Reaction products of 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid, coupled twice with diazotized 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate, sodium salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

GLP guideline studies on similar substances justified by analog approach for RA.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Additional information

From radio kinetic studies with the test substance, it is well known that the major metabolite is sulfuric acid mono-[2-(4-amino-benzenesulfonyl)-ethyl] ester. The other main component of the test substance 5, 3,5-Diamino-4-hydroxy-naphthalene-2,7-disulfonic acid was not absorbed and only found as not recoverable substance in the feces. It is also expected for the read across substance A to have these two metabolites with a similar kinetic behavior. In addition, a di-fluoro, mono-chloro-triazin group is contained in the read across substance C. This led to a higher content (0.3%) of fluoride in the test substance resulting in fragility of the incisors and a very low food uptake in high-dose dams. Consequently, the survival rate in the high-dose group was rather low. In summary, daily oral administration of the read across substance C to rats during the premating, mating, gestation and lactation period at dose levels of 62.5 or 250 mg/kg body weight did not affect food consumption, body weight development, male or female mating/reproductive performance, fertility, gestation length as well as development of their progeny. Daily oral administrations of 1000 mg/kg body weight were well tolerated in rats within the first 5 weeks of treatment, but thereafter, from week 6 onwards, caused mortality due to dental lesions with subsequent disability of food uptake and starvation (clinical picture of dental fluorosis). This finding was time-dependent, with a threshold dose of 250 mg/kg body weight for males, and is most likely related to the fluoride impurity (0.3%) of this batch tested. Although there was marked pigment storage of the test compound in several organs, there was no clear functional or histopathological correlate that could be related to compound-induced systemic toxicity and/or specific reproductive toxicity. Impairment of reproduction and fertility at high dose parental animals was primarily the result of severe dental problems. In the presence of severe dental problems at 1000 mg/kg bw and threshold dose of 250 mg/kg bw for this finding, there was no evidence of selective reproductive toxicity in rats for the read across substance C, according to the classification criteria of Commission Directive 2001/59/EC. Consequently, due to the fact that no fluoride is contained in the test substance, a NOAEL of 1000 mg/kg body weight is expected for the test substance for parental reproductive performance and their offspring.

A second one-generation study with the read across substance B, covering the sulfuric acid mono-[2-(4-amino-benzenesulfonyl)-ethyl] ester metabolite was performed.

There were no test item related effect on the general state and behavior of animals, but an increased urine excretion and water consumption was found at 750 mg/kg bw/day group from day 2 until the termination of the treatment.Polyuria and polydipsia are well-known side effects for lithium. As the content of lithium is rather high in this test substance, these effects were most likely related to the lithium salt content. As a secondary effect of the polyuria in high-dose dams, the mortality of pups was a slightly higher at this dose level. The NOEL for reproductive performance of parental animals was 750 mg/kg body weight (high dose). Due to the secondary higher mortality of high-dose pups, the NOEL for the offspring was set to 300 mg/kg body weight. Due to the fact that no lithium is contained in the test substance no adverse effects on reproductive performance of parental animals or their offspring is expected for the test substance up to the limit dose of 1000 mg/kg body weight.

Short description of key information:
Read across for toxicity to reproduction from one generation studies of two reactive vinyl sulphone dyes

Justification for selection of Effect on fertility via oral route:
Both studies to be considered

Effects on developmental toxicity

Description of key information

No effects on embryofetal development were observed at the limit dose of 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Limit test performed according to OECD guideline 414

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a GLP compliant limit test performed according to OECD guideline 414, the test substance, dissolved in distilled water, was administered orally by stomach tube in a single daily dose of 1000 mg/kg body weight to a group of 20 pregnant female Wistar rats from the 7th - 16th day of pregnancy. On the 21st day the foetuses delivered by caesarean section were then examined morphologically for developmental disorders.There were no impairment observed ingeneral physical condition of the dams or impaired intrauterine development of conceptuses. the internal organs and the skeleton showed no indication of an embryotoxic or teratogenic effect of the compound.

On the basis of the results of this limit test, the “no observed adverse effect level” for the test item in rats following oral administration lies at 1000 mg/kg body weight with regard to maternal and embryofoetal toxicity and teratogenicity.

No teratogenic effect was observed.Maternal NOAEL: 1000 mg/kg/day; Fetal NOEL: 1000 mg/kg/day

Justification for selection of Effect on developmental toxicity: via oral route:
GLP guideline study

Justification for classification or non-classification

No adverse effects on reproduction toxicity observed - no classification necessary