title: A two-generation reproductive toxicity study of octamethylcyclotetrasiloxane (D4) in rats exposed by whole-body vapor inhalation.
abstract: This study evaluated the potential toxicity of whole-body vapor inhalation of octamethylcyclotetrasiloxane (D(4)) on reproductive capabilities in exposed F(0) and F(1) parental animals and the potential effects on neonatal survival, growth, and development of the F(1) and F(2) offspring. F(0) male and female Sprague-Dawley rats (30/sex/group) were exposed to D(4) vapor at concentrations of 0, 70, 300, 500 or 700 ppm 6h per day for at least 70 consecutive days prior to mating and lasted through weaning of the pups on postnatal day (PND) 21. Female exposures were suspended from gestation day (GD) 21 through PND 4 to allow for parturition and permit continuous maternal care for the early neonates. Starting on PND 22, F(1) weanlings were exposed to D(4) as described for the F(0) generation. The F(2) pups were not directly exposed to D(4). F(0) animals were mated once to produce the F(1) generation; F(1) parental animals were mated twice to produce two F(2) litters. In addition, the F(1) males were mated with unexposed females. Prolonged estrous cycles, decreased mating and fertility indices were observed in the F(1) generation exposed to D(4) for the first and second matings. Significant reductions in the mean number of pups born and mean live litter size were observed in the 500 and 700 ppm groups for both the F(0) and F(1) generations. Implantation sites were also reduced at 700 ppm for both F(0) and F(1) generations. No adverse effects were observed at any exposure level on anogenital distance, vaginal patency and preputial separation. No adverse effects were seen on male functional reproductive parameters, spermatogenic endpoints, microscopic evaluation of male reproductive tissue, or when the D(4)-exposed F(1) males were mated with the unexposed females, demonstrating that the reproductive toxicity observed was due to D(4) exposure to the females. Based on the lack of effect on reproduction when the D(4)-exposed males were mated to näive females, the NOAEL for male reproductive toxicity was considered to be 700 ppm. Based on the statistically significant effects on fertility and litter size, NOAEL for female reproductive toxicity was considered to be 300 ppm. The findings observed in this study are consistent with suppression or delaying of LH surge as well as acceleration of the onset of female reproductive senescence in the rat. While analogous pathways control ovulation in both rats and humans, there are significant differences in the mechanism for timing and release of LH and resulting changes in the control of ovulation and mating behavior between the two species. If D(4) delays rather than causes a prolonged suppression or ablation of the LH surge, the reproductive mode of action of D(4) would not likely be relevant for humans.
authors.affiliation: Dow Corning Corporation, Midland, MI, USA. Waheed.Siddiqui@dowcorning.com
authors.forename: Waheed H
authors.initials: WH
authors.lastname: Siddiqui
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stump
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Plotzke
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Holson
authors.forename: Robert G
authors.initials: RG
authors.lastname: Meeks
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D010064:Embryo Implantation / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects / Q000473:pathology; D019570:Inhalation Exposure; D008098:Litter Size / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012833:Siloxanes / Q000633:toxicity*; D013081:Sperm Motility / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D012833:Siloxanes; C024064:octamethylcyclotetrasiloxane