Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.164 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):
75
Dose descriptor starting point:
LOAEL
Value:
30 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
12.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

A long term study (>12 months) which can be used for assessment and derivation of a respective DNEL is not available. Furthermore, there are no quantitative data on inhalation absorption of m-toluidine. Therefore, the available OECD TG 422 study can be taken using oral application (MHLW 1995). The LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003).

According to the ECHA guidance document R8 (Characterisation of dose [concentration]-response for human health) a factor 3 (When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor 3 (as minimum/majority of cases)) is used. Therfore the corrected human NOAEL/LOAEL = 1/3.

Bioavailability: animal experiment (oral) = 50% (default)

Bioavailability human route = 100% (default inhalation)

For the expose in animal study/exposure in humans a correction factor of 7/5 is used.

Corrected human LOAEC = 37 mg/m³ (30 x 1/0,38 x7/5 x50/100 x 6.7/10)

Corrected human NOAEC = 12.34 mg/m³

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Sub-acute exposure to chronic exposure (defalut value ECHA)
AF for interspecies differences (allometric scaling):
1
Justification:
Rat versus human According to Table R8-4 in chapter R8 of EChA Guidance Document (Version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation (defalut value ECHA)
AF for other interspecies differences:
2.5
Justification:
(defalut value ECHA)
AF for intraspecies differences:
5
Justification:
Sub-acute exposure to chronic exposure (defalut value ECHA)
AF for the quality of the whole database:
1
Justification:
There are valid studies available for all required toxicological endpoints for that tonnage band
AF for remaining uncertainties:
1
Justification:
As the increased susceptibility of humans to methemoglobinemia is already considered by using factors for intraspecies and interspecies differences the remaining differences between worker and rats might be low and a factor of 1 justified.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.82 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
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:
0.046 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):
300
Dose descriptor starting point:
LOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
14 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In a study according to OECD TG 422 and GLP conditions male and female SD (Crj:CD) rats received 0, 30, 100, or 300 mg/kg bw/day m-toluidine by gavage (MHLW 1995). Hematological and biochemical analysis was conducted only for males. Compound related clinical signs were low locomotor activity and pale skin at 300 mg/kg bw. At the lowest dose of 30 mg/kg bw marginal deposit pigmentation and extramedullary hematopoiesis in the spleen were observed suggesting that a slight hemolysis occurred. Therefore, the dose of 30 mg/kg bw/day should be considered to be adverse effect level because of suggestive evidence of hemolytic anemia. LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003).

According to the ECHA gueidance document R8 (Characterisation of dose [concentration]-response for human health) a factor 3 (When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor 3 (as minimum/majority of cases)) is used. Therfore the corrected human NOAEL/LOAEL = 1/3.

Bioavailability: animal experiment (oral) = 50% (default)

Bioavailability human route = 50% (default inhalation)

For the expose in animal study/exposure in humans a correction factor of 7/5 is used.

DNEL (systemic long term) = 0.046 mg/kg ( (14 / 300)

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure (defalut value ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
rat versus human (defalut value ECHA)
AF for other interspecies differences:
2.5
Justification:
defalut value ECHA
AF for intraspecies differences:
5
Justification:
defalut value ECHA
AF for the quality of the whole database:
1
Justification:
There are valid studies available for all required toxicological endpoints for that tonnage band.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.029 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:
LOAEC
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

A long term study (>12 months) which can be used for assessment and derivation of a respective DNEL is not available. Furthermore, there are no quantitative data on inhalation absorption of m-toluidine. Therefore, the available OECD TG 422 study can be taken using oral application (MHLW 1995). The LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003).

According to the ECHA gueidance document R8 (Characterisation of dose [concentration]-response for human health) a factor 3 (When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor 3 (as minimum/majority of cases)) is used. Therfore the corrected human NOAEL/LOAEL = 1/3.

Bioavailability: animal experiment (oral) = 50% (default)

Bioavailability human route = 100% (default inhalation)

Corrected human LOAEC = 13.04 mg/m³ (30 x 1/1,15 x 50/100)

Corrected human NOAEC = 4.34 mg/m³

DNEL (systemic long term) = 0.029 mg/m³ (4.34 / 150)

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure (defalut value ECHA)
AF for interspecies differences (allometric scaling):
1
Justification:
Rat versus human: According to Table R8-4 in chapter R8 of EChA Guidance Document (Version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation (defalut value ECHA).
AF for other interspecies differences:
2.5
Justification:
defalut value ECHA
AF for intraspecies differences:
10
Justification:
defalut value ECHA
AF for the quality of the whole database:
1
Justification:
There are valid studies available for all required toxicological endpoints for that tonnage band
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.145 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
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:
0.016 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:
LOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In a study according to OECD TG 422 and GLP conditions male and female SD (Crj:CD) rats received 0, 30, 100, or 300 mg/kg bw/day m-toluidine by gavage (MHLW 1995). Hematological and biochemical analysis was conducted only for males. Compound related clinical signs were low locomotor activity and pale skin at 300 mg/kg bw. At the lowest dose of 30 mg/kg bw marginal deposit pigmentation and extramedullary hematopoiesis in the spleen were observed suggesting that a slight hemolysis occurred. Therefore, the dose of 30 mg/kg bw/day should be considered to be adverse effect level because of suggestive evidence of hemolytic anemia. LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003).

According to the ECHA gueidance document R8 (Characterisation of dose [concentration]-response for human health) a factor 3 (When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor 3 (as minimum/majority of cases)) is used. Therfore the corrected human NOAEL/LOAEL = 1/3.

Bioavailability: animal experiment (oral) = 50% (default)

Bioavailability human route = 50% (default inhalation)

DNEL (systemic long term) = 0.016 mg/kg (10 / 600)

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure (defalut value ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
defalut value ECHA
AF for other interspecies differences:
2.5
Justification:
defalut value ECHA
AF for intraspecies differences:
10
Justification:
defalut value ECHA
AF for the quality of the whole database:
1
Justification:
There are studies available for all required toxicological endpoints for that tonnage band
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
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:
0.016 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:
LOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In a study according to OECD TG 422 and GLP conditions male and female SD (Crj:CD) rats received 0, 30, 100, or 300 mg/kg bw/day m-toluidine by gavage (MHLW 1995). Hematological and biochemical analysis was conducted only for males. Compound related clinical signs were low locomotor activity and pale skin at 300 mg/kg bw. At the lowest dose of 30 mg/kg bw marginal deposit pigmentation and extramedullary hematopoiesis in the spleen were observed suggesting that a slight hemolysis occurred. Therefore, the dose of 30 mg/kg bw/day should be considered to be adverse effect level because of suggestive evidence of hemolytic anemia. LOAEL for repeat dose toxicity was 30 mg/kg bw/day (UNEP 2003).

According to the ECHA guidance document R8 (Characterisation of dose [concentration]-response for human health) a factor 3 (When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor 3 (as minimum/majority of cases)) is used. Therfore the corrected human NOAEL/LOAEL = 1/3.

Bioavailability: animal experiment (oral) = 50% (default)

Bioavailability human route = 50% (default inhalation)

DNEL (systemic long term) = 0.016 mg/kg (10 / 600)

AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chornic exposure (defalut value ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
rat versus human (defalut value ECHA)
AF for other interspecies differences:
2.5
Justification:
defalut value ECHA
AF for intraspecies differences:
10
Justification:
defalut value ECHA
AF for the quality of the whole database:
1
Justification:
There are valid studies available for all required toxicological endpoints for that tonnage band.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
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

Categories Display