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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
3 040 mg/kg bw/day
Additional information

In a one-generation study intended as a range-finding study for a two-generation study, 8 male and 8 female CD rats were exposed orally via the diet to FR-370 for 28 days prior to mating (1/1) and during the mating period. Thereafter males were sacrificed and females were further exposed during pregnancy and lactation until weaning of their offspring. Intake of FR-370 was 0, 160, 760, and 1590 mg/kg bw/day for males and 0, 170, 905 and 1775 mg/kg bw/day for females at dietary levels of 0, 2,000, 10,000 and 20,000 ppm in food. From the pups 12/sex/treatment were selected at the age of 4 weeks to form the F1. These animals received FR-370 in diet for another 2 (females) or 3 (males) weeks.

Achieved intake of FR-370 in the F1 generation was 0, 285, 1500 and 3040 mg/kg bw/day for males and 0, 290, 1580 and 3095 mg/kg bw/day for females.Bodyweight (gain) in treated males of the F0 generation was slightly, but significantly decreased without a relationship with the dose received. No effects on mating performance were observed. Treatment with FR-370 did not affect gestation length (and index), the number of implantation sites and litter size in any of the F0 treatment groups. No effects on pup number, pup weight and sex ratio were found. At 10,000 ppm high postnatal mortality was observed in two litters between day 4 and 14 of lactation. At 2,000 ppm 4 pups within one litter showed hydrocephaly.

In the F1 generation one control male was killed in extremis. Body weight was decreased in males and females at 10,000 and 20,000 ppm (ca. 10% decrease compared to controls). No delay in sexual maturation was observed in all treated males (preputial separation) and females (vaginal opening) at 2,000 and 10,000 ppm. In 2/12 females at 20,000 ppm vaginal opening was delayed. Macroscopic examination revealed one control male, two males at 2,000 ppm and one male at 20,000 ppm with small testes, prostate gland, epididymides and seminal vesicles. One control male had an enlarged left testis and a small left epididymides and one male at 2,000 ppm had an enlarged testis. These incidental findings are considered to be unrelated to treatment with FR-370 (HLS: DSV004/020061).

In this study the number of animals in this study is rather small and no histopathological examinations were performed. Therefore, no definite conclusion can be drawn. However, based on the information available, there are strong indications that FR-370 does not affect reproductive performance of rats.


Short description of key information:
Preliminary Study of Effects on Reproductiive Performance in CD Rats by Dietary Administration

Effects on developmental toxicity

Description of key information
 Study of effects on embryo-fetal development in CD rats treated by oral gavage administration
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

Pregnant Sprague-Dawley CD rats (22 females/dose) were treated with FR-370 in corn oil by gavage at doses of ca. 0, 100, 300 and 1000 mg/kg bw during day 1 to 19 of gestation. At gestation day 21 dams were necropsied and the contents of the uterus was evaluated. All foetuses were examined externally and half of the foetuses were examined for visceral and skeletal abnormalities. Uterus weight was very slightly decreased in females at 1000 mg/kg bw/day compared to controls. Placental weight was increased at 1000 mg/kg bw/day. Foetal weight was slightly, but significantly below control values for both males and females. At 1000 mg/kg bw/day an increased incidence of delayed ossification of the sternebrae was observed.

In addition variations of the contralateral eye size and increased incidence of partially undescended horn of the thymus were reported at 1000 mg/kg bw/day. The effect on eye size remained within historical control ranges, while the thymus effect was slightly higher than historical control values. Control groups of 5 studies were evaluated to determine the historical control ranges (HLS: DSV 001/014159).

 

A relationship between delayed ossification and the lowered body weights is considered plausible. As the delayed ossification remained within historical control values, the biological significance of the lowered foetal weights is doubtful.

In a letter dated 16 September 2003, 25 studies performed at Huntingdon were analysed on the incidence of partially undescended thymus horn. Based on the findings in these 25 studies, it can be concluded that the incidences in the study on FR-370 (8 foetuses affected within 6 litters) are similar to maximum incidence levels in control groups of 25 studies (7 foetuses within 6 litters). Together with the fact that it is not clear whether a partially undescended thymus horn represents a long-term structural damage to the foetus or a teratogenic effect, this finding indicates that the observed effect on the thymus is not related to exposure to FR-370.

Therefore it can be concluded that the NOAEL for maternal and developmental effects derived from the study on FR-370 is 1000 mg/kg bw.

Justification for classification or non-classification

No effects on reproductive performance and development were observed at 1000mg/kg bw/day.