Valganciclovir Hydrochloride

SECTION 2: Hazards identification

CHEMWATCH HAZARD RATINGS Min Max Flammability: 1 Toxicity: 2 Body Contact: 0 Min/Nil=0 Low=1 Reactivity: 1 Moderate=2 High=3 Chronic: 2 Extreme=4 CANADIAN WHMIS SYMBOLS EMERGENCY OVERVIEW RISK Limited evidence of a carcinogenic effect.

Potential Acute Health Effects

SWALLOWED Accidental ingestion of the material may be damaging to the health of the individual. Adverse effects include bone-marrow suppression have been seen following use of ganciclovir. . EYE Although the material is not thought to be an irritant, direct contact with the eye may cause transient discomfort characterized by tearing or conjunctival redness (as with windburn). Slight abrasive damage may also result. SKIN The material is not thought to produce adverse health effects or skin irritation following contact (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting. Open cuts, abraded or irritated skin should not be exposed to this material. Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected. INHALED The material is not thought to produce either adverse health effects or irritation of the respiratory tract following inhalation (as classified using animal models). Nevertheless, adverse effects have been produced following exposure of animals by at least one other route and good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting. Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled. Limited evidence exists that the substance may cause irreversible but non-lethal mutagenic effects following a single exposure.

Potential chronic health

There has been concern that this material can cause cancer or mutations, but there is not enough data to make an assessment. Ample evidence from experiments exists that there is a suspicionthis material directly reduces fertility. Exposure to the material may result in a possible risk of irreversible effects. The material may produce mutagenic effects in man. This concern is raised, generally, on the basis of appropriate studies with similar materials using mammalian somatic cells in vivo. Such findings are often supported by positive results from in vitro mutagenicity studies. Long term exposure to high dust concentrations may cause changes in lung function i.e. pneumoconiosis; caused by particles less than 0.5 micron penetrating and remaining in the lung. Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1 and 1.4, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons.All tumours were of epithelial or vascular origin except for histiocytic sarcoma of the liver.. No carcinogenic effects were seen at 1 mg/kg/day. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. In an 18 month study, ganciclovir was carcinogenic in mice after oral doses of 20 mg and 100 mg daily. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7 the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1 the AUC of the recommended human intravenous dose. Daily intravenous doses of 20 mg/kg did not impair female fertility but doses as low as 3 mg/kg caused reduction in the weight of pups; higher doses were associated with hypoplasia of testes and seminal vesicles in male pups. In male mice fertility was decreased after daily intravenous doses of 2 mg/kg. Effects were reversible at this dose level but became irreversible at 10 mg/kg. Valganciclovir (which metabolises to ganciclvir) caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir (and valganciclovir) could cause inhibition of human spermatogenesis Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered doses that produced 2 the human exposure based on AUC comparisons. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.7 the human AUC. Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion.