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Key value for chemical safety assessment

Effects on fertility

Description of key information

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 Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6). Male and female reproductive parameters were unaffected by test material administration and no evidence of parental systemic toxicity was noted in any group. Hence, NOAEL was estimated to be 577.5mg/kg bw when male and femaleCrj: CD(SD) rats were exposed with Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) orally.

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 v3.3 and the QMRF report has been attached.
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Specific details on test material used for the study:
- Name of test material (IUPAC name): Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate
- Common name: trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate
- Molecular formula: C34H21N6Na3O11S2
- Molecular weight: 822.673 g/mol
- Smiles notation: c12c(cc(c(c2S(=O)(=O)[O-])\N=N\c2ccc(cc2)C(=O)[O-])O)cc(NC(=O)Nc2cc3cc(S(=O)(=O)[O-])c(\N=N\c4ccccc4)c(c3cc2)O)cc1.[Na+].[Na+].[Na+]
-InChl:1S/C34H24N6O11S2.3Na/c41-27-16-19-14-24(11-13-26(19)32(53(49,50)51)29(27)39-38-22-8-6-18(7-9-22)33(43)44)36-34(45)35-23-10-12-25-20(15-23)17-28(52(46,47)48)30(31(25)42)40-37-21-4-2-1-3-5-21;;;/h1-17,41-42H,(H,43,44)(H2,35,36,45)(H,46,47,48)(H,49,50,51);;;/q;3*+1/p-3/b39-38+,40-37+;;;
- Substance type: Organic
-Physical sttate: Solid
Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: NOT_SPECIFIED
Vehicle:
CMC (carboxymethyl cellulose)
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:
Treatment of the parental (P) generation began 10 weeks prior to mating and continued until euthanasia.
Frequency of treatment:
once daily
Details on study schedule:
No data available
Dose / conc.:
577.5 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
26 male and 26 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
No data available
Oestrous 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:
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
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:
no effects observed
Dose descriptor:
NOAEL
Effect level:
577.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
reproductive performance
Remarks on result:
other: No effect was observed 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:
no effects observed
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 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:
NOAEL
Generation:
F1
Effect level:
577.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: overall teratogenic effects
Remarks on result:
other: No Teratogenic effects were 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" or "e" or "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 SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas by DNA binding by OECD ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl OR Azo OR Carboxylic acid OR Fused carbocyclic aromatic OR Naphtalene OR Phenol OR Sulfonic acid OR Urea derivatives by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Azo OR Carboxylic acid OR Fused carbocyclic aromatic OR Overlapping groups OR Phenol OR Sulfonic acid OR Urea derivatives by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR Azo [-N=N-] OR Carbonyl, olefinic attach [-C(=O)-] OR Carbonyl, one aromatic attach [-C(=O)-] OR Hydroxy, aromatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Suflur {v+4} or {v+6} OR Sulfonate, aromatic attach [-SO2-O] OR Urea [-OC(=O)N-] OR Urea, N and N'-diaryl subsrituted  by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR Azo [-N=N-] OR Carbonyl, olefinic attach [-C(=O)-] OR Carbonyl, one aromatic attach [-C(=O)-] OR Hydroxy, aromatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Suflur {v+4} or {v+6} OR Sulfonate, aromatic attach [-SO2-O] OR Urea [-OC(=O)N-] OR Urea, N and N'-diaryl subsrituted  by Organic functional groups (US EPA) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Anion OR Aromatic compound OR Azo compound OR Carbonic acid derivative OR Carboxylic acid derivative OR Carboxylic acid salt OR Cation OR CO2 derivative (general) OR Hydroxy compound OR Phenol OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds by DNA binding by OASIS v.1.3

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.37

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 18.9

Conclusions:
NOAEL was estimated to be 577.5mg/kg bw when male and female Crj: CD(SD) rats were exposed with Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) orally.
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 Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6). Male and female reproductive parameters were unaffected by test material administration and no evidence of parental systemic toxicity was noted in any group. Hence, NOAEL was estimated to be 577.5mg/kg bw when male and femaleCrj: CD(SD)rats were exposed with Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
577.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (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 study

In different studies, Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) 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 Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6).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 Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6). Male and female reproductive parameters were unaffected by test material administration and no evidence of parental systemic toxicity was noted in any group. Hence, NOAEL was estimated to be 577.5mg/kg bw when male and femaleCrj: CD(SD)rats were exposed with Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) orally.

 

It is supported by experimental study conducted by US EPA (High Production Volume Information System (HPVIS)| OPPT | US EPA, 2017) on structurally similar read across substance Benzoic acid, 2-hydroxy-, mono-C14-18-alkyl derivs., calcium salts (2:1)(114959-46-5).The reproductive and developmental toxicity study of Benzoic acid, 2-hydroxy-, mono-C14-18-alkyl derivs., calcium salts (2:1)(114959-46-5) was performed according to OECD guideline 421 on male and female Crl:CD(SD)rats. 96 animals i.e 24/dose group were used in the study. The test material dissolved in corn oil in dose concentration0, 50, 150 and 500 mg/kg/day and administered by oral gavage route in dose volume 5ml/kg for once/day, 7 days/week. Analysis of dosing solutions confirmed that the preparations were homogeneous and that they were at the appropriate concentrations. The stability of the dosing solutions was previously determined. Doses were selected based on prior studies conducted with this test article.F0 males were exposed to test material on 0-27, 14 day premating period through lactation day 3 females were exposed. Mating ratio was One male to one female for up to 1 4 days or until positive evidence of mating was observed. All the animals were observed for clinical signs and toxicity Twice daily throughout the study. Detailed Individual examinations conducted once weekly. Body Weights in F0 males pre-test, weekly through termination. Body weight of F0 females were observed weekly during premating and mating; gestation days 0, 4, 7, 11, 14, 17 and 20; females with litters weighed on lactation days 1 and 4.Food Consumption was Pre-test and weekly during treatment period. In F0 males it pre-test, weekly throughout the study except during mating while in F0 females it pre-test, weekly during premating, days 0, 4, 7, 11, 14, 17 and 20 of gestation and days 1- 4 of lactation for females with litters.  

Macroscopic Examinations were performed on all animals. Organ Weights also noted in all animals. In microscopic Examinations Special emphasis was placed on the stages of spermatogenesis and histopathology of interstitial testicular cell structure. Microscopic examination was performed on the cervix, coagulating glands, mammary gland, thyroids with parathyroids, testes with epididymides and vas deferens, seminal vesicles, ovaries and oviducts, pituitary gland, uterus with vagina, prostate gland and all gross lesions for all animals in the control and 500 mg/kg/day groups at the scheduled necropsies; gross lesions from all dosage groups were also examined.

Litters observed as soon as possible after delivery for number of live and dead pups and pup abnormalities. Thereafter litters observed daily for dead pups and/or obvious irregularities. Litter Size was recorded daily. Individual Pup Body Weights recorded on days 1 and 4 of lactation. While sex determination performed on Days 0 and 4 of lactation. Macroscopic Examination carried out to on pups found dead and pups sacrificed on day 4 post-partum were carefully examined externally for gross external abnormalities, and a macroscopic examination was performed. Gross lesions and malformations were retained.

Clinical findings of excessive pawing at the cage floor and/or walls and wiping of the mouth on the cage floor and/or walls were noted for all 12 females in the 150 and 500 mg/kg/day groups at the time of dose administration, and for 1 and 8 females in these same groups 1-2 hours following dose administration. Salivation and related findings (consisting of clear material on various body surfaces) were noted for females in the 150 and 500 mg/kg/day groups just prior to, at the time of and/or 1-2 hours following dose administration. Excessive pawing at the cage floor and/or walls and salivation-related findings were noted to a lesser degree for males in the 500 mg/kg/day group at the time of dose administration. Salivation-related findings were also noted for males in this group just prior to and 1-2 hours following dose administration. The behavioural findings of excessive pawing of the cage floor and/or walls (males and females) and wiping of the mouth on the cage floor and/or walls (females) were likely due to test article taste aversion. Therefore, salivation-related findings noted for males and females were attributed to the test article, but were not considered adverse. Body weight, food consumption were unaffected by test article administration at 50, 150 and 500 mg/kg/day. Higher mean liver weights were noted for males (↑ 5.7%) and females (↑ 14.6%) in the 500 mg/kg/day group, but were not considered adverse, as these differences are probably consistent with hepatic enzyme induction that was adaptive in nature. Similar effects on liver weights with no morphologic correlates were reported for this test article in a previous study. No test article-related macroscopic or microscopic findings and no adverse effects on mean organ weights were observed for males and females at any dosage level. Reproductive parameters (e.g., mating, fertility and copulation/conception indices) were unaffected by test article administration at 50, 150 and 500 mg/kg/day. F1 pups were unaffected by maternal test article administration.

The mean number of pups born, live litter size on postnatal day (PND) 0, general physical condition, pup body weights and postnatal survival from birth to PND 4 were unaffected at 50, 150 and 500 mg/kg/day. Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity in F0 and for F1 generation on the basis of reproductive parameter and overall developmental effects was considered to be 500 mg/kg/day. When female Crl:CD(SD)rats were treated with Benzoic acid, 2-hydroxy-, mono-C14-18-alkyl derivs., calcium salts (2:1)(114959-46-5)orally.

It is supported by experimental study conducted byC. Burnett, E. I. Goldenthal , S. B. Harris , F. X. Wazeter  , J. Strausburg  , R. Kapp  & R. Voelker( Journal of Toxicology and Environmental Health, 1:1027-1040, 1976) on structurally similar read across substance Direct Red 23(3441-14-3)by dermal application.The reproductive and developmental toxicity study of  Direct Red 23(3441-14-3)was performed on femaleCharles River CDrats. 20 animals dose group were used in the study while 20 animals positive control group were used while 60 animals in 3 different negative control group were used. The test material present in the semi-permanent type hair dye formulation that consists of preformed pigments that are deposited on the hair shaft from solvent-detergent bases was applied as 2ml/kg (100mg/kg i.e.0.2% test material) on the dorso- scapular area which was shaved closely the day before the solution was applied.Ye animals were exposed to test material on every third day of gestation i.e. 1, 4, 7, 10, 13, 16, and 19 of gestation day. The mated females used in the study and presence of sperm in the vagina considered day 0 of gestation. The positive control group received acetylsalicylic acid by gavage at a dose of 250 mg/kg on days 6 through 16 of gestation. All the animals were observed for clinical signs , body weight and food consumption. Twenty pregnant rats from each group were sacrificed on day 20 of gestation by chloroform anaesthesia. The uteri were examined, corpora lutea of pregnancy counted, and the number, distribution, and location of live, dead, and resorbed foetuses recorded. All fetuses were examined for gross anomalies, sexed, and weighed. Approximately one-third the fetuses from each litter were fixed in Bouin's solution and subsequently examined for visceral anomalies by razor blade sectioning (Wilson and Warkany, 1965). The remaining foetuses in each litter were fixed in 95% ethyl alcohol, eviscerated, cleared, stained with KOH-alizarin red S (Staples and Schnell, 1964), and examined for skeletal anomalies. Fetal examinations were performed in a random order with treatment group identity unknown to the examiner.

 

No signs of toxicity were seen throughout the study. Except for the changes in the color of the skin and hair at the site of dye application, no irritation or other changes in appearance were seen. Changes in female body weights were similar for rats in the untreated Controls. A marked reduction in maternal weight gain through gestation was observed in the rats receiving acetylsalicylic acid as compared with either the untreated control rats or dye-treated rats. Mean food consumption for all groups throughout gestation was similar except for rats in the acetylsalicylic acid group; these rats showed a moderate decrease in food consumption from days 7 to .13 of gestation. This decrease was not seen from days 13 to 20 of gestation. The dye formulations produced no significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio when compared with the untreated control groups. No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy. No significant changes were observed regarding soft-tissue anomalies between the dye-treated groups and the untreated control groups. Normally occurring skeletal variations were present in all groups; the most frequent variation noted was accessory ribs. HenceNo Observed Adverse Effect Level (NOAEL) forF0 reproductive and systemic toxicity and for F1 neonatal toxicitywas considered to be 100mg/kg.When femaleCharles River CDrats were treated with Direct Red 23 (3441-14-3) by dermal application on every third day of the gestation period.

 

 Thus, based on the above studies and predictions on Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) 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 Trisodium 4-[[1-hydroxy-6-[[[[5-hydroxy-6-(phenylazo)-7-sulphonato-2-naphthyl]amino]carbonyl]amino]-3-sulphonato-2-naphthyl]azo]benzoate (6598-63-6) cannot be classified as reproductive toxicant.

Additional information

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