Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.8 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):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 300 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 408 study in rats with treatment of male and of female rats for 90 days (Kruijssen, 2020), is taken forward for DNEL derivation. The corrected inhalatory NOAEC for workers as starting point is calculated with 370 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 * 1.4 (for differences in experimental/human exposure conditions, i.e. 7 days/week in animal study versus 5 days/week for workers, see Appendix R.8-6 of ECHA Guidance R8). Based on the oral NOAEL of 300 mg/kg bw/day for systemic toxicity, obtained in a study on rats with subchronic treatment, the starting point is calculated with 370 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:
2
Justification:
For differences in the experimental exposure duration (= subchronic) 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 2 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:
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:
4.2 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):
100
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 300 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 408 study in rats with treatment of male and of female rats for 90 days (Kruijssen, 2020), 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). However, since there are differences in experimental/human exposure conditions (7 days/week in animal study versus 5 days/week for workers) adaption with a factor of 1.4 seems appropriate (Appendix R.8-6 of ECHA Guidance R8). Based on the oral NOAEL of 300 mg/kg bw/day for systemic toxicity, obtained in an oral study on rats with subchronic treatment, the starting point is calculated with 420 mg/kg bw/day (300 * 1.4).

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:
2
Justification:
For differences in the experimental exposure duration (= subchronic) 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 2 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:
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Overall, the systemic toxicity of the registered substance is low; it is not a skin or eye irritant, not sensitizing, not mutagenic, not toxic to reproductive organs, and not a developmental toxicant in rats and rabbits.

A subchronic oral gavage toxicity study in Wistar rats following OECD TG 408 was performed recently with the substance. Based on the experiences gained in a subacute oral toxicity study the dose levels for the OECD TG 408 were selected with 0, 100, 300 and 1000 mg/kg bw/day. Administration of the test item by once daily oral gavage was well tolerated in rats at levels up to 1000 mg/kg/day. Adverse morphologic alterations at minimal to mild degree were present in the liver of males treated at 1000 mg/kg/day and consisted of centrilobular cytoplasmic alteration, hepatocellular vacuolation and single cell necrosis.

Based on these results of this subchronic study, the no-observed-adverse-effect level (NOAEL) was considered to be 300 mg/kg/day for male rats and 1000 mg/kg bw for female rats.

In this study, a marked reduction of total T4 was observed in males treated at 1000 mg/kg/day which was considered to be test item-related. However, under the conditions of this study no adverse effect was observed that could be linked to the reduction of total T4 and therefore this reduction was not taken into account when determining the parental male NOAEL.

The findings in the subchronic study are well in line with the findings of a subacute oral toxicity study, in which liver of male rats was also slightly affected at 1000 mg/kg bw/day only. Slight morphological changes corresponded to centrilobular vacuolation together with eosinophilia in this group. The vacuolation was proven as hepatocellular fat deposition and might indicate an (adverse) influence on fat metabolism. Females were not affected. The NOAEL was consistently 300 mg/kg bw for males due to liver findings and 1000 mg/kg bw for females in the subacute oral toxicity study.

Since the NOAEL of 300 mg/kg bw/day for the male rat was used as starting point for DNEL derivation, the resulting DNEL values can be considered as worst-case.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.6 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):
50
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 300 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 408 study in rats with treatment of male and of female rats for 90 days (Kruijssen, 2020), is taken forward for DNEL derivation. The corrected inhalatory NOAEC for the General Population as starting point is calculated with 130 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 300 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:
2
Justification:
For differences in the experimental exposure duration (= subchronic) 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 2 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:
1.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 300 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 408 study in rats with treatment of male and of female rats for 90 days (Kruijssen, 2020), 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:
2
Justification:
For differences in the experimental exposure duration (= subchronic) 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 2 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:
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:
1.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 300 mg/kg bw/day that was considered relevant for human risk assessment purposes, obtained in an oral OECD 408 study in rats with treatment of male and of female rats for 90 days (Kruijssen, 2020), 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:
2
Justification:
No difference in the experimental exposure duration (= subchronic) 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 2 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Overall, the systemic toxicity of the registered substance is low; it is not a skin or eye irritant, not sensitizing, not mutagenic, not toxic to reproductive organs, and not a developmental toxicant in rats and rabbits.

A subchronic oral gavage toxicity study in Wistar rats following OECD TG 408 was performed recently with the substance. Based on the experiences gained in a subacute oral toxicity study the dose levels for the OECD TG 408 were selected with 0, 100, 300 and 1000 mg/kg bw/day. Administration of the test item by once daily oral gavage was well tolerated in rats at levels up to 1000 mg/kg/day. Adverse morphologic alterations at minimal to mild degree were present in the liver of males treated at 1000 mg/kg/day and consisted of centrilobular cytoplasmic alteration, hepatocellular vacuolation and single cell necrosis.

Based on these results of this subchronic study, the no-observed-adverse-effect level (NOAEL) was considered to be 300 mg/kg/day for male rats and 1000 mg/kg bw for female rats.

In this study, a marked reduction of total T4 was observed in males treated at 1000 mg/kg/day which was considered to be test item-related. However, under the conditions of this study no adverse effect was observed that could be linked to the reduction of total T4 and therefore this reduction was not taken into account when determining the parental male NOAEL.

The findings in the subchronic study are well in line with the findings of a subacute oral toxicity study, in which liver of male rats was also slightly affected at 1000 mg/kg bw/day only. Slight morphological changes corresponded to centrilobular vacuolation together with eosinophilia in this group. The vacuolation was proven as hepatocellular fat deposition and might indicate an (adverse) influence on fat metabolism. Females were not affected. The NOAEL was consistently 300 mg/kg bw for males due to liver findings and 1000 mg/kg bw for females in the subacute oral toxicity study.

Since the NOAEL of 300 mg/kg bw/day for the male rat was used as starting point for DNEL derivation, the resulting DNEL values can be considered as worst-case.