SILATRIZOLE

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No other information

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Two GLP studies of high quality (Klimisch score = 1).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A key study was identified (FABR, 2001, rel. 1). In this study of fertility and early embryonic development to implantation performed in compliance with GLP, the test material diluted in 4% aqueous methylcellulose with 1% Tween 80 (w/w) was administered orally (gavage) to groups of 24 male and 24 female rats, each day as follows: throughout premating period (29 days), mating period and until final sacrifice, in the males, throughout premating period (15 days), mating and pregnancy periods until day 7 post-coitum inclusive) in the females. The dose levels were 100, 300 and 1000 mg/kg bw/d with a similar sized control group receiving vehicle alone. A mating trial was carried out on all animals: male and female animals were paired until mating, for a maximum of 3 weeks. On day 15 post-coitum, all females were killed, the concepti were removed by hysterectomy and the dams were examined macroscopically.  

                 

No treatment-related clinical signs and no mortality were noted in parent animals. The body weight gain and food consumption were similar in the control group and the 100 and 300 mg/kg bw/day groups. Slightly lower body weight gain (-4 g) and lower food consumption (-10% and -5%, p<0.001, between days 1 to 8 and days 8 to 15 respectively) were recorded in females given the test substance at 1000 mg/kg/day during the premating period. There was no effect on the pre-coital time, the mating index and on the fertility index. The gestation index was 100% in all female groups. There was no effect of the test substance on the evaluated sperm parameters in any treated group, nor on the estrous cycle. At hysterectomy there was no evidence of an effect on ovulation, pre- or post-implantation of concepti in any treated group. No treatment-related macroscopic post-mortem findings were noted in the parent animals. There was no noteworthy difference from controls in the testes or epididymides weight in any treated male group.

 

When the test substance, was administered daily by oral gavage at 100, 300 or 1000 mg/kg bw/day to male and female rats, from the premating period, during the mating period and until sacrifice (males) or until day 7 post-coitum (females), no signs of paternal or maternal toxicity were noted at any dose-level, except a slightly lower body weight gain and food consumption during the premating period in females of the top dose-group.

There were no toxicologically significant effects upon reproductive performance or fertility and no effects upon offspring viability and development.

The No Observed Adverse Effect Level (NOAEL) for fertility and early embryonic development is therefore 1000 mg/kg bw/d.

 

A supporting study was also identified (RICH, 2001, rel. 1). In this study of the effects on pre- and post-natal development performed in compliance with GLP, the test material diluted in 4% aqueous methylcellulose with 1% Tween 80 (w/w) was administered orally, by gavage, to groups of 24 mated female rats, each day as follows: once a day from implantation (day 6 post-coitum), through gestation and lactation, up to weaning (day 21 postpartum) of the F1 pups. The dose levels were 100, 300 and 1000 mg/kg bw/d with a similar sized control group receiving vehicle alone. The (P) females were allowed to deliver normally, and pregnancy and litter data were recorded. On day 4 post-partum, the size of each litter was adjusted to eight pups (where possible 4 males and 4 females). On day 22 post-partum, one male and one female pups per litter were selected to constitute the F1 generation. At the age of sexual maturity, (F1) males and females of the same group were paired. Hysterectomy was performed on the females on day 15 post-coitum and litter parameters were recorded.

 

There were no deaths or clinical signs indicative of toxicity in any treated groups of the (P) females. Slight reduction in body weight gain and food consumption were noted during the gestation and/or lactation periods of treated females but were considered to be of no toxicological importance. The gestation index, gestation length, delivery data (pups delivered, sex ratio), postimplantation and neonatal losses were not affected by treatment with the test substance.

The survival of the (F1) pups during the lactation period was not affected and no clinical signs indicative of toxicity were observed. Body weight was reduced in pups from all treated groups, from day 14 post-partum. This slight effect was considered to be possibly related to the reduced food consumption of the (P) dams. The physical and reflex development of the pups during the lactation period was unaffected by treatment with the test substance. There were no findings at the macroscopic examination, in the (P) females nor the pups sacrificed at the end of the lactation period, which could be related to treatment with the test substance.

During the pre-mating and pregnancy periods of the F1 offspring, there were neither treatment-related clinical signs indicative of toxicity nor mortality in any treated group. Overall food consumption, overall body weight gain and sexual development were unaffected by treatment with the test substance. No neurobehavioural effects were observed. The fertility parameters of the F1females (mating index, pre-coital time, fertility and gestation indexes) or the pregnancy parameters were not affected by the treatment. There were no noteworthy macroscopic changes found at necropsy of the F1 animals in the treated or control groups.

 

The test substance was well tolerated at all dose-levels with the exception of minor and generally statistically insignificant effects considered to be of no toxicological significance. There were no effects of treatment with the test substance in the development of the concepti or the offspring through to sexual maturity (F1 generation).

There were no toxicologically significant effects upon reproductive performance or fertility and no effects upon offspring viability, growth and development.

The No Observed Adverse Effect Level (NOAEL) for maternal tolerance in pregnant lactating (F0 females) and for pre- and post-natal development and for effects on fertility in the F1 animals is therefore 1000 mg/kg bw/day.

Short description of key information:
Study of fertility and early embryonic development to implantation: NOAEL (fertility) = 1000 mg/kg bw/d (GLP, K, rel. 1)
Pre- and post-natal development study: NOAEL (fertility) = 1000 mg/kg bw/d (GLP, K, rel. 1)

Justification for selection of Effect on fertility via oral route:
Two GLP studies were available on the registered substance. Indications of toxicity to reproduction and development were not observed in a fertility and early embryonic development study (with a design and endpoints similar to a standard one- generation reproduction toxicity study) and a prenatal / developmental toxicity study at the highest practicable and biologically-relevant concentration on toxicological endpoints (1000 mg/kg bw/day). No histological alterations of the sexual organs were observed in both repeated dose studies (13wks/26wks) up to 1000 mg/kg bw/day which suggest a lack of intrinsec toxicity of the test substance and/or bioavailability. Moreover, no significant absorption is expected based on physico-chemical properties. Thus, a two-generation reproduction toxicity study is not deemed necessary based on the whole data available. No study was selected since they gave complementary results and were of high quality (Klimisch score = 1).

Effects on developmental toxicity

Description of key information

Pre-natal developmental toxicity study: NOAEL for developmental toxicity = 1000 mg /kg bw/d (OECD 414, GLP, K, rel.1)
Pre- and post-natal development study: NOAEL (fertility) = 1000 mg/kg bw/d (GLP, K, rel. 1)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The studies are GLP compliant and of high quality (Klimisch score = 1).

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

The substance is of low toxicological activity, the NOAEL for developmental toxicity from the pre- and post-natal development study (RICH, 2001, rel. 1) is 1000 mg/kg bw/d and the NOAEL from the subacute/repeated dose studies is 1000 mg/kg bw/d with none of the minor effects seen at higher dose levels having any concern for reproductive toxicity.

Moreover, a key study was identified (BECK, 1996, rel. 1). In this developmental toxicity study conducted according to the OECD guideline No. 414 and in compliance with GLP, the test material diluted in bi-distilled water with 4% Methylcellulose and 1% Tween 80 was administered to 25 mated females Sprague-Dawley rats/dose by gavage at dose levels of 0, 100, 300 and 1000 mg/kg bw from day 6 post coitum through day 15 post coitum. The females were sacrificed on Day 21 of gestation, examined macroscopically and the uterine contents examined. There were no deaths, no clinical signs or symptoms and no abnormal findings attributed to treatment with the test item. Treatment with the test article caused slightly reduced food consumption during the dosing period in the dams at 1000 mg/kg bw/day, considered to be incidental. There were no effects on the reproduction parameters of the dams. The foetal parameters - external examination, visceral or skeletal examinations, sex ratios and body weights - yielded no reference to test article related effects.

The oral administration of the test material at dose levels up to 1000 mg/kg bw/day, to pregnant rats from Day 6 to 15 of gestation resulted in no significant systemic effects on the adults. There were no significant effects on any of the uterine parameters examined. There were no significant effects upon offspring viability, growth or development.

The No Observed Adverse Effect Level (NOAEL) for adult toxicity and developmental toxicity was 1000 mg /kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
Two GLP studies were available on the registered substance. No study was selected since they gave complementary results and were of high quality (Klimisch score = 1).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008 including ATP7.

Self-classification:

Based on the available information, no additional classification is proposed according to the Annex VI of the Regulation (EC) No. 1272/2008.