Dominant lethal studies with the halogenated olefins vinyl chloride and vinylidene dichloride in male CD-1 mice

Abstract

The mutagenic activity of vinyl chloride (VC) and vinylidene dichloride (VDC) at three exposure levels was assessed in fertile male CD-1 mice with the dominant lethal test. Each compound was assessed in a separate study. Male mice were exposed by inhalation to VC at 3000, 10,000, and 30,000 ppm and to VDC at 10, 30, and 50 ppm for 6 hr/day for 5 days. By comparison with control males exposed to air, no mutagenic effects on any maturation stage of spermatogenesis in treated males were detected. There was no significant increase in the number of postimplantational early fetal deaths as shown by the number of females with one or more early deaths or the number of early deaths/pregnancy or the number of early deaths/total implants/pregnancy. There was no evidence of pre-implantational egg losses as indicated by the total implants/pregnant female. There was also no reduction in fertility. (The reduction in fertility at 50 ppm VDC was unproven). The lack of effect was not due to the insensitivity of the system used, since both the VC and VDC study a mutagenic effect was clearly demonstrated in male mice dosed IP with the positive control compounds cyclophosphamide (CTX) and/or ethylmethane sulfonate (EMS). During dosing these animals were housed under similar exposure conditions to those animals exposed to the test substances but with a flow of air through the exposure chambers. Thus, neither VC nor VDC is mutagenic in the mouse at the stated exposure levels as measured by the dominant lethal test.

Detection of phase specificity of in vivo germ cell mutagens in an in vitro germ cell system

“…A particular problem in germ cell mutagenicity studies is the relative lack of suitable tools for detecting mutation induction (Yauk et al, 2015). Historically, studies have utilized huge numbers of animals in assays such as the morphological specific locus (MSL) test (Russell et al, 1979) and dominant lethal assay (Anderson et al, 1977), to reveal valuable information about the relative sensitivities male germ cells at different phases of development (phase-specificity). Nevertheless, there is still a general paucity of information on how endogenous factors, for example genetic polymorphisms and exogenous factors such as environmental-toxin exposure, affect the type of germ cell mutations induced and the risk of their induction (Beal et al, 2012).…”

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Vinylidene Chloride (CASRN 75-35-4) in F344/N Rats and B6C3F1/N Mice (Inhalation Studies)

“…In studies assessing reproduction, exposure to vinylidene chloride via inhalation or drinking water had no effects on reproduction in male mice or in either sex of rats [72][73][74] . No evidence of maternal toxicity or teratogenic effects was observed in rats exposed to 200 ppm vinylidene chloride on gestation days 6 to 15 in the drinking water 75 .…”

“…Bone marrow micronucleus tests in ddY male mice following single (25 to 200 mg/kg) or multiple (25 to 100 mg/kg) daily gavage treatments with vinylidene chloride were negative, and no increases in micronucleated cells of fetal liver or fetal blood were seen 24 hours after a single intraperitoneal injection (25 to 100 mg/kg) administered to pregnant ICR mice on gestational day 18 92 . Negative results were also reported in dominant lethal tests (germ cell mutagenicity assays) in male CD-1 mice treated with 3,000 to 30,000 ppm vinylidene chloride 6 hours/day for 5 days followed by mating 72 , and male CD rats exposed to 55 ppm vinylidene chloride for at least 11 weeks prior to mating 73 . However, evidence of vinylidene chloride interaction with DNA was seen in one study in which alkylated DNA was recovered from the livers and kidneys of mice and rats exposed to radiolabeled vinylidene chloride (10 or 50 ppm for 6 hours), although the number of alkylated nucleotides recovered was very low compared to those recovered after intraperitoneal dosing with 10 mg/kg of the potent alkylating agent dimethylnitrosamine 93 .…”

Mutagenicity Studies of Vinyl Chloride

“…In one of these studies, increased metabolites were observed in Chinese hamster V79 cells (15). However, in a study by Anderson et al (16), an increase in murine embryonic mortality was not seen in females mated to male mice who had received vinyl chloride prior to mating. These authors did report decreased fertility in the males which had received the highest dosage of vinyl chloride, or 50 ppm for 6 hr/day for 5 days.…”