AG 825

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

Potential Acute Health Effects

SWALLOWED Accidental ingestion of the material may be damaging to the health of the individual. The most common side-effects, associated with the clinical use of Epidermal Growth Factor Receptor (EGFR) inhibitors of tyrosine kinase, in the treatment of non-small cell lung cancers (NSCLC), include diarrhoea, skin rash, nausea, vomiting, headache, dizziness, asthenia, fatigue and loss of appetite. Less common side-effects may include dryness of the mouth, skin dryness, exfoliative dermatitis, pruritus, and itchiness. Rare side-effects may include dryness of the eyes, eye pain and liver injury. Interstitial pneumonia (sometimes fatal), may also develop as a side-effect of treatment. High doses of some EGFR inhibitors, administered to dogs, produced decreased body weight, absence of food intake, bloody stools, tremors, emaciation, prostration, ocular changes (palpebral and bulbar conjunctiva redness, partially closed eyes, lachrymation, purulent discharge, corneal opacities, oedema, ulceration and corneal perforation), increased neutrophils and fibrinogen, cachexia, dehydration, abnormal corneal surface, and abnormal surface of the digestive tract. Microscopic findings included diffuse corneal atrophy, corneal ulcers and uveal inflammation, papillary necrosis of kidneys, inflammation and/ or haemorrhage of the digestive tract and degeneration of skeletal muscle. 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. <\p>. 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.

Potential chronic health

Limited evidence suggests that repeated or long-term occupational exposure may produce cumulative health effects involving organs or biochemical systems. Exposure to the material may cause concerns for human fertility, on the basis that similar materials provide some evidence of impaired fertility in the absence of toxic effects, or evidence of impaired fertility occurring at around the same dose levels as other toxic effects, but which are not a secondary non-specific consequence of other toxic effects. . Animal studies with some Epidermal Growth Factor Receptor (EGFR) inhibitors of tyrosine kinase, indicate that repeated doses may produce adverse effects in many tissues including the eyes. Repeated exposures may also produce adverse effects on fertility as well as embryo- or foeto-toxicity (generally at maternally toxic levels). Some chronic administration studies with rats have produced eosinophilic chief cells in the stomach mucosa, haematuria, hair follicular degeneration, papillary necrosis and increased ovarian atrophy, liver necrosis and mononuclear cell infiltration of the liver (in females). In dogs, chronic studies have produced sporadic emesis, salivation, erythema, decreased absolute red blood cell counts, haematocrit and haemoglobin (in males), increased regeneration of renal proximal tubules, hair loss, ocular changes, and corneal ulceration. The material may inhibit protein kinase. This family of kinases enzymatically catalyses the phosphorylation of protein . Because phosphorylation triggers a signaling cascade which in turn produces cell growth, inhibition effectively retards the process. There are several different inhibitors which act in this manner but most common are genistein (a naturally occurring steroid-like substance from soybeans), lavendustin (a microbial metabolite) and the tyrphostins (synthetic analogues). Two families of protein kinase have been identified; · serine-threonine kinases (also known as PKC) require calcium ion for their activation. The activated PKC phosphorylates proteins of the cellular signal cascade, which eventually induce expression of growth regulatory genes. · tyrosine kinases which similarly regulate signal transmission to growth regulatory genes Inhibition may suppress cell or tissue growth or development. 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. <\p>.