1,4-bis[(2-methylphenyl)amino]anthraquinone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 714.5 mg/kg bw when rats were orally exposed with 1,4-bis[(2-methylphenyl)amino]anthraquinone.

Thus, as per criteria of CLP regulation, 1, 4-bis[(2-methylphenyl)amino]anthraquinone can be not classified for reproductive toxicity. 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material : 1,4-bis[(2-methylphenyl)amino]anthraquinone
- Molecular formula : C28H22N2O2
- Molecular weight : 418.494 g/mole
- Smiles notation : c1cc2C(=O)c3c(C(=O)c2cc1)c(Nc1ccccc1C)ccc3Nc1c(cccc1)C
- InChl : 1S/C28H22N2O2/c1-17-9-3-7-13-21(17)29-23-15-16-24(30-22-14-8-4-10-18(22)2)26-25(23)27(31)19-11-5-6-12-20(19)28(26)32/h3-16,29-30H,1-2H3
- Substance type : Organic
- Physical state : Solid

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Remarks on MMAD:

not specified

Vehicle:

corn oil

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

54 days

Frequency of treatment:

7 days/week

Details on study schedule:

not specified

Dose / conc.:

713.5 mg/kg bw/day

No. of animals per sex per dose:

40 males and 40 females

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

713.5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

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

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" )  and ("c" and ( not "d") )  )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and "l" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >>  Michael-type addition, quinoid structures AND AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes AND Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes by DNA binding by OASIS v.1.4

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as SN1 >> Nitrenium Ion formation >> Aromatic azo by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND Carbonyl compound AND Ketone AND Secondary amine AND Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as CO2 derivative (general) by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.81

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 10.9

Conclusions:

NOAEL was estimated to be 714.5 mg/kg bw when rats were orally exposed with 1,4-bis[(2-methylphenyl)amino]anthraquinone.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 1,4-bis[(2-methylphenyl)amino]anthraquinone. The NOAEL was estimated to be 714.5 mg/kg bw when rats were orally exposed with 1,4-bis[(2-methylphenyl)amino]anthraquinone.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

714.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

In different studies, 1,4-bis[(2-methylphenyl)amino]anthraquinone has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 1,4-bis[(2-methylphenyl)amino]anthraquinone along with the study available on structurally similar read across substance Acid Violet 43. The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 1,4-bis[(2-methylphenyl)amino]anthraquinone. The NOAEL was estimated to be 714.5 mg/kg bw when rats were orally exposed with 1,4-bis[(2-methylphenyl)amino]anthraquinone.  

In another experimental study given by Scientific Committee on Consumer Safety SCCS (OPINION ON Acid Violet 43 COLIPA n° C63, 2013) on structurally similar read across substance Acid Violet 43 (CAS no 4430-18-6), Wistar female rats were treated with Acid Violet 43 in the concentration of0, 94, 282 or 940mg /kg bw/day through day 6-17 of gestation period by oral gavage. The test substance (in1%carboxymethylcellulose in water) was given daily at dose volumes of 10 ml/kg bw by oral gavage. Discoloured faeces were observed at 940 mg/kg bw/day. No mortality was observed in treated female rat. Similarly, at the does group of 94 mg /kg bw/day one female had only embryonic resorptions. At the dose group of 282 and 940 mg /kg bw/day two females were not pregnant, one female had only empty implantation sites and a further one only embryonic resorptions at Caesarean section. These findings were considered to be incidental as a dose relation was missing. In addition, No effect on foetuses weight and noexternal, soft tissue and skeletal anomalies were observed as compared to control. Therefore, NOAEL was considered to be 940 mg/kg bw for P and F1 generation whenWistar female rats were treated with Acid Violet 43 orally by gavage through day 6-17 of gestation.

 

Further supported by experimental study given by Scientific Committee on Consumer Safety SCCS (OPINION ON Acid Violet 43 COLIPA n° C63, 2013) on structurally similar read across substance Acid Violet 43 (CAS no 4430-18-6),, Sprague Dawley female rats were treated with Acid Violet 43 in the concentration of 0 , 27, 109 or 435 mg /kg bw/day through day 6-15 of gestation period by oral by gavage. The test substance was given in water daily at dose volumes of 5 ml/kg bw. Increased salivation was observed at 435 mg /kg bw/day. Discolored feces at 109 and 435 mg /kg bw/day were observed. No mortality was observed in treated group compare to control group. Discoloration of placenta was also observed at 435 mg /kg bw/day. No effect on reproductive performance was observed in treated female rats. In addition, No effect on body weight of foetuses were observed as compared to control. No external soft tissue or skeletal anomalies were observed in treated foetuses. Therefore, NOAEL was considered to be 435 mg /kg bw/day for P and F1 generation when Sprague Dawley female rats were treated with Acid Violet 43 through day 6-15 of gestation period.

Thus, based on the above study and predictions on 1, 4-bis[(2-methylphenyl)amino]anthraquinone and its read across substances, it can be concluded that NOAEL value is 714.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 1, 4-bis[(2-methylphenyl)amino]anthraquinone can be not classified for reproductive toxicity. 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above study and predictions on 1, 4-bis [(2-methylphenyl) amino] anthraquinone and its read across substances, it can be concluded that NOAEL value is 714.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 1, 4-bis [(2-methylphenyl) amino] anthraquinone can be not classified for reproductive toxicity.