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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. 

Additional information

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