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Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductivetoxicity of 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor andNOAEL was estimated to be 755.65 mg/kg bw. When male and female Wistar rats were exposed with 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) orally.

Thus, based on the above predictions and experimental study of 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)and its structurally and functionally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 755.65mg/kg bw.Thus, comparing this value with the criteria of CLP regulation 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)cannot be classified as reproductive toxicant.

 

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 from OECD QSAR toolbox v3.4 and the QMRF report has been attached.
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.4, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material: 4-amino-3,6-bis[[4-[[4-chloro-6-[(3-sulphophenyl)amino]-1,3,5-triazin-2-yl]amino]-2-sulphophenyl]azo]-5-hydroxynaphthalene -2,7-disulphonic acid
- IUPAC name: 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid
- Molecular formula: C40H29Cl2N15O19S6
- Molecular weight: 1287.0571 g/mole
- Smiles : c1cc(cc(c1)S(=O)(=O)O)Nc2nc(nc(n2)Cl)Nc3ccc(c(c3)S(=O)(=O)O)/N=N/c4c(cc5cc(c(c(c5c4N)O)/N=N/c6ccc(cc6S(=O)(=O)O) Nc7nc (nc(n7)Cl)Nc8cccc(c8)S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)O
- Inchl: 1S/C40H29Cl2N15O19S6/c41-35-48-37(44-18-3-1-5-22(13-18)77(59,60)61)52-39(50-35)46-20-7-9-24(26(15-20)79(65,66)67)54-56-32-28(81 (71,72)73)11-17-12-29(82(74,75)76)33(34(58)30(17)31(32)43)57-55-25-10-8-21(16-27(25)80(68,69)70)47-40-51-36(42)49-38(53-40)45-19-4-2-6-23(14-19)78(62,63)64/h1-16,58H,43H2,(H,59,60,61)(H,62,63,64)(H,65,66,67)(H,68,69,70)(H,71,72,73)(H,74,75,76)(H2,44,46,48,50,52)(H2,45,47,49,51,53)/b56-54+,57-55+
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
other: Cri :WI(Han)
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: 34 / 35 days; females: 49 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Dose / conc.:
755 mg/kg bw/day (nominal)
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
No data available
Estrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
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
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Reproductive function: estrous cycle:
not examined
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
755.65 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: overall no effects on reproductive performance
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:
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 specified
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:
NOAEL
Generation:
F1
Effect level:
755.65 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: overall no developmental toxic effects was 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
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" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and "j" )  and ("k" and ( not "l") )  )  and ("m" and "n" )  )

Domain logical expression index: "a"

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.1.4

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition to quinoid structures  OR AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.4 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety OR Anilines (Unhindered) OR Phenol Amines OR Phenols OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "j"

Similarity boundary:Target: Nc1c(N=Nc2ccc(Nc3nc(Nc4cccc(S(O)(=O)=O)c4)nc(Cl)n3)cc2S(O)(=O)=O)c(S(O)(=O)=O)cc2cc(S(O)(=O)=O)c(N=Nc3ccc(Nc4nc(Nc5cccc(S(O)(=O)=O)c5)nc(Cl)n4)cc3S(O)(=O)=O)c(O)c12
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B OR Oxyphenistain (Hepatotoxicity) Alert OR p-Alkylphenols (Hepatotoxicity) Rank A OR Phenols (Mucous membrane irritation) Rank C OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.764

Domain logical expression index: "n"

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

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 755.65 mg/kg bw. When male and female Wistar rats were exposed with 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) orally
Executive summary:

The reproductivetoxicity of 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor andNOAEL was estimated to be 755.65 mg/kg bw. When male and female Wistar rats were exposed with 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
755.65 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.4 (2017)
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 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)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 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductivetoxicity of 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and NOAEL was estimated to be 755.65 mg/kg bw. When male and female Wistar rats were exposed with 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5) orally.

Further supported by experimental study conducted byI.F. Gaunt, Madge Farmer, P. Grasso, S.D. Gangolli(Food and Cosmetics Toxicology Volume 5, 1967, Pages 171-177)on structurally and functionally similar read across substance Black PN (2519-30-4). Reproductive toxicity study for Black PN was conducted on male and female rats for 90 days by administrating in diet. When they were exposed at dose concentration of 0, 150, 500, 1000 mg/kg/day by oral diet for 90 days. Clinical sign, body weight, food consumption, colour intake, Haematology, clinical chemistry, urine analysis, organ weight and histopathology was observed. No significant change was 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 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 in 150 and 1000 mg/kg/day in treated female 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.  On the basis of results NOEL was considered to be 500 mg/kg/day in male rats and 1000 mg/kg/day in female rats respectively, for 90 days reproductive toxicity study.

Another experimental study conducted byThe Joint FAO/WHO Expert Committee on Food Additives (JECFA) (Brilliant Black PN: Toxicological Evaluation of certain food additives (WHO Food additives Series 16- 1981))on structurally and functionally similar read across substance Black PN (2519-30-4). A multigeneration reproductive toxicity study of Brilliant Black PN (2519-30-4) was performed on male and female wistar rats. The test material mixed with feed in dose concentration 0, 0.1, 1.0 or 3% (0, 50, 500, 1500 mg/kg bw per day) and administered orally for three successive generations. Each generation having 60 animals of each sex in the control and 40 animals of each sex in test animals. No adverse effects were observed with respect to fertility, litter size and weight, general condition, male/female ratio, growth during lactation, survival or maturation. Autopsy of parent rats and pups at weaning did not reveal any treatment related changes in organ weights other than caecal enlargement in the 3% dose group. Gross and microscopic examination of the F3 generation at weaning did not reveal any abnormalities due to treatment and no adverse effects were seen in the teratology study. It was concluded that Brilliant Black PN did not exert any adverse effects on reproductive function of Wistar rats when fed at dietary levels up to 3% (1500 mg/kg bw per day) for three successive generations. Therefore, NOAEL was considered to be at 3% (1500 mg/kg bw per day) for F0 F1 and F2 generation .When male and female wistar rats were treated with Brilliant Black PN (2519-30-4) orally.

Thus, based on the above predictions and experimental study of 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)and its structurally and functionally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 755.65mg/kg bw Thus, comparing this value with the criteria of CLP regulation 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)cannot be classified as reproductive toxicant.

 

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

Thus, comparing this value with the criteria of CLP regulation 4-amino-3,6-bis[(E)-2-[4-({4-chloro-6-[(3-sulfophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfophenyl]diazen-1-yl]-5-hydroxynaphthalene -2,7-disulfonic acid (51357-74-5)cannot be classified as reproductive toxicant.