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Forty Days Oral Toxicity of 2,6‐ cis ‐Diphenylhexamethylcyclotetrasiloxane (KABI 1774) in Beagle Dogs with Special Reference to Effects on the Male Reproductive System

1975; Wiley; Volume: 36; Issue: s3 Linguagem: Inglês

10.1111/j.1600-0773.1975.tb03087.x

0001-6683

Lennart Albanus, Nils‐Erik Björklund, B. Gustafsson, Monica Jönsson,

Glutathione Transferases and Polymorphisms

Abstract: The oral toxicity of KABI 1774 ** , a siloxane compound with estrogen‐like effect, was studied for 40 successive days in 20 male and female beagle dogs. The test compound was dissolved in soy bean oil and dosed at the levels of 10 or 250 mg/kg. Controls received soy bean oil only. Increased WBC count, mainly due to increased neutrophils, and enhanced alkaline phosphatase activity were evident at 250 mg/kg. No death occurred. The treatment with KABI 1774 caused marked effects on the reproductive system which is the target for the principal pharmacological effects. One typical feature was an adverse influence on the ability to ejaculate. In spite of pelvic movements and rhythmic contractions of penis as in normal ejaculation the dogs delivered a very small amount of semen or no semen at all (‘dry ejaculate’). The ejaculate volume and the total number of sperm per ejaculate decreased gradually. Other striking changes were pathological sperm motility, high frequency of sperm tail abnormalities and increased occurrence of distal cytoplasmic droplets. At the end of the experiment all males presented arrested spermatogenesis to the degree of complete degeneration of all germ cells, epithelial atrophy and fibrosis in epididymis and prostate. In the latter also epithelial metaplasia was displayed. The weights of the testes were decreased in the high dose group. In females receiving 250 mg/kg the findings were hypertrophy of the lining epithelium in the endometrium of uterus, dilatation of uterine glands, oedema of the stroma and hypertrophy of the stratified squamous epithelium in vagina. In pars anterior of the hypophysis small tinctorial changes in chromophobic and basophilic cells and some hypertrophy and hyperplasia of acidophilic cells were observed in all the dosed animals. Single as well as repeated administration of 10 and 250 mg/kg gave peak plasma levels of 1–5 μg/ml at 2–4 hours and 30–60 μg/ml at 2 hours, respectively. Urinary excretion of KABI 1774 was extremely low. A series of low molecular‐weight linear and cyclic phenylmethylsiloxanes have been shown to cause suppression of the male endocrine system, including testicular atrophy and inhibition of spermatogenesis ( Palazzolo et al. 1972 , Le Fevre et al. 1972 ). The most active member of these siloxanes was 2,6‐ cis ‐diphenylhexamethylcyclotetrasiloxane ( Bennett et al. 1972 ), hereafter referred to as KABI 1774. The purpose of the present study was to investigate the subacute oral toxicity of KABI 1774 in dogs and to evaluate the effects of the drug on the sexual behaviour and on the semen characteristics.