
Not needed
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.02 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Value:
20.2 mg/m³
AF for dose response relationship:
1
Justification:
Not needed
AF for differences in duration of exposure:
2
Justification:
Default AF
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed
AF for other interspecies differences:
1
Justification:
The NOAEC of 5 ppm is based on local contact toxicity in the form of degeneration of the nasal olfactory epithelium in rats. There are a number of references that show that the local effects of vapours in the rat nasal cavity when extrapolated to the human nasal cavity will over-estimate the effect by a factor of approximately 2 to 4 (ECETOC TR No. 86). In a study of an inhaled organic acid vapour, acrylic acid, computational fluid dynamics and physiologically based inhalation model simulation showed that the human nasal cavity was exposed to two- or threefold lower tissue concentrations than the olfactory epithelium of the rodent nasal cavity in similar exposure conditions attributable to the large olfactory epithelium surface area (>50%) of the rat nasal cavity and its highly susceptible location compared to the smaller (<5%) area in the human nasal cavity with its less accessible dorsal posterior location (Frederick et al., Toxicol Appl Pharmacol. 1998 Sep;152(1):211-31). The study confirmed that the histological structure of olfactory epithelium varies little between mammalian species and the susceptibility of the tissue to inhaled irritants also varies little between species, consequently the dominant factor influencing interspecies differences in susceptibility to inhaled irritants is olfactory tissue dose which is significantly higher in rodents. Bearing in mind the anatomical differences identified by Frederick et al between rat and human an inter-species AF of 1 will be protective when setting the DNEL.
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC
Value:
48 mg/m³
AF for dose response relationship:
1
Justification:
Not needed
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed
AF for other interspecies differences:
1
Justification:
The NOAEC of 12.5 ppm is based on local contact toxicity in the form of degeneration of the nasal olfactory epithelium in rats. There are a number of references that show that the local effects of vapours in the rat nasal cavity when extrapolated to the human nasal cavity will over-estimate the effect by a factor of approximately 2 to 4 (ECETOC TR No. 86). In a study of an inhaled organic acid vapour, acrylic acid, computational fluid dynamics and physiologically based inhalation model simulation sh owed that the human nasal cavity was exposed to two- or threefold lower tissue concentrations than the olfactory epithelium of the rodent nasal cavity in similar exposure conditions attributable to the large olfactory epithelium surface area (>50%) of the rat nasal cavity and its highly susceptible locati on compared to the smaller (<5%) area in the human nasal cavity with its less accessible dorsal pos terior location (Frederick et al., Toxicol Appl Pharmacol. 1998 Sep;152(1):211-31). The study confirmed that the histological structure of olfactory epithelium varies little between mammalian species and the susceptibility of the tissue to inhaled irr itants also varies little between species, consequently the dominant factor influencing interspecies differences in susceptibility to inhaled irritants is olfactory tissue dose which is significantly higher ifferences identified by Frederick et al between rat and human an inter-species AF of 1 will be protective when setting the DNEL.
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.97 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEC
Value:
77 mg/m³
Modified dose descriptor starting point:
NOAEL
Value:
196.9 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The weight of evidence suggests a NOAEC for systemic toxicity of 20 ppm (77 mg/m3) from 13-week inhalation toxicity studies (Collins, 1992; Kim et al., 2006; Nemec, 2006).

For a calculation of an endogenous dose using the alveolar ventilation rate it has to be considered that only 70% of the total ventilation air is available for exchange via the alveoli per unit time (REACH guidance Chapter R.7c, 2017). With a ventilation rate of 0.29 m3/kg for 6 hours of exposure, the equivalent endogeneous dose level is 21.9 mg/kg/d (77 mg/m3 x 0.29 m3/kg x 7d/5d x 0.7) after correction for the exposure duration in study (7 days/week) to default worker exposure (5 days/ week). Finally, the PoD for DNEL derivation is 196.9.6 mg/kg considering an inhalation absorption rate of 90% and a dermal absorption rate of 10%.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
Default (DNEL calculator)
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:
0.1 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
90
Dose descriptor:
other: LOAEC: 8.58 mg/cm²
AF for dose response relationship:
3
Justification:
Default value
AF for differences in duration of exposure:
6
Justification:
Default value
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed for local effects
AF for other interspecies differences:
1
Justification:
Not needed for local effects
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Not needed
AF for remaining uncertainties:
1
Justification:
Not needed
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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:
0.38 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEC
Value:
77 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
19.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

The weight of evidence suggests a NOAEC for systemic toxicity of 20 ppm (77 mg/m3) from 13-week toxicity studies (Collins, 1992; Kim et al., 2006; Nemec, 2006). After correction for the exposure duration in study (6 hrs/day, 7 days/week) to default general population exposure (24 hrs/day, 7 days/ week), the NAEC for general population is 19.2 mg/m3.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.8 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEC
Value:
385 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
96 mg/m³
Explanation for the modification of the dose descriptor starting point:

For rats the NOAEC for systemic toxicity was 100 ppm (385 mg/m3) in an acute (6 -hour) neurotoxicity study (Nemec, 2005). After correction for the exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day), the NAEC for general population is 96 mg/m3.

AF for dose response relationship:
1
Justification:
default value
AF for interspecies differences (allometric scaling):
1
Justification:
default value
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
default value
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
default value

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.24 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor:
NOAEC
Value:
4.75 mg/m³
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
2
Justification:
default value
AF for interspecies differences (allometric scaling):
1
Justification:
default value
AF for other interspecies differences:
1
Justification:
The NOAEC of 5 ppm is based on local contact toxicity in the form of degeneration of the nasal olfactory epithelium in rats. There are a number of references that show that the local effects of vapours in the rat nasal cavity when extrapolated to the human nasal cavity will over-estimate the effect by a factor of approximately 2 to 4 (ECETOC TR No. 86). In a study of an inhaled organic acid vapour, acrylic acid, computational fluid dynamics and physiologically based inhalation model simulation showed that the human nasal cavity was exposed to two- or threefold lower tissue concentrations than the olfactory epithelium of the rodent nasal cavity in similar exposure conditions attributable to the large olfactory epithelium surface area (>50%) of the rat nasal cavity and its highly susceptible location compared to the smaller (<5%) area in the human nasal cavity with its less accessible dorsal posterior location (Frederick et al., Toxicol Appl Pharmacol. 1998 Sep;152(1):211-31). The study confirmed that the histological structure of olfactory epithelium varies little between mammalian species and the susceptibility of the tissue to inhaled irritants also varies little between species, consequently the dominant factor influencing interspecies differences in susceptibility to inhaled irritants is olfactory tissue dose which is significantly higher in rodents. Bearing in mind the anatomical differences identified by Frederick et al between rat and human an inter-species AF of 1 will be protective when setting the DNEL.
AF for intraspecies differences:
10
Justification:
default value
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
default value
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.8 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
Value:
48 mg/m³
AF for dose response relationship:
1
Justification:
default value
AF for interspecies differences (allometric scaling):
1
Justification:
default value
AF for other interspecies differences:
1
Justification:
The NOAEC of 12.5 ppm is based on local contact toxicity in the form of degeneration of the nasal olfactory epithelium in rats. There are a number of references that show that the local effects of vapours in the rat nasal cavity when extrapolated to the human nasal cavity will over-estimate the effect by a factor of approximately 2 to 4 (ECETOC TR No. 86). In a study of an inhaled organic acid vapour, acrylic acid, computational fluid dynamics and physiologically based inhalation model simulation showed that the human nasal cavity was exposed to two- or threefold lower tissue concentrations than the olfactory epithelium of the rodent nasal cavity in similar exposure conditions attributable to the large olfactory epithelium surface area (>50%) of the rat nasal cavity and its highly susceptible location compared to the smaller (<5%) area in the human nasal cavity with its less accessible dorsal posterior location (Frederick et al., Toxicol Appl Pharmacol. 1998 Sep;152(1):211-31). The study confirmed that the histological structure of olfactory epithelium varies little between mammalian species and the susceptibility of the tissue to inhaled irritants also varies little between species, consequently the dominant factor influencing interspecies differences in susceptibility to inhaled irritants is olfactory tissue dose which is significantly higher in rodents. Bearing in mind the anatomical differences identified by Frederick et al between rat and human an inter-species AF of 1 will be protective when setting the DNEL.
AF for intraspecies differences:
10
Justification:
default value
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
default value

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEC
Value:
77 mg/m³
Modified dose descriptor starting point:
NOAEL
Value:
140.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The weight of evidence suggests a NOAEC for systemic toxicity of 20 ppm (77 mg/m3) from 13-week inhalation toxicity studies (6h/day, 7 days/week) (Collins, 1992; Kim et al., 2006; Nemec, 2006).

For a calculation of an endogenous dose using the alveolar ventilation rate it has to be considered that only 70% of the total ventilation air is available for exchange via the alveoli per unit time (REACH guidance Chapter R.7c, 2017). With a ventilation rate of 0.29 m3/kg for 6 hours of exposure the equivalent endogeneous dose level is 15.6 mg/kg/d (77 mg/m3 x 0.29 m3/kg x 0.7). Considering an inhalation absorption rate of 90% and a dermal absorption rate of 10%, the PoD for DNEL derivation is 140.4 mg/kg/d (15.6 mg/kg/d x 90%/10%).

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
Default (DNEL calculator)
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:
0.05 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
180
Dose descriptor:
other: LOAEL: 8.5 mg/cm²
AF for dose response relationship:
3
Justification:
Default value
AF for differences in duration of exposure:
6
Justification:
Default value
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed for skin irritation
AF for other interspecies differences:
1
Justification:
Not needed for skin irritation
AF for intraspecies differences:
10
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value
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:
0.078 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
200
Dose descriptor starting point:
other: NOAEC: 77 mg/m3
Modified dose descriptor starting point:
NOAEL
Value:
15.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The weight of evidence suggests a NOAEC for systemic toxicity of 20 ppm (77 mg/m3) from 13-week inhalation toxicity studies (6h/day, 7 days/week) (Collins, 1992; Kim et al., 2006; Nemec, 2006).

For a calculation of an endogenous dose using the alveolar ventilation rate it has to be considered that only 70% of the total ventilation air is available for exchange via the alveoli per unit time (REACH guidance Chapter R.7c, 2017). With a ventilation rate of 0.29 m3/kg for 6 hours of exposure the equivalent endogeneous dose level is 15.6 mg/kg/d (77 mg/m3 x 0.29 m3/kg x 0.7). Considering an inhalation absorption rate of 90% and an oral absorption rate of 90%, the PoD for DNEL derivation is 15.6 mg/kg/d (15.6 mg/kg/d x 90%/90%).

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population