Reproductive or Developmental Toxicity

Sarin appears to produce no reproductive effects in rats, rabbits, or dogs. Pregnant female rats were administered sarin (100, 240, and 380 μg/kg per day) by gavage on gestational day (gd) 6–15 and were sacrificed on gd 20. There was no evidence of developmental toxicity related to any dose or formulation of sarin, even at doses that produced maternal toxicity and 28 percent mortality in the high dose group (LaBorde et al., 1996).

Pregnant female rabbits (New Zealand White) were studied in a similar fashion, receiving sarin on gd 6-19 and sacrificed on gd 29. None of the groups had any evidence of developmental toxicity at doses that produced maternal toxicity and 25 percent mortality in the high-dose group (LaBorde et al., 1996). Male dogs exposed to sarin vapor concentration of 10 mg/min/m3 for 6 months successfully mated and produced normal litters (Jacobson et al., 1959).

CYCLOSARIN TOXICOLOGY

Cyclosarin (cyclohexyl methylphosphonofluoridate) also belongs to the organophosphate group of nerve agents. Like other OPs, cyclosarin exerts its toxic effects by inhibition of AChE. This section reports on the limited number of toxicological studies of cyclosarin, whereas a later section reports on a study of military volunteers exposed to anticholinesterase nerve agents, including sarin and cyclosarin.

Cyclosarin produces maximal inhibition of AChE in less than 1 minute, with inhibition rate constants of 7.4 and 3.8 × 108 M−1 min−1 for AChE and BuChE, respectively (Worek et al., 1998). The aging half-life of the cyclosarin–esterase complex is 8.7 hours for AChE and 2.2 hours for BuChE (Worek et al., 1998).

The LD50 for cyclosarin in mice is estimated at 243 μg/kg by subcutaneous administration (Clement, 1992). In comparison, sarin’s LD50 in this same study was somewhat lower (170 μg/kg). In protection studies, a 3LD50 dose was used, and pralidoxime chloride (2-PAM) was found to be ineffective against cyclosarin, but the antidotes toxogonin and HI-6 are effective at higher doses than were necessary to protect against sarin.5 The author correlated the rapid recovery of HI-6-treated mice with a 67 percent reactivation of AChE 30 minutes after cyclosarin administration.

The LD50 for an intramuscular dose of cyclosarin in rhesus monkeys was 46.6 μg/kg (Koplovitz et al., 1992). Animals dosed with 30–75.4 μg/kg became unconscious within 2 minutes of administration. Those that survived were able to sit in their cages by 5–12 hours, and clinical signs disappeared by 12–24 hours. The primary pathological findings in most of the animals that died soon after exposure were neuronal degeneration or necrosis of the brain and spinal cord and spinal cord hemorrhage. The most affected brain regions were the

5  

HI-6 = 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]-pyridinium dichloride monohydrate.



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