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EC number: 402-170-5
CAS number: 106359-91-5
C.I. REACTIVE YELLOW 174; GIALLO REATTIVO 174; JAUNE REACTIF 174; REAKTIV GELB 174
A reduced fertility index (number of pregnant females/ number of copulated females X 100) was observed in the C (60 %) and medium dose group (90 %). MD, and HD groups exhibited 100 %. The copulation index ((No. of rats copulated / No. of pairs) X 100) as well as delivery index (No. of dams with live newborns / No.of pregnant dams) X 100) were 100 % for each group. The viablity index was 100 % for C, LD, MD, and HD animals. The reduced fertility index is assumed to be incidental.
The aim of this study was to assess the possible effects of FAT 40224/H on male and female fertility and embryofetal development after repeated dose administration in Wistar rats according to OECD guideline 421. The test item was administered daily in graduated doses to 3 groups of test animals, one dose level per group for a treatment period of 54 days, i.e. during 14 days of pre-mating and 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days were completed. Animals of an additional control group were handled identically as the dose groups but received aqua ad injection (sterile water), the vehicle used in this study. The 4 groups comprised 10 male and 10 female Wistar rats. Three doses used in the study were 100, 300 and 1000 mg/kg body weight. The test item formulation was prepared freshly on each day of administration. The test item was dissolved in aqua ad injection (sterile water) and administered daily during 14 days of pre-mating and 14 days of mating in both male and female animals, during the gestation period and up to post-natal day 3 in females. Males were dosed for 28-30 days. Dose volumes were adjusted individually based on weekly body weight measurements. The administration volume was 5 mL/kg body weight. During the period of administration, the animals were observed each day for signs of toxicity. Animals that died were examined macroscopically and at the conclusion of the test, surviving animals were sacrificed and observed macroscopically. Body weight and food consumption were measured weekly, except for food consumption measurements which were not taken during the mating period in female animals and the mating and post-mating period in male animals. After 14 days of treatment to both male and female, animals were mated (1:1) for a maximum of 14 days. The subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating. After the confirmation of the mating, females were separated and housed individually. Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours of parturition and on day 4 post-partum. The males were sacrificed after completion of the mating period on treatment days 29 and 30 and the females along with their pups were sacrificed on post natal day 4. Non-pregnant females were sacrificed on day 26. The number of implantation sites and corpora lutea was recorded for each parental female at necropsy. Pups sacrificed on postnatal day 4 and those found dead, were carefully examined for gross external abnormalities. A full histopathological evaluation of the tissues was performed on high dose and control animals. Organs showing gross alterations were also examined histopathologically.
No mortality occurred in the control or any of the dose groups during the treatment period of this study. For female animals, more clinical symptoms were found in HD group when compare to C group. In particular, slight piloerection (9/10 HD animals; 1/10 C animals), moderate piloerection (4/10 HD animals; 0/10 C animals), slight salivation (4/10 HD animals; 0/10 C animals), and moving the bedding (5/10 HD animals; 0/10 C animals) were observed. In male animals, a slight tendency towards a decreased body weight development was observed for HD animals during the whole treatment period. In this regard, a significantly decreased body weight gain in HD group was found during treatment days 1-7. In female animals, no test item related influence on body weight development during the pre-mating period was measured. A significantly decreased (p<0.05) body weight gain during pre-mating days 1-7. In male animals, food consumption was not different in treatment groups when compared to C group. In female animals, a significantly increased (p<0.05) food consumption was recognized for HD group during premating days 7-14. A slightly decreased total number of pups born was observed for HD animals. In particular, 9.1 (HD) and 11.17 (C) were counted/calculated. In correlation with PND 0, the total number of living pups was still slightly (p>0.05) decreased in HD group at PND 4. No difference was found for mean litter weights at PND 0 and PND 4 of treatment groups when compared to C group. The total litter weight was slightly (p>0.05) reduced in HD group. Furthermore, the male litter weight was slightly (p>0.05) decreased, too, at PND0 and PND4 in HD group. No treatment-related effect was observed during the precoital interval or during the duration of gestation when compared with the control group. Successful mating resulted in 6 pregnancies in the control, 9 in low, and 10 in medium and high dose group animals. A slightly reduced number of implantation sites was counted for HD group (p>0.05).
In this regard, an increased percentage of pre-implantation loss was detected in HD group: 23.26 % (HD) and 7.83 (C) were calculated. No significant effect on survival of the pups from PND 0 to PND 4 was observed in any treatment group when compared with controls. No treatment-related gross external findings were observed in any of the treated groups. Few specific gross pathological changes were recorded for the male and female animals. The most common were discoloured yellow testes (2/10 HD; 0/10 C) and discoloured yellow oviduct and cervix (2/10 HD; 0/10 C).
In male animals, the relative weight of testes (to body weight) was significantly increased (p<0.05) in HD group. In this regard, also the relative weight (to body weight) of the left testis was significantly (p<0.05) increased in HD group when compared to C group. Histologically, in the males, yellow-brown pigment in interstitial macrophages was seen at a minimal or mild degree in the testis and at a minimal degree in the epididymis in all rats treated at 1000 mg/kg/day.
No test item-related histological findings were noted in the other male and in the female reproductive organs. Reproductive organs of those control and high dose females having undergone pregnancy showed typical post-partum histomorphology. So, based on the reproduction/ developmental toxicity screening test after oral administration in Wistar rats with FAT 40224/H, the no observed adverse effect level (NOAEL) is considered to be 1000 mg/kg/d for developmental toxicity in males and females.
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