Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Justification for selection of Effect on fertility via oral route:
There is limited information to suggest that RDX is a reproductive toxicant following oral exposure. An increased incidence of spermatic granuloma in the prostate was observed in rats following exposure to 40 mg/kg/day for 6 months; however, this effect was not observed at longer durations (1 or 2 years) in the same study. A nonsignificant increase in testicular degeneration was also observed in this study in rats exposed for 6 months to 40 mg/kg/day, but testicular effects were not observed in another study of rats exposed to 100 mg/kg/day for 13 weeks.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Additional information

Reproductive effects:

No studies were located regarding reproductive effects in humans after oral exposure to RDX.

Toxicity studies lasting 13 weeks showed no pathological changes in the gonads or uteri of rats (Levine et al, 1981; Levine, 1990; Cholakis et al, 1980, Levine et al, 1983) or mice (Cholakis et al, 1980) exposed to RDX. No functional tests were performed. One study did report spermatic granulomas in the prostates of rats exposed to 40 mg/kg/day for 6 months (Levine et al, 1983); this effect was not observed in rats exposed after 1 or 2 years of exposure (Levine et al, 1983). This study (Levine et al, 1983) also reported an increase in the incidence of testicular degeneration in rats exposed to 40 mg/kg/day for 6 months (3/10, not statistically significant) or 1 year (4/10), but not after 2 years (0/4).

Histological examinations of rats exposed to ≥1.5 mg/kg/day in the feed for 2 years revealed suppurative inflammation in the prostate (Levine et al, 1983). The prostate effects were predominantly observed in rats dying early and may have been secondary to a bacterial infection of the urinary tract. Urinary bladder distention and cystitis were observed in rats exposed to 40 mg/kg/day for 1 or 2 years. Testicular degeneration was observed in rats exposed to 40 mg/kg/day for 1 year (Levine et al, 1983); a nonstatistically significant increase in testicular degeneration was also observed in mice exposed to ≥35 mg/kg/day for 1–2 years (Lish et al, 1984). No significant histological alterations have been observed in the ovaries or uterus of rats (Levine et al, 1983) or mice (Lish et al, 1984) chronically exposed to RDX.

Two studies examined reproductive function. In a two-generation study, no significant alterations in reproduction were observed in the F0 and F1 rats exposed to 16 mg/kg/day in the diet (Cholakis et al, 1980).

At 50 mg/kg/day, nonstatistically significant decreases in fertility were observed in the F0 generation. In a dominant lethality assay (Cholakis et al, 1980), decreases in fertility were observed in male rats exposed to 50 mg/kg/day for 15 weeks prior to mating with unexposed females; however, the investigators noted that this effect may have been secondary to the impaired well-being of the males.

Developmental effects:

No studies were located regarding developmental effects in humans after oral exposure to RDX.

There are two available developmental studies in rats (exposed for 9 or 13 days during gestation) that are inconclusive because of excessive maternal toxicity at the high dose (20 mg/kg/day). In one study, no excessive gross, visceral, or skeletal anomalies were found in fetuses when the dams were exposed to 2 mg/kg/day of RDX (Cholakis et al, 1980). High maternal lethality, decreased maternal body weights, and adverse maternal neurological effects precluded judgment regarding fetal toxicity at 20 mg/kg/day. The other rat study (Etnier et al, 1986) also showed high maternal toxicity (increased mortality and seizures) at 20 mg/kg/day. These investigators also reported a significant decrease in fetal weights and lengths at ≥2 mg/kg/day when data were analyzed on an individual basis rather than a litter basis. However, it appears that there was an overlap in the standard deviations for the fetal body weight and length values; when analyzed on a litter basis, decreases in fetal weights and lengths were only significant at the 20 mg/kg/day dose level. In contrast to rats, rabbits (exposed for 22 days during gestation) showed no adverse fetal or maternal effects at 20 mg/kg/day (Cholakis et al, 1980). In a two-generation reproduction study, an increase in the number of stillbirths, a decrease in the number of pups per litter at birth, and a decrease in the number of live litters at weeks 7, 14, and 21 were observed in the F1 offspring of rats exposed to 50 mg/kg/day (a dose that also resulted in increased maternal deaths and decreased feed consumption) (Cholakis et al, 1980). In the F2 generation, a decrease in terminal body weights and an increase in renal tubular epithelial-lined cysts were observed at 16 mg/kg/day. Similar cysts were observed in F2 pups exposed to 0 or 5 mg/kg/day.


Justification for selection of Effect on developmental toxicity: via oral route:
Adverse developmental effects have been observed in rats, particularly at maternally toxic doses. Decreases in pup survival and increases in the occurrence of stillbirths were observed at 50 mg/kg/day; this dose also resulted in maternal deaths. A decrease in pup body weight and an increase in the incidence of renal cysts were observed in F2 pups at 16 mg/kg/day in a two-generation study of rats and a decrease in fetal body weight and length were observed in the offspring of rats administered 20 mg/kg/day on gestation days 6–15. No adverse developmental (or maternal) effects were observed in rabbits.

Justification for classification or non-classification