| Toxizitätsübersicht | IDENTIFICATION AND USE: Dimethyl fumarate is a white to off-white powder formulated into delayed release capsules. It is used for the treatment of patients with relapsing forms of multiple sclerosis. Dimethyl fumarate is also used as a biocide to kill molds that may cause products such as furniture or shoes to deteriorate during storage or transportation in a humid climate. Placed in "Desiccant" sachets inside the furniture or footwear boxes, dimethyl fumarate evaporates and impregnates the product, protecting it from molds. HUMAN EXPOSURE AND TOXICITY: When used as a biocide, dimethyl fumarate has caused painful dermatitis. The fact that in serious cases the dermatitis is particularly difficult to treat adds to the damage. Dimethyl fumarate also has toxicity related to its use as a treatment for multiple sclerosis. A patient with multiple sclerosis who was being treated with dimethyl fumarate developed progressive multifocal leukoencephalopathy (PML), and later died. The patient who died was not taking any other drugs that affect the immune system or drugs that are thought to be associated with PML. Patients taking dimethyl fumarate should be advised to contact their clinician if they develop any symptoms that may be suggestive of PML. Treatment with dimethyl fumarate should not be initiated in patients with signs and symptoms of a serious infection. Dimethyl fumarate was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. ANIMAL STUDIES: Acute toxicity studies were performed in mice and rats using oral and intraperitoneal routes. In mice, reduced motility, ataxia, dyspnea, cyanosis, muscular hypotonia were observed at oral doses as low as 681 mg/kg. Ataxia and hypopnea were observed at i.p. doses as low as 464 mg/kg. In rats, ataxia, muscular hypotonia, inhibited respiratory rate and motility were noted at oral doses as low as 2610 mg/kg. Reduced food intake and decreased body weight gain were seen at 1470 and 2150 mg/kg, respectively. Ataxia, muscular hypotonia, reduced motility and respiratory rate were also observed at intraperitoneal doses as low as 681 mg/kg. Dyspnea (825 mg/kg)tremor, pilo-erection (1000 mg/kg)abdominal positioning (1470 mg/kg) were also noted. In these studies, the kidneys, forestomach and liver were identified as target organs. In mice, oral administration of dimethyl fumarate (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/dayleiomyosarcomas of the forestomach at 400 mg/kg/day in males and femalesrenal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in malesand renal tubule adenomas at 400 mg/kg/day in females. In rats, oral administration of dimethyl fumarate (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. In rats administered dimethyl fumarate orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryo fetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Oral administration of dimethyl fumarate (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. In rabbits administered dimethyl fumarate orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryo lethality and decreased maternal body weight were observed at the highest dose tested. In male rats, oral administration of dimethyl fumarate (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertilityhowever, increases in non-motile sperm were observed at the mid and high doses. In female rats, oral administration of dimethyl fumarate (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryo lethality at the highest dose tested. Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of dimethyl fumarate. Dimethyl fumarate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay, and it was not clastogenic in the in vivo micronucleus assay in the rat. |
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