M.L. Keplinger

Reproductive and teratologic studies with Δ9-tetrahydrocannabinol and crude marijuana extract

Abstract Synthetic Δ 9 -tetrahydrocannabinol ( Δ 9 -THC) and crude marijuana extract (CME) containing 16% Δ 9 -THC were administered orally to albino rats at doses of 0.5, 1.5, and 5 mg of Δ 9 -THC from either source/kg body weight. In the general reproductive study, males were dosed from 60 days prior to mating until termination of mating and females were dosed from 14 days prior to mating until 21 days postpartum. Mating and fertility indices were similar for control and treatment groups. No differences between control and treatment groups were seen at an interim sacrifice on gestation Day 14 with respect to corpora lutea, implantation sites, resorption sites, and viable fetuses. The average numbers of pups delivered and viable at birth did not differ among control and treatment groups, and pup survival was unaffected by treatment. In a perinatal/lactation study, females were dosed from gestation Day 15 until lactation Day 21. No adverse effects of treatment were observed directly or in a cross-fostering study. No evidence of teratogenic activity was obtained for either Δ 9 -THC or CME at Δ 9 -THC equivalent doses of 5, 15, and 50 mg/kg on gestation Days 6–15 in rats and 0.5, 1.5, 5, and 15 mg/kg on gestation Days 6–18 in rabbits. Fetal survival and pup survival were reduced at the highest CME treatment level.

Reproductive and teratologic studies with halothane

9 groups of 10 male and 20 female Charles River albino rats were used in a 3-phase study to determine the effect of 2-bromo-2-chloro-1,1,1,-trifluroethane (halothane) in anesthetic concentrations, on reproduction in rats treated prior to mating, on fetal development in rats and rabbits when administered during various stages of gestation, and on fetal survival in rats treated during late pregnancy. Exposures were conducted in a 250-liter Plexiglas chamber. Food consumption and body weights were determined at 5-day intervals. At 100 days of age, females were caged with a male from the same group on a rotating basis until fertilization was confirmed. Half of the females from each group were sacrificed on Day 14 of gestation and the ovaries and uterus examined, corpora lutea, implantation sites, resorption sites, and fetuses counted. The remaining females were allowed to go to term. In teratologic studies, pregnant rats in 3 groups, were exposed on gestation Days 1-5 to mean halothane concentrations of 1.35%, on Days 6-10 to concentrations of 1.43% and on Days 11-15 to 1.43%. Rabbits were exposed to 2.16, 2.16 and 2.3% on respective gestation days. Perinatal and lactation performance in rats was tested after inhalation of halothane at a mean concentration of 1.44% for 1 hour/day on gestation Days 15-20. Adverse reproductive effects were absent as was evidence of teratologic activity. There was a suggested effect on fetal survival in rats exposed during late pregnancy, but further research is required to give significant results.

Teratologic studies with FD & C Red No. 2 in rats and rabbits

Abstract Studies to evaluate the teratogenic potential of FD & C Red No. 2 were conducted in albino rats at dosage levels of 15, 50 and 150 mg/kg and in albino rabbits at doses of 1.5, 5 and 15 mg/kg. These studies yielded no evidence of adverse effects. Sodium salicylate, 200 mg/kg, and thalidomide, 37.5 mg/kg, increased resorptions and the incidence of abnormalities in rats and rabbits, respectively.

Dominant lethal studies with alkylating agents: Dose-response relationships

Abstract Dominant lethal studies were conducted to establish dose-response relationships for the mutagenic alkylating agents, methyl methanesulfonate (MMS), and ethyl methanesulfonate (EMS). Male albino mice were treated via single ip injections at doses ranging from 3.125 to 100 mg of MMS/kg and from 50 to 400 mg of EMS/kg. The mutagenic events induced following mating with untreated females were scored on the basis of early fetal deaths. Useful effect dosages were found to be 50 mg/kg for MMS and 200–300 mg/kg for EMS. Dosages of 100 mg of MMS/kg and >300 mg of EMS/kg were judged to be undesirable because of excessive preimplantation losses at these levels. It was not possible to differentiate the response of animals treated with up to 6.25 mg of MMS/kg or 100 mg of EMS/kg from that of the untreated control animals.

The concentration of hexachlorophene in the blood of albino rats as a function of time postexposure, number of exposures, route of exposure, previous exposure, and age

Abstract The concentration of hexachlorophene (HCP) in the blood of albino rats was studied as a function of time following the last exposure, number of consecutive exposures, route of exposure, previous exposure, and age. All HCP blood concentration determinations were conducted using gas chromatographic techniques. Highest blood concentrations were found approximately 4 hr following oral dosing and 24 hr following dermal treatment, although detectable concentrations were found at earlier evaluations. Repeated oral dosing did not result in increased blood HCP concentrations over the 42-day period of the study. HCP is removed from the blood fairly rapidly, little being detected 4 to 7 days following exposure. Previous exposure to HCP, either in rats exposed for a short term or in the third generation of exposed rats, failed to alter the observed HCP blood concentrations. Rats varying in age from 21 to 200 days had similar blood HCP concentrations.following oral administration. The HCP blood concentration following dermal application to rats of varying ages showed no age-dependent differences.

Reproductive, teratogenic, perinatal and postnatal studies with cyclazocine

Abstract Cyclazocine, a mixed narcotic agonist-antagonist, was evaluated for teratogenic effects in rats and rabbits and for effects on reproductive performance, perinatal and postnatal development in rats. To evaluate teratogenic effects, Charles River albino rats were treated orally from days 6 through 15 of gestation with 3, 10, or 30 mg/kg/day of cyclazocine; New Zealand rabbits were dosed orally from days 6 through 18 of gestation with 1, 3, or 10 mg/kg/day. Rats and rabbits were sacrificed on day 20 or day 29 of gestation, respectively. Numbers of implantation sites, resorption sites, corpora lutea, and viable fetuses, as well as external, internal, and skeletal abnormalities were similar in test and control groups. No dose-related, external, internal or skeletal abnormalities were found in the offspring of either species. To evaluate effects on fertility and general reproductive performance, male or female rats were dosed orally for either 63 or 14 days, respectively, prior to mating with 3, 10, or 30 mg/kg/day. Dosing continued until day 14 of gestation for one-half of the females or after weaning for the other half. Control and treated groups displayed comparable food consumption values, behavior, mating, and fertility indices. To evaluate perinatal and postnatal effects, pregnant female rats were treated from day 15 of gestation throughout lactation. No untoward, drug-related effects were observed in any of the groups. Moreover, when the pups of the high-dose drug group were cross-fostered with control pups, no noticeable drug-related effects were apparent.