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Key value for chemical safety assessment

Effects on fertility

Description of key information
Uterotrophic assay: no anti-/estrogen- efficacy of Uvinul A Plus.  
Hershberger assay: no anti-androgen efficacy of Uvinul A Plus.
Additional information

In the key study, i.e. a 2-generation reproduction study according to OECD TG 416 and GLP, Uvinul A Plus (>= 98 %) was administered to 25 Wistar rats/sex/dose in diet at dose levels of 0, 100, 300, 1000 mg/kg bw/day (BASFAG70R0636/02075).

Uvinul A Plus caused no impairments of the reproductive performance of the low and mid dose F0 and F1 parents. Estrous cycle data, mating behaviour, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were not influenced. There occurred, however, several substance-related irregularities of the reproductive performance of the high dose parental F0 and F1 females (1000 mg/kg body weight/day) substantiated by a lower gestation index and an increased postimplantation loss value (due to the fact, that 3 F0 dams delivered no pups and had only resorptions in utero), a significantly reduced mean number of implantation sites per dam and a significantly reduced mean number of delivered pups per dam. All of these findings are considered to have developed secondarily to the impairments of maternal homeostasis. They do not demonstrate a selective impairment on the dams' reproductive performance.

General systemic toxicity, in terms of adverse clinical findings, distinct decreases in food consumption and clear impairments of body weights and - in the F1 males only - increased kidney weights and alpha2u-globuline storage, became evident at a dose level of 1000 mg/kg body weight/day. Some of these findings still appeared in the F0 and/or F1 male and/or female rats at 300 mg/kg in a much less pronounced form. Borderline effects on food consumption and body weights were still detected in the low dose F1 males (100 mg/kg body weighty/day). They may be indicative of a limited palatability of the diet - substance mixture rather than specific toxicity of the test compound. Additionally, the small magnitude of the changes justifies them to be assessed as non adverse.

Substance-induced signs of developmental toxicity were predominantly observed in the progeny of the high dose F0 and F1 parents (i.e. in the F1 and F2 litters); additionally, some marginal effects on the 300 mg/kg F2 pups became apparent. The mean number of delivered high dose pups per litter was reduced and the postnatal pup mortality was statistically significantly increased at 1000 mg/kg. Moreover, statistically significantly lower pup body weights and impaired pup body weight gains occurred in the high dose F1 and F2 pups (1000 mg/kg body weight/day) and - much less pronounced - in the mid dose F2 progeny. The delayed general development of the offspring secondarily also affected the pup organ weights and slightly postponed the time of sexual maturation of F1 reared offspring. There was, however, no evidence of a selective influence of the test compound on sexual maturation. Clinical as well as gross necropsy examinations of the F1 and F2 pups revealed only findings, which were considered to be spontaneous in nature, due to their scattered occurrence without any relation to dosing.

The NOAEL is 100 mg/kg bw/day (male and female, F0 and F1 parental) for general toxicity based on clinical signs, reduction of food consumption and body weights observed in both parental generations.

The LOEL is 100 mg/kg bw/day (male, F1 paternal), based on the borderline reduction of food consumption and body weight in one paternal generation only.

The NOAEL is 300 mg/kg bw/day (male and female), for fertility and reproductive performance based on lower gestation index, increased postimplantation loss, reduced mean number of implantation sites, reduced number of delivered pups secondary to maternal homeostasis.

The NOAEL is 100 mg/kg bw/day (male and female, offspring), for developmental toxicity based on growth and development of the offspring.

In addition, sperm parameters were assessed in a 90-day feeding study in rats (BASFAG50S0408/99093; see also IUCLID Chapter 7.5.1.). The right testis and cauda epididymis were taken from all male animals after dosing of 600, 3000, and 15000 ppm Uvinul A Plus via diet. The following parameters were determined: Sperm motility, sperm morphology, sperm head count (cauda epididymis), sperm head count (testis). Sperm examinations revealed no test compound-related changes. Furthermore, no histological changes have been observed in primary and secondary sex organs in males and females, such as testis, ovaries, oviducts, uterus, vagina, seminal vesicles, pituitary gland, adrenal glands, prostate gland, mammary gland.

Short description of key information:
One 2-generation study according to OECD TG 416 with rats is available for Uvinul A Plus. The overall NOAEL for fertility and reproductive performance was set to 300 mg/kg body weight/day for the F0M and F0F and F1M and F1F parental rats. The NOAEL for overall general toxicity was determined to be 100 mg/kg body weight/day for the F0 and F1 parental rats. The LOEL for general toxicity was 100 mg/kg body weight/day (low dose) for F1 parental males, since effects on food consumption/body weight data were interpreted as indicative of limited palatability of the treated diet and not as specific toxicity per se. The overall NOAEL for developmental toxicity (growth and development of the offspring) was set at 100 mg/kg body weight/day. Under the conditions of this 2-generation reproduction toxicity study Uvinul A Plus had no adverse effects on fertility of the F0 or F1 parental animals of both genders at 100; 300 and 1000 mg/kg body weight/ day.
Sperm examinations and histopathological examinations of sex organs in a 90-day feeding study revealed no test compound-related adverse effects.

Effects on developmental toxicity

Description of key information
In a developmental toxicity study according to OECD TG 414, no substance induced effects were observed in prenatal developmental parameters. The maternal NOAEL is determined to be 200 mg/kg bw/day whereas the NOAEL for the prenatal developmental toxicity is determined to be 1000 mg/kg bw/day.
Additional information

In the key study, i.e. a developmental toxicity study according to OECD 414 and GLP,  Uvinul A Plus was orally administered as an oily suspension to 25 mated female Wistar rats per dose group by gavage at dose levels of 0, 40, 200 and 1000 mg/kg bw/day from day 6 through day 19 post coitum (BASFAG30R0408/99112). Maternal toxicity was substantiated in the high-dose group (1000 mg/kg bw/day) by transient salivation, urine smeared fur, reduced food consumption on days 6- 13 p.c and slight impairment in absolute and corrected body weight gain. No signs of substance- induced maternal toxicity occurred at the low and mid dose levels (40 or 200 mg/kg body weight/ day).

The maternal NOAEL is 200 mg/kg bw/day based on clinical signs, reduced food consumption and (corrected) body weight gain.

There were no treatment-related effects in developmental parameters up to and including the highest dose level (1000 mg/kg body weight/day).

The NOAEL is 1000 mg/kg body weight/day for prenatal developmental toxicity.

Toxicity to reproduction: other studies

Additional information

In an uterotrophic (estrogenic) assay, Uvinul A Plus was orally administered in olive oil to 10 female Wistar rats per group by gavage at dose levels of 0, 250 and 1000 mg/kg bw/day for three days (BASFAG07R0228/99121). No uterotrophic effects expressed in uterus weight and uterus morphology (histopathology) were observed in animals of all dosed groups when compared with the negative control (vehicle only) and the positive control (diethylstilbestrol dipropionate). The statistically significantly retarded body weight gain in the 1000 mg/kg bw/day dose group animals was regarded as sign of systemic toxicity.

In a Hershberger assay, 6 castrated male Wistar rats per dose group - substituted with testosterone propionate - were administered with Uvinul A Plus in corn oil by gavage for 10 days at dose levels of 200 and 1000 mg/kg bw/day (BASAGF47S0495/00149). Control groups of 6 castrated male rats per group were treated with corn oil by gavage with and without testosterone propionate replacement.

No substance-related findings were observed during the clinical examinations. In the animals of the co-administered group of 1000 mg/kg bw/day of Uvinul A Plus and testosterone propionate, no effect was observed regarding hormone levels of testosterone, dihydrotestosterone and luteinizing hormone in the serum of the castrated male rats, compared to the castrated animals of the control group that received same amount of testosterone propionate. Pathology examination showed a significant relative liver weight increase in a dose-response relationship (which is not to be regarded as an anti-androgenic effect). The absolute and relative weights of the accessory sex organs in the test substance treated groups were not significantly reduced in comparison to the animals of the control vehicle group who received hormonal supplement. Moreover, histology of prostate, seminal vesicle and the bulbo-urethral gland was comparable to the control group who received the testosterone propionate supplement. Thus no anti–androgenic effect was detected after treatment with Uvinul A Plus under the study conditions.

The presented study was performed in accordance with “OECD protocol and Guidance for the Conduct of the Rodent Hershberger Assay; phase 2 of the validation of the Rodent Hershberger Assay”.

Justification for classification or non-classification

The present data on reproductive toxicity do not fulfill the criteria laid down in 67/548/EEC and 272/2008/EEC, and therefore, a non-classification is warranted.