Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.25 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):
12.5
Dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

Justification for route to route extrapolation:

The NOAEL from a chronic oral toxicity feeding study in rats (Takagi 1994) of 12.7 mg/kg bw/day is taken forward for DNEL derivation. The corrected inhalatory NOAEC for workers as starting point is calculated with 15.6 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 (based on the oral NOAEL of 12.7 mg/kg bw/day for systemic toxicity obtained in a chronic feeding study on rats the starting point is calculated with 15.6 mg/m³. Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers).

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:
1
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):
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:
DNEL (Derived No Effect Level)
Value:
6.25 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.36 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):
50
Dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

Justification for route to route extrapolation

The NOAEL from a chronic oral toxicity feeding study in rats (Takagi 1994) of 12.7 mg/kg bw/day is taken forward for DNEL derivation. The corrected dermal NOAEC for workers as starting point is calculated with 17.8 mg/kg bw/day according to the conditions given below.

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). Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers)

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:
1
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:
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:
DNEL (Derived No Effect Level)
Value:
1.8 mg/kg bw/day
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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

Several repeated dose toxicity studies are available for the test substance 6,6'-di-tert-butyl-2,2'-methylenedi-p-cresol. Comparable effects were seen in subacute, subchronic and chronic toxicity rodent studies. Effects on body weight gain, increases in liver weights and adverse effect on reproduction organs were noted. In the subchronic feeding study with 2 dogs/sex and dose histopathological effects on the liver were noted at 330 ppm (ca. 11 mg/kg bw/day) and above. However, the number of dogs used is very limited and thus the study is used only for supporting reasons. Based on the findings from the numerous rodent toxicity studies a NOAEL of 12.7 mg/kg bw and day is used for DNEL calculation, which is based on a relative increase in male liver weight at 42.3 mg/kg bw/day and above in the chronic feeding study with Wistar rats (Takagi, 1994). At higher doses a suppression of body weight gain, liver weight increase in both sexes, decrease in testis weight, and histopathological lesions in the testis and the epididymis was observed (Takagi, 1994).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.22 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
Explanation for the modification of the dose descriptor starting point:

Justification for route to route extrapolation:

The NOAEL from a chronic oral toxicity feeding study in rats (Takagi 1994) of 12.7 mg/kg bw/day is taken forward for DNEL derivation. The corrected inhalatory NOAEC for workers as starting point is calculated with 5.52 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 12.7 mg/kg bw/day for systemic toxicity obtained in a 90-day feeding study on rats).

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:
1
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):
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:
DNEL (Derived No Effect Level)
Value:
1.1 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.13 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
Explanation for the modification of the dose descriptor starting point:

The NOAEL from a chronic oral toxicity feeding study in rats (Takagi 1994) of 12.7 mg/kg bw/day is taken forward for DNEL derivation. No modification of the starting point is required according to the conditions given below.

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).

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:
1
Justification:
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.
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:
DNEL (Derived No Effect Level)
Value:
0.65 mg/kg bw/day
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.13 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
Explanation for the modification of the dose descriptor starting point:

The NOAEL from a chronic oral toxicity feeding study in rats (Takagi 1994) of 12.7 mg/kg bw/day is taken forward for DNEL derivation. No modification of the starting point is required according to the conditions given below.

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:
1
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:
DNEL (Derived No Effect Level)
Value:
0.65 mg/kg bw/day
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Several repeated dose toxicity studies are available for the test substance 6,6'-di-tert-butyl-2,2'-methylenedi-p-cresol. Comparable effects were seen in subacute, subchronic and chronic toxicity rodent studies. Effects on body weight gain, increases in liver weights and adverse effect on reproduction organs were noted. In the subchronic feeding study with 2 dogs/sex and dose histopathological effects on the liver were noted at 330 ppm (ca. 11 mg/kg bw/day) and above. However, the number of dogs used is very limited and thus the study is used only for supporting reasons. Based on the findings from the numerous rodent toxicity studies a NOAEL of 12.7 mg/kg bw and day is used for DNEL calculation, which is based on a relative increase in male liver weight at 42.3 mg/kg bw/day and above in the chronic feeding study with Wistar rats (Takagi, 1994). At higher doses a suppression of body weight gain, liver weight increase in both sexes, decrease in testis weight, and histopathological lesions in the testis and the epididymis was observed (Takagi, 1994).