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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
40 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
165 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Neurological effects after repeated exposure by ingestion:

Seizures and convulsions have been observed in rats, monkeys, and dogs exposed to RDX for intermediate or chronic durations. Seizures and convulsions were observed in rats administered gavage doses ≥8 mg/kg/day for 90 days (Crouse et al, 2006), in rats exposed to dietary RDX at doses of ≥25 mg/kg/day (Sunderman, 1944; Levine et al, 1983; von Oettingen et al, 1949), dogs exposed to 50 mg/kg/day via a capsule (von Oettingen et al, 1949), and monkeys administered 10 mg/kg/day via gavage (Martin and Hart, 1974). Few studies have reported the time course of the convulsions/seizures. In the Crouse et al (2006) study,convulsions/seizures were observed at the beginning of the study in rats administered 12 or 15 mg/kg/day and were seen throughout the study; convulsions/seizures were also observed at 8 and 10 mg/kg/day, however, the investigators did not note when the convulsions/seizures first occurred for these dose levels. In a chronic dietary study, seizures and convulsions were first observed after 26 weeks of exposure to 40 mg/kg/day (Levine et al, 1983). In monkeys, the effects were typically observed after 34–57 doses, although effects were also seen in some monkeys after the 2nd or 12th dose, and did not occur on a regular basis (Martin and Hart, 1974). Other overt neurological signs observed following intermediate or chronic exposure include hyperactivity, hyperreactivity, increased arousal, and increased fighting in rats exposed to gavage doses of ≥10 mg/kg/day (Crouse et al, 2006), in rats exposed to ≥25 mg/kg/day in the diet (Levine et al, 1990; Levine et al, 1983; Von Oettingen et al, 1949), and dogs administered capsules containing 50 mg/kg/day (Von Oettingen et al, 1949). The highest NOAELs for overt neurological effects were 4 mg/kg/day in rats receiving gavage doses (Crouse et al, 2006), 15 mg/kg/day in rats exposed via the diet (Von Oettingen et al, 1949), and 1 mg/kg/day in monkeys receiving gavage doses (Martin and Hart, 1983). Neurobehavioral performance was assessed in rats receiving gavage doses of RDX for 30 or 90 days. No RDX-related alterations in foot splay, front limb grip strength, or response to stimuli were found in rats administered 15 mg/kg/day for 90 days (Crouse et al, 2006). No significant histological alterations have been found in the brain (Levine et al, 1983; Crouse et al, 2006).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A lower adverse effect level (8 mg/kg/day) was reported in an intermediate-duration study, with a no-observed-adverse-effect level (NOAEL) of 4 mg/kg/day. At higher doses (≥40 mg/kg/day), hyperactivity, hyperirritability, hyperreactivity, and increased fighting have been observed in rats.
Although the database is mostly comprised of studies in rats, intermediate-duration studies in monkeys and dogs do not suggest species differences in RDX-induced seizures/convulsions.
In chronic-duration oral studies, seizures and convulsions were observed at 40 mg/kg/day; this dose was also associated with 88% lethality. No neurological effects were observed in rats chronically exposed to 8 or 10 mg/kg/day.
The animal data suggest that there may be other targets of RDX toxicity, including the hematological system and liver following oral exposure.
Small, although significant, decreases in hemoglobin and erythrocyte levels were observed following intermediate-duration exposure, but this was not consistently found in other intermediate or chronic studies.
Several studies found minor changes in serum chemistry parameters suggestive of a slight impairment of liver function.
These alterations include decreases in alanine aminotransferase and in serum triglyceride and/or cholesterol levels and increases in serum cholesterol levels.
A decrease in blood glucose levels observed in one study of rats may also be related to impaired liver function.
Hepatomegaly and hepatocellular vacuolization have been reported in rats; however, most studies did not report histological alterations in the liver.
An intermediate-duration study in monkeys reported an increase in vomiting following gavage administration of 10 mg/kg/day RDX; the occurrence of vomiting at 0.1 or 1 mg/kg/day was similar to controls.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
REACH annexes VII to X ask to perform two acute toxicity studies by two relevant routes, one being oral, except for gases. The substance is not a gas and two routes have been tested, oral and dermal. Therefore, testing by inhalation is not required.
However one non-reliable data exist. Death attributed to impairment of the respiratory system was observed in rabbits and guinea pigs exposed to an unspecified concentration of RDX.

Furthemore, according to Reach Annex VIII end point 8.5.2, the study does not need to be conducted if inhalation is unlikely taking into account the substance particles of an inhalable size. The granulometry study shows that <10% by mass of HMX particles are <10µm, therefore an acute inhalation study is not warranted. Furthermore, >77% by mass of particles are > 100 µm, this is accepted as a non-respirable fraction.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
REACH annexes VII to X ask to perform two acute toxicity studies by two relevant routes, one being oral, except for gases. The substance is not a gas and two routes have been tested, oral and dermal. Therefore, testing by inhalation is not required.
However one non-reliable data exist. Death attributed to impairment of the respiratory system was observed in rabbits and guinea pigs exposed to an unspecified concentration of RDX.

Furthemore, according to Reach Annex VIII end point 8.5.2, the study does not need to be conducted if inhalation is unlikely taking into account the substance particles of an inhalable size. The granulometry study shows that <10% by mass of HMX particles are <10µm, therefore an acute inhalation study is not warranted. Furthermore, >77% by mass of particles are > 100 µm, this is accepted as a non-respirable fraction.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Three animal studies examined the potential systemic toxicity of RDX following a repeated dermal application (McNamara et al, 1974). Howver, no details were providded regarding the "pathological examination". No adverse effects were observed during these studies.
A No Observe Adverse Effect Level of 165 mg/kg bw was reported in an intermediate-duration study in guinea pig and rabbit after an exposure period of 3 d/week during 3 weeks and 5 d/week during 5 weeks, respectively.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
In rabbits repeatedly exposed to 165 mg/kg RDX in DMSO 5 days/week for 4 weeks, dermatitis was observed after 14 and 30 days of exposure; no dermal effects were observed at 16.5 mg/kg RDX in DMSO or in rabbits administered lower RDX doses in cyclohexanone (37.5 mg/kg/day) or acetone (27 mg/kg/day) vehicles (McNamara et al, 1974).
However, these local effects were limited and the effects observed with the solvents alone were not significantely different with the RDX in solution with solvents.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: liver; neurologic: central nervous system

Justification for classification or non-classification

With a low observe adverse effect level of 40 mg/kg for seizures, RDX is considered as "May cause damage to organs" after repeated exposure by ingestion

, according to the criteria of Regulation EC n°1272/2008 modified (CLP).

The classification of RDX is:

- STOT RE Category 2; H373 (oral)