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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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:
8.4 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):
52.5
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
441 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 500 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 422 study in rats with treatment of males for 29-33 days and of females for 50-64 days (van Otterdijk, 2019) is taken forward for DNEL derivation. The corrected inhalatory NOAEC for workers as starting point is calculated with 132 mg/m³ according to the conditions given below.

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012). According to Figure R. 8-3 in the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012) additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral LOAEL * 50 %/100 % * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ (based on the oral NOAEL of 500 mg/kg bw/day for systemic toxicity obtained in a study on rats with ≥ subacute treatment) the starting point is calculated with 441 mg/m³.

AF for dose response relationship:
1
Justification:
Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
4.2
Justification:
For differences in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 a factor of 6 is considered. This factor is corrected for differences in experimental/human exposure conditions (7 days/week in animal study versus 5 days/week for workers), resulting in a factor of 4.2 (6 x 0.7).
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
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:
2.38 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):
210
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 500 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 422 study in rats with treatment of males for 29-33 days and of females for 50-64 days (van Otterdijk, 2019) is taken forward for DNEL derivation.

For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose for humans. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (ECHA guidance R.8, chapter 8.4.2). Thus, no modification of the dose descriptor starting point is warranted.

AF for dose response relationship:
1
Justification:
Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
4.2
Justification:
For differences in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 a factor of 6 is considered. This factor is corrected for differences in experimental/human exposure conditions (7 days/week in animal study versus 5 days/week for workers), resulting in a factor of 4.2 (6 x 0.7).
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

A Screening Repeated Dose and Reproduction Toxicity Study following OECD 422 was performed with the registered substance (van Otterdijk, 2019). The NOAEL for repeated dose toxicity in this study was determined with 150 mg/kg bw/day for male rats, based on hyaline droplet accumulation with granular casts and tubular basophilia recorded in the male kidneys. The NOAEL for females was 500 mg/kg bw/day, the highest dose tested. The hyaline droplets were considered to represent alpha2uglobulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation leading ultimately to proximal cortical tubule cell injury as manifested by formation of granular casts and increased tubular basophilia.  This male rat specific protein is neither present in female rats nor in higher mammals, including man. Since these renal findings are regarded as a male rat specific response, a NOAEL of 500 mg/kg/day is indicated for humane risk assessment purposes.

No other relevant adverse effects have been recorded at this dose in the OECD 422 study. Reproduction and developmental NOAELs are determined with 500 mg/kg bw/day. Therefore, taken into consideration the relevance for humans, the dose of 500 mg/kg bw/day will be considered for DNEL derivation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.45 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:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
217 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 500 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 422 study in rats with treatment of males for 29-33 days and of females for 50-64 days (van Otterdijk, 2019) is taken forward for DNEL derivation. The corrected inhalatory NOAEC for General Population as starting point is calculated with 217 mg/m³ according to the conditions given below.

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a ‘default factor of 2 is recommended according to chapter R.8.4.2 of ECHA guidance R.8. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 0.5 * 1/1.15 m³ per kg and day (based on the oral NOAEL of 500 mg/kg bw/day for systemic toxicity).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
6
Justification:
For differences in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 a factor of 6 is considered.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
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:
0.83 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:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 500 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 422 study in rats with treatment of males for 29-33 days and of females for 50-64 days (van Otterdijk, 2019) is taken forward for DNEL derivation.

For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose for humans. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (ECHA guidance R.8, chapter 8.4.2). Thus, no modification of the dose descriptor starting point is warranted.

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
6
Justification:
For differences in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 a factor of 6 is considered.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 150 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 422 study in rats with treatment of males for 29-33 days and of females for 50-64 days (van Otterdijk, 2019) is taken forward for DNEL derivation. Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore a route-to-route extrapolation is not necessary and the NOAEL from the rat study is used as starting point.

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
6
Justification:
No difference in the experimental exposure duration (= chronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
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

A Screening Repeated Dose and Reproduction Toxicity Study following OECD 422 was performed with the registered substance (van Otterdijk, 2019). The NOAEL for repeated dose toxicity in this study was determined with 150 mg/kg bw/day for male rats, based on hyaline droplet accumulation with granular casts and tubular basophilia recorded in the male kidneys. The NOAEL for females was 500 mg/kg bw/day, the highest dose tested. The hyaline droplets were considered to represent alpha2uglobulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation leading ultimately to proximal cortical tubule cell injury as manifested by formation of granular casts and increased tubular basophilia.  This male rat specific protein is neither present in female rats nor in higher mammals, including man. Since these renal findings are regarded as a male rat specific response, a NOAEL of 500 mg/kg/day is indicated for humane risk assessment purposes.

No other relevant adverse effects have been recorded at this dose in the OECD 422 study. Reproduction and developmental NOAELs are determined with 500 mg/kg bw/day. Therefore, taken into consideration the relevance for humans, the dose of 500 mg/kg bw/day will be considered for DNEL derivation.