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Toxic effect type:
dose-dependent

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
12 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Recently performed GLP study
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 554 mg/m³
Study duration:
subacute
Species:
rat
Additional information

An EOGRTS was recently carried out in rats using oral gavage. A dose level of 120 mg/kg bw resulted in reduced body and brain weights, slight to moderate retinal atrophy, a reduction in primary and primordial follicle count, reduced post-implantation survival index and litter size. No other effects were seen on the female or male reproductive system. The effects seen at 120 mg/kg bw were not seen at the next lower dose tested, viz. 12 mg/kg bw.

Tepe & Zenick (1984) found no effects on the reproductive organs nor in plasma gonadotropin levels of rats exposed for 4 -10 weeks to 350 ppm. In a second study (Zenick et al., 1984), exposure at 600 ppm affected the copulatory behaviour (ejaculation latency, sperm count and mount latency). According to Holson (1992), no effects were observed in a one-generation study on the reproductive function and reproductive performance (estrous cycling, mating index or fertility index) of female rats at 500 ppm via inhalation (6 h/d, during 2 -wk premating, mating and until day 19 of gestation). However, some signs of maternal toxicity (body weight loss, decreased food consumption), dystocia and neonatal toxicity (mortality of the pups, decreased viability, decreased litter size) were seen at this concentration. Based on these results, the NOAEC for maternal and neonatal toxicity was considered to be 250 ppm (777 mg/m3), while the NOAEC for reproduction toxicity was at least 500 ppm (1554 mg/m3). As indicated in DECOS (1993), exposure of rats and rabbits to 20 or 40 ppm for 7 weeks, did not reveal any changes on the reproductive organ weights or any histopathological lesions (Belisles et al., 1980 -NIOSH).

In a study by Patel et al. (1999) rats were exposed by means of intraperitoneal injection for 30 days. The observations indicated effects of CS2 on the male reproduction system (histopathological examination, serum testosterone levels) at the lowest concentration of 25 mg/kg bw and higher. The relevance of the study is, however, questionable due to the invasive route of exposure (intraperitoneal injection).

Chen et al. (2005) exposed male rats to 0, 1.6, 8, or 40 ppm of CS2 prior to mating for 10 weeks, and then mated the animals. The results revealed some adverse effects (body weight, growth, etc) in all exposed groups. According to DECOS (1993), in a study of Acadzhanova (1978), exposure to 3 ppm CS2 by inhalation resulted in a prolonged estrous cycle in rats, accompanied by some effects on the endocrine glands. Exposure to CS2 at 32 and 63 ppm, resulted in preimplantation losses in the F0 females (statistically significant at 63 ppm) (Tabacova et al., 1978). However, these inhalation studies cannot be used for assessment as there is only limited information and no data are available on analytical measurements which is very critical in case of inhalation studies. Therefore, the significance of these inhalation studies is questionable and it is not justified to use these for the derivation of a NOAEC for reproduction toxicity. These results are also contradicted by the recently carried out EOGRTS.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
LOAEL
25 mg/kg bw/day
Species:
rabbit
Quality of whole database:
Limited, older studies
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
948 mg/m³
Additional information

Toxicokinetics show that CS2 and its metabolites can pass through the placenta at all stages of gestation and distribute throughout the fetal body, mainly to the brain, blood, liver and eyes (Danielson et al., 1984). Denny (PAI, 1991) found that CS2 is embryotoxic and fetotoxic (increased resorption rate, decreased fetal body weight) at exposure levels of 600 ppm and above (animals exposed in utero during gestation), while overt maternal toxicity was observed at the 1200 ppm exposure level. Additionally, clear malformations in the offspring were seen at 1200 ppm. No effects were seen at 300 ppm, and thus this level was set as a NOAEC. Decreased fetal viability and increased pre-implantation mortality were detected in rats, after exposure during gestation at 640 ppm (Yaroslavskii et al., 1969). Exposure to 400 ppm during gestation resulted in decreased maternal and fetal body weight, while malformations in the neonates were found at 800 ppm (Saillenfeit et al., 1989).

A series of studies performed by Tabacova et al. demonstrated fetotoxicity and teratogenic effects, as well as changes in the behaviour of the offspring, following exposure of pregnant mothers to concentrations of 32 and 63 ppm. Additionally, Tabacova et al. (1983) suggested that exposure over two generations resulted in higher sensitivity to the teratogenic effects, producing malformed offspring in the 2nd generation at a concentration as low as 0.01 ppm, compared to 32 ppm in the first study. In utero exposure to CS2 at 32 and 63 ppm, resulted in preimplantation losses in the F0 (parents) animals and in malformations in the offspring of the F1 generation. Fertility of F1 animals, and fetal body weights of F2 animals were not affected. However, teratogenic effects of the same type and incidence as in the F1 generation were also noted in the F2 generation (Tabacova et al., 1978). However, these Tabacova studies are poorly reported and there is no information on analytical measurements whihc is very critical in inhalation studies.

It is therefore questionable whether the above information from the Tabacova et al. publications can be used to derive a reliable NOAEC for inhalation, as regards to developmental toxicity. Based on the key study, the NOAEC is 300 ppm (948 mg/m3).

In the recently performed EOGRTS, including neurodevelopmental toxicity examinations, no neurodevelopmental toxicity was observed in rats up to and including the highest dose tested of 120 mg/kg bw. The only effects observed were a reduced post-implantation survival index and litter size at 120 mg/kg bw; these effects were seen in the presence of maternal toxicity. Oral administration of 25, 75, and 150 mg/kg bw CS2 to rabbits during gestation, resulted in significant dose-related increases in the percent resorptions and dead or affected fetuses/litter. A dose-related increase in the percentage of malformed fetuses/litter was also observed; the increase was statistically significant, at 150 mg/kg bw (Jones-Price, 1984b). A nonequivalent teratogenic effect was seen among female and male fetuses, with males being more sensitive. In contrast, oral exposure of rats to CS2 produced dose-related maternal and fetal toxicity at doses including and above 200 mg/kg bw, but it did not increase the incidence of malformed fetuses (Jones-Price, 1984a). In the investigation of Tsai et al. (2000) oral exposure to concentrations up to 1200 mg/kg bw during gestation, did not result in alterations in the number of implantation sites, the mean fetal body weights, as well as the rate of fetal live births. 

Justification for classification or non-classification

Overall, the animal data indicate reproductive effects of carbon disulfide in rats, as well as developmental toxicity in rats and rabbits. The current classification is based on human data; the experimental data do not justify the current classification to be changed.

Additional information