Sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 486 mg/kg bw when rats were orally exposed with sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate.    

Thus, as per criteria of CLP regulation, sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate can be not classified for reproductive toxicity.  

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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 3.3 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 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: Sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate
SMILES:Nc1ccc2cc(S(=O)(=O)O{-}.[Na]{+})cc(O)c2c1N=Nc1ccc(Cl)cc1C(F)(F)F
InChI:1S/C17H11ClF3N3O4S.Na/c18-9-2-4-13(11(6-9)17(19,20)21)23-24-16-12(22)3-1-8-5-10(29(26,27)28)7-14(25)15(8)16;/h1-7,25H,22H2,(H,26,27,28);/q;+1/p-1/b24-23-;
Mol. formula: C17H10ClF3N3NaO4S
Molecular Weight: 467.786 g/mole

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

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:

males 42 days;
females: from day 14 prior to mating to day 3 of lactation ( ca.42 days)

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

486 mg/kg bw/day

No. of animals per sex per dose:

13

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:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

486 mg/kg bw/day (actual dose received)

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:

no mortality observed

Body weight and weight changes:

no effects observed

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 specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group AND Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acid moiety AND Anilines (Unhindered) AND Phenol Amines AND Phenols AND Salt by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group AND Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkyl fluoride AND Alkyl halide AND Amine AND Anion AND Aromatic compound AND Aryl chloride AND Aryl halide AND Azo compound AND Cation AND Halogen derivative AND Hydroxy compound AND Phenol AND Primary amine AND Primary aromatic amine AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkyl fluoride AND Alkyl halide AND Amine AND Anion AND Aromatic compound AND Aryl chloride AND Aryl halide AND Azo compound AND Cation AND Halogen derivative AND Hydroxy compound AND Phenol AND Primary amine AND Primary aromatic amine AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.43

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.84

Conclusions:

The NOAEL was estimated to be 486 mg/kg bw when rats were orally exposed with sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate.

Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate. The NOAEL was estimated to be 486 mg/kg bw when rats were orally exposed with sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate.    

 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

486 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, sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate 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 sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate along with the study available on structurally similar read across substance RED 2G (CAS no 3734-67-6), Black PN (CAS no 2519-30-4) and Acid Violet 43 (CAS no 4430-18-6). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. 

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate. The NOAEL was estimated to be 486 mg/kg bw when rats were orally exposed with sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate.    

In another experimental study given by WHO (WHO FOOD ADDITIVES SERIES NO. 12, INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY WORLD HEALTH ORGANIZATION, 18-27 April 1977) on structurally similar read across substance RED 2G (CAS no 3734-67-6), male and female Colworth C57B1 mice were treated with RED 2G in the concentration of 0, 7.5, 37.5, 187.5 or 937.5 mg/kg bw/day in feed. No effects on survival or growth of treated mice were observed. Heinz bodies and increased methemoglobin were observed in 187.5 and 937.5 mg/kg bw/day treated mice. No effect on brain, heart, liver, spleen, kidneys or testes weight were observed in treated mice as compared to control. Splenic darkening and enlargement, increased splenic hemosiderin content and accelerated splenic erythropoiesis were observed in treated mice as compared to control, but no effect was observed on testes of male mice. Therefore, NOAEL was considered to be 937.5 mg/kg bw for male mice when male and female Colworth C57B1 mice were treated with RED 2G orally in diet for 80 weeks.

Further supported by experimental study given by NTRL(NTRL, OTS0516606-2, 1989) on structurally similar read across substance RED 2G (CAS no 3734-67-6), male and female mice were treated with RED 2G in the concentration of 0, 30, 150,750 and 1500 mg/kg bw/day in feed. No effect on survival, body weight and food consumption of treated mice were observed as compared to control. Increased heinz bodiez and methaemoglobins and decreased packed cell volumes were observed at 750 and 1500 mg/kg bw/day as compared to control. Similarly, Increase in relative spleen weight and splenic size were observed at 750 and 1500 mg/kg bw/day treated mice as compared to control. In addition, increased erythropoiesisand increased haemosiderin content, increase in haemosiderin in tile pruximal convoluted tubules of the kidney and Erytbroid hyperplasia of bone marrow were observed at 750 and 1500 mg/kg bw/day, Lesions in the liver were observed at 1500 mg/kg bw/day and Haemosiderin in the spleens were observed at 150 mg/kg bw/day treated mice as compared to control. No effect on histopathology of testes, uterus and ovaries were observed in treated mice. Therefore, NOAEL was considered to be 1500 mg/kg bw/day for F0 generation when male and female mice were treated with RED 2G orally in diet for6 weeks.

Again supported by experimental study conducted by Gauntet al(Food and Cosmetics Toxicology Volume 5, 1967, Pages 171-177) on structurally similar read across substance Black PN (CAS no 2519-30-4), male and female rats were treated with Black PN in the concentration of 0, 150, 500, 1000 mg/kg/day oral in diet for 90 days. No significant changes were observed at any dose level in both treated male and female rats compare to control. Significant growth retardation was observed in males at the 1000mg/kg/day level and it associated with a reduced food intake. There were significant increase in the relative weights of the testes and kidneys at the dose level of 1000 mg/kg/day in treated male was observed as compare to control. The elevated relative kidney weights were not accompanied by changes in the kidney function tests or in organ pathology. Decrease liver weight was also observed at 150 and 1000 mg/kg/day in treated female as compare to control. Significant change was observed in the foci of inflammatory cell infiltration of the myocardium in treated males at 1000 mg/kg/day .The foci of inflammatory cell infiltration of the myocardium which occurred occasionally in males of the 1000 mg/kg/day group were of spontaneous origin. Therefore, NOAEL was considered to be 500 mg/kg/day in male rats and 1000 mg/kg/day in female rats respectively when male and female rats were treated with Black PN for 90 days.

Above studies are supported by experimental study conducted by Gauntet al(Food and Cosmetics Toxicology Volume 10, Issue 1, 1972, Pages 17-27) on structurally similar read across substance Black PN (CAS no 2519-30-4), CFE male and female rats were treated with Black PN the concentration of 0, 50, 250 and 500 mg/kg bw for 2 years by oral feed. No statistically significant change were observed on survival, body-weight gain, food intake, hematology, serum chemistry, renal concentration tests, organ weights and pathological findings at dose level of 50, 250 and 500 mg/kg bw in male and female as compared to control. No effect was observed on gonads, thyroid and pituitary of male and female treated rats as compare to control. Therefore, NOAEL was considered to be 500 mg/kg/day when CFE male and female rats were treated with Black PN by oral (feed) for 2 years. 

Further again 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), female Sprague Dawley rats were treated with Acid Violet 43 in the concentration of 0, 27, 109 or 435 mg /kg bw/day through 6-15 of gestation period by oral (gavage). The test substance was given in water daily at dose volumes of 5 ml/kg bw by oral gavage. No mortality was observed in treated group compare to control group. Increased salivation was observed at 435 mg /kg bw/day. Discolored feces at 109 and435 mg /kg bw/day were observed. Discoloration of placenta was also observed at 435 mg /kg bw/day. No significant changes were observed on litter parameters and foetal weight. No significant changes were observed on external soft tissue and skeletal anomalies of treated female fetuses as compared to control. Therefore, NOAEL was considered to be 435 mg /kg bw/day when Sprague Dawley female rats were treated with Acid Violet 43 orally by gavage through 6-15 of gestation period.   

Thus, based on the above studies and predictions on sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate and its read across substances, it can be concluded that NOAEL value is 486 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate 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 studies and predictions on sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate and its read across substances, it can be concluded that NOAEL value is 486 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, sodium 6-amino-5-[[4-chloro-2-(trifluoromethyl)phenyl]azo]-4-hydroxynaphthalene-2-sulphonate can be not classified for reproductive toxicity.