1,4-bis(p-tolylamino)anthraquinone

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the data available, the No Observed Adverse Effect Level (NOAEL) for the test chemical was considered to be 230 mg/Kg bw using male and female rats. Hence the test chemical is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: inhalation

This end point was considered for waiver since according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. The test chemical has very low vapor pressure of 9.40E-11 Pa (7.05E-013  mmHg). Also, the test chemical has a particle size distribution of 25-150 micron, so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: dermal

Based on the data available, the No Observed Adverse Effect Level (NOAEL) for the test chemical was considered to be 500 mg/Kg bw using rabbits. Hence the test chemical is not likely to be toxic upon repeated exposure by dermal route as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Experimental data from study report

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

The 90 days subchronic repeated dose oral toxicity study was designed to evaluate the toxic effects of test chemical in dogs.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of the test chemical: D and C green 6
- IUPAC name: 1,4-bis[(4-methylphenyl)amino]-9,10-anthraquinone
- Molecular formula: C28H22N2O2
- Molecular weight: 418.4938 g/mol
- Substance type: Organic

Species:

dog

Strain:

not specified

Details on species / strain selection:

No data

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other: diet

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Dose / conc.:

290 other: mg/kg/day

Remarks:

Basis: nominal in diet

Dose / conc.:

570 other: mg/kg/day

Remarks:

Basis: nominal in diet

Dose / conc.:

500 other: mg/kg/day

Remarks:

Basis: nominal in diet

No. of animals per sex per dose:

At 290 mg/kg/day: 2 dogs

Control animals:

not specified

Details on study design:

In a 90 day subchronic study, two dogs were fed a diet containing 1 percent test chemical during week 1 (290 mg/kg/day); the concentration was increased to 2 percent during week 3 (570 and 500 mg/kg/day) and 3 percent during week 5. The weight normalized doses fluctuated between 610 and 1400 mg/kg/day during the remainder of the experiment.

Positive control:

No data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Other examinations:

No data

Statistics:

No data

Clinical signs:

no effects observed

Description (incidence and severity):

There were no gross signs of toxicity was observed.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant changes in body weight was observed in treated dogs.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Only an accumulation of dye in the pelvis of the kidney, in the mucosa of the small and large intestines, in adipose tissue, and in the gall bladder were observed.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No histopathological alterations were observed in treated dogs.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

570 other: mg/kg/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No effect on body weight, gross pathology and histopathology

Remarks on result:

other: No toxic effects were observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Conclusions:

The No observed Adeverse Effect Level (NOAEL) for test chemical in dogs by the oral route is considered to be 570 mg/kg body weight upon repeated exposure by oral route for 90 days.

Executive summary:

The 90 days subchronic toxicity study was designed to evaluate the toxic effects of test chemical in dogs. Two dogs were fed a diet containing 1 percent test chemical 3 during week 1 (290 mg/kg/day); the concentration was increased to 2 percent during week 3 (570 and 500 mg/kg/day) and 3 percent during week 5. The weight normalized doses fluctuated between 610 and 1400 mg/kg/day during the remainder of the experiment. There were no gross signs of toxicity, and no significant changes in body weight. Necropsy revealed only an accumulation of dye in the pelvis of the kidney, in the mucosa of the small and large intestines, in adipose tissue, and in the gall bladder. No histopathological alterations were observed; therefore, test chemical was not found to be toxic under the conditions of this test. Based on the observations made, The No observed Adeverse Effect Level (NOAEL) for test chemical in dogs by the oral route is considered to be 570 mg/kg body weight upon repeated exposure by oral route for 90 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

230 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is from K2 article

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation, other

Data waiving:

exposure considerations

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Experimental data from study report

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

95 weeks chronic repeated dose toxicity study of test chemical in mouse was conducted to evaluate the adverse effects by dermal route.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of the test chemical: D and C green 6
- IUPAc name: 1,4-bis[(4-methylphenyl)amino]-9,10-anthraquinone
- Molecular formula: C28H22N2O2
- Molecular weight: 418.4938 g/mol
- Substance type: Organic

Species:

mouse

Strain:

not specified

Details on species / strain selection:

No data

Sex:

male

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

not specified

Vehicle:

other: Benzene

Details on exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

95 weeks

Frequency of treatment:

Weekly

Dose / conc.:

1 other: mg

No. of animals per sex per dose:

no data

Control animals:

not specified

Details on study design:

Single weekly applications of 1 mg of Solvent Green 3 in 0.1 mL of benzene to the skin of mice for 95 weeks.

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Dermal irritation:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

The thyroid glands in the male mice were enlarged.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological examination did not show any effect.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No significant local or systemic effects were observed in treated mice.

Dose descriptor:

NOAEL

Effect level:

1 other: mg

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No significant local or systemic effects. The thyroid glands in the male mice were enlarged, but histopathological examination did not show an effect.

Remarks on result:

other: No toxic effects were observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Conclusions:

The No observed adverse effect level (NOAEL) was considered to be 1 mg when mice were treated with test chemical for 95 weeks.

Executive summary:

In a repeated dose dermal toxicity study, mice were treated with test chemical A single weekly application of 1 mg of test chemical in 0.1 mL of benzene to the skin of mice for 95 weeks did not cause significant local or systemic effects. The thyroid glands in the male mice were enlarged, but histopathological examination did not show an effect. Therefore, the No observed adverse effect  level (NOAEL) was considered to be 1 mg when mice were treated with test chemical for 95 weeks.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

The data is from K2 article

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data available for the target chemical was reviewed to determine the toxic nature of upon repeated exposure. The studies are as mentioned below:

Repeated dose toxicity: Oral

Study 1

In a 6-week dose range-finding study in rats, test chemical was administered in the diet at concentrations of 0.1, 0.23, 0.55, 1.29, or 3,0 percent (100, 230, 550, 1290 or 3000 mg/kg bw). There were no deaths or gross signs of toxicity. Food consumption and body weights were within normal range. The thyroid gland was small in animals fed the 0.55 (550 mg/kg bw/day) and the 3.0 (3000 mg/kg bw/day) percent diets, but histopathological evaluation did not reveal abnormalities in the thyroid gland. Gross degenerative changes in the liver were observed and confirme the by histopathological examination, which showed an increase in vacuolated cells around the hepatic central vein. No other effects were observed. Therefore, the No observed adverse effect level (NOAEL) was considered to be 230 mg/kg bw/day when rats were treated with test chemical orally in feed for 6 weeks.

Study 2 

The 90 days subchronic toxicity study was designed to evaluate the toxic effects of test chemical in dogs. Two dogs were fed a diet containing 1 percent test chemical 3 during week 1 (290 mg/kg/day); the concentration was increased to 2 percent during week 3 (570 and 500 mg/kg/day) and 3 percent during week 5. The weight normalized doses fluctuated between 610 and 1400 mg/kg/day during the remainder of the experiment. There were no gross signs of toxicity, and no significant changes in body weight. Necropsy revealed only an accumulation of dye in the pelvis of the kidney, in the mucosa of the small and large intestines, in adipose tissue, and in the gall bladder. No histopathological alterations were observed; therefore, test chemical was not found to be toxic under the conditions of this test. Based on the observations made, The No observed Adeverse Effect Level (NOAEL) for test chemical in dogs by the oral route is considered to be 570 mg/kg body weight upon repeated exposure by oral route for 90 days.

Repeated dose toxicity: inhalation

This end point was considered for waiver since according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. The test chemical has very low vapor pressure of 9.40E-11 Pa (7.05E-013  mmHg). Also, the test chemical has a particle size distribution of 25-150 micron, so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

 

Repeated dose toxicity: Dermal

Study1

Repeated dose dermal toxicity were evaluated in rabbit by using test chemical.The test chemical was applied at a dose of 500 mg for 13 weeks. No local toxic and no systemic toxic effects were observed in treated rabbits. Therefore, the No observed Adeverse Effect Level (NOAEL) was considered to be 500 mg/kg when rabbits were treated with test chemical for 13 weeks.

Study 2

In a repeated dose dermal toxicity study, mice were treated with test chemical A single weekly application of 1 mg of test chemical in 0.1 mL of benzene to the skin of mice for 95 weeks did not cause significant local or systemic effects. The thyroid glands in the male mice were enlarged, but histopathological examination did not show an effect. Therefore, the No observed adverse effect  level (NOAEL) was considered to be 1 mg when mice were treated with test chemical for 95 weeks.

Based on the above mentioned subchronic and chronic repeated-dose study conducted in experimental animals, no significant toxic effects were seen to occur upon repeated exposure by oral route. Hence, based on the above studies summarized with dermal routes it can be observed that the test chemical is not likely to be toxic as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical, is not likely to be toxic upon repeated exposure by oral, dermal and inhalation route of exposure as per the criteria mentioned in CLP regulation.