Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 908 mg/kg bw when Wistar male and female rats were orally exposed with disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate. 

Thus, as per criteria of CLP regulation, disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate 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 3.3 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:

- IUPAC Name: Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate
- SMILES:O=S(=O)(c1ccccc1Nc1ccc(C(=C2C=CC(=N{+}c3ccccc3S(=O)(=O)O{-}.[Na]{+})C=C2)c2ccc(Nc3ccccc3S(=O)(=O)O{-})cc2)cc1)O{-}.[Na]{+}
- InChI:1S/C37H29N3O9S3.2Na/c41-50(42,43)34-19-13-31(14-20-34)38-28-7-1-25(2-8-28)37(26-3-9-29(10-4-26)39-32-15-21-35(22-16-32)51(44,45)46)27-5-11-30(12-6-27) 40-33-17-23-36(24-18-33)52(47,48)49;;/h1-24,38-39H,(H,41,42,43)(H,44,45,46)(H,47,48,49);;/q;2*+1/p-1
- Mol. formula: C37H26N3Na2O9S3
- Molecular Weight: 800.8182 g/mol

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: food

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

F0 and F1 generation: 75 days premating exposure; during mating and gestation until post natal day (PND) 21

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

908 mg/kg bw/day

No. of animals per sex per dose:

25

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:

908 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 specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

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 6 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" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Aryl OR Sulfonic acid by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Aryl OR Overlapping groups OR Sulfonic acid by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, hydrogen attach {v+5} OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Ortho-substitutes on N=C<, aromatic OR Suflur {v+4} or {v+6} OR Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amine OR Anion OR Aromatic compound OR Cation OR Secondary amine OR Secondary aromatic amine OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) 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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= -9.56

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.12

Conclusions:

The NOAEL was estimated to be 908 mg/kg bw when Wistar male and female rats were orally exposed with disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate.

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 disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate. The NOAEL was estimated to be 908 mg/kg bw when Wistar male and female rats were orally exposed with disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate. 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

908 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, disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimation in rodents, i.e. most commonly in rats for disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate along with the study available on structurally similar read across substance Carmoisine (CAS no 3567-69-9).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 disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate. The NOAEL was estimated to be 908 mg/kg bw when Wistar male and female rats were orally exposed with disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate. 

In another study conducted by Fordet al(Food Chemical Toxicology. Vol. 25, No. 12, pp. 919-925, 1987) on structurally similar read across substanceCarmoisine (CAS no 3567-69-9), Wistar male and female rats were treated with Carmoisine in the concentration of  0 (control), 100, 400 or 1200 mg /kg body weight/day orally in feed for 115 weeks. No significant change of carmoisine on the condition or behaviour of the animals, apart from coloration of the fur, urine and faeces with an intensity increasing with dose. No effect on survival of treated rats was observed. No effect on mating, pregnancy, lactation and weaning of P treated rats as compared to control. In addition, Effect like coloration of the fur, urine and faeces with an intensity increasing with dose in F1 pups. But no significant change was observed in animals behaviour and condition in treated group compare to control. No significant change was observed in the survival of F1 treated group compare to control. Significant change was observed in the body weights of F1 males receiving 400 and 1200 mg/kg/day were lower than those of the controls throughout the study. Females receiving 1200 mg/kg/day weighed significantly less than the controls from week 32 onwards. In both sexes the magnitude of the observed differences increased with time. Significant change was observed in the food intakes of the1200 mg /kg/day males was observed compare to control. Even in female 1200 mg/kg/day were greater than those of the controls, but the differences in females was unrelated to dose. Water intakes of treated animals showed some inconsistency during the study. For the first 12 months there was a dose-related higher intake in both sexes receiving 400 or 1200 mg /kg/day. During the second year the water intake of males receiving 1200mg/kg/day or of females receiving 400 mg/ kg/day was no longer different from that of the controls. No significant change was observed at all dose level 100, 400 or 1200 mg /kg body weight/day of treated group compare to control. Lower glucose concentrations were observed in males at dose level of 1200 mg/kg/day compare to control. While a Lower glucose concentration was observed in females at dose level of 400 and 1200 mg/kg/day compare to control. Semi-quantitative analyses of urine were hindered in treated animals, particularly at the 1200 mg/kg/day, by the colour of the urine which obscured the colour reaction of the reagent test strips. Despite these limitations, which meant that some samples obtained from 1200 mg/kg/day animals were not usable, a higher proportion of samples from the 1200 mg/kg/day females showed a high level of protein at both 18 and 24 months. No significant change was observed in any organ except caecum weight. The caecum was the only organ whose weight and relative weight (g/100 g body weight) showed changes associated with treatment. At 1200 and 400 mg/kg/day dose level in males both weight and relative weight of the caecum, with and without contents, were greater than the control values, although the increases were only statistically significant at the1200 mg /kg body weight/day. In females at the dose level of 1200 mg /kg body weight/day only the relative weight of the empty caecum was significantly greater than that of the controls. The changes in caecum weight were accompanied by observations at autopsy that the caecum wall was thicker in the treated animals. Similarly, significant thickness was observed in caecum wall at 1200 mg /kg body weight/day group of treated animals compare to control. Age-related changes to be expected in rats of the strain used. Some of the changes recorded showed a positive dose-related trend together with a significantly higher incidence when individual groups were compared with the controls. These were pupillary hyperplasia of the bladder in males and blood/fibrin cysts of the adrenal gland and internal hyperplasia / medial hypertrophy of the pancreatic blood vessels in females. The total incidences of benign or malignant tumours showed no treatment-related differences. There were no differences between the treated and control groups in the incidences of individual types of tumour apart from adrenal phaeochromocytoma which showed a statistically significant treatment-related difference in males based on four tumours in the 1200 mg/kg/day group compare to controls. A similar difference was not observed in females. Therefore, NOAEL was considered to be 1200 mg/kg bw for P generation and 400 mg/kg bw for F1 generation when Wistar male and female rats were treated with Carmoisine orally in feed for 115 weeks.

Further supported by experimental study conducted by Holmeset al(Toxicology, 10 (1978) 169-183)on structurally similar read across substanceCarmoisine (CAS no 3567-69-9), Sprague-Dawley male and female rats were treated with Carmoisine in the concentration of 0,175, 400 and 1000 mg/kg bw orally in feed for 480 days. No significant changes in body weight and food consumption of P rats were observed as compared to control. Similarly, no effect on viability of F1a, F1b, F2a, F2b, F3a and F3b pups as compared to control. In addition, No effect on reproductive parameters such as Fertility index, Copulation index, Number of pups/litter at birth, Stillbirth incidence, Viability index of pups and Lactation index were observed in P, F1b and F2b rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg bw for P, F1b and F2b generation when Sprague-Dawley male and female rats were treated with Carmoisine orally in feed for 480 days.

Thus, based on the above study and predictions on disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate and its read across substances, it can be concluded that NOAEL value is 908 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate 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 disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate and its read across substances, it can be concluded that NOAEL value is 908 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate can be not classified for reproductive toxicity.