Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

LETROZOLE

NFPA

PRODUCT USE

Antineoplastic which suppresses oestrogen synthesis. Treatment of breast cancers. Also
used to induce ovulation.

SYNONYMS

C17-H11-N5, "4, 4'-(1H-1, 2, 4-triazol-1-ylmethylene)bisbenzonitrile", "4, 4'-(1H-1, 2, 4-
triazol-1-ylmethylene)bisbenzonitrile", "1-[bis(4-cyanophenyl)methyl]-1, 2, 4-triazole",
"1-[bis(4-cyanophenyl)methyl]-1, 2, 4-triazole", "4-[1-(4-cyanophenyl)-1-(1, 2, 4-triazol-
1-yl)methyl]benzonitrile", "4-[1-(4-cyanophenyl)-1-(1, 2, 4-triazol-1-
yl)methyl]benzonitrile", CGS-20267, Femara, "fadrozole analogue", "nonsteroidal aromatase
inhibitor", antineoplastic, "ovulation inducer"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

EMERGENCY OVERVIEW

RISK

Danger of cumulative effects.
May impair fertility.
May cause harm to the unborn child.

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Accidental ingestion of the material may be damaging to the health of the individual.  Aromatase inhibitors produce several side effects including mood swing, depression, weight gain, hot flushes, vaginal dryness, bloating, early onset of menopause. Long-term use may result in bone weakness, increased risk of blood clots, gastrointestinal disturbance,and sweats.  Aromatase inhibitors lower the level of oestrogen in post-menopausal women who have hormone-receptor-positive breast cancers. Prior to menopause oestrogen is mostly produced in the ovaries. Post-menopausal women produce oestrogen from another hormone, androgen. Aromatase inhibitors prevent the enzyme, aromatase from catalysing this reaction. Breast cancer cell growth in post-menopausal women is stimulated by oestrogen.  

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. The material may produce foreign body irritation in certain individuals.  

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.  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.  

CHRONIC HEALTH EFFECTS

  Repeated or long-term occupational exposure is likely to produce cumulative health effects involving organs or biochemical systems.  Ample evidence exists from experimentation that reduced human fertility is directly caused by exposure to the material.  Ample evidence exists, from results in experimentation, that developmental disorders are directly caused by human exposure to the material.  There has been some concern that this material can cause cancer or mutations but there is not enough data to make an assessment.  Azole fungicides show a broad antifungal activity and are used either to prevent fungal infections or to cure an infection. Therefore, they are important tools in integrated agricultural production. According to their chemical structure, azole compounds are classified into triazoles and imidazoles; however, their antifungal activity is due to the same molecular mechanism. The cell membrane assembly of fungi and yeast is disturbed by blocking the synthesis of the essential membrane component ergosterol. This fundamental biochemical mechanism is the basis for the use of azole fungicides in agriculture and in human and veterinary antimycotic therapies. The enzyme involved is sterol 14[alpha]-demethylase, which is found in several phyla. In mammals, it converts lanosterol into the meiosis-activating sterols (MAS) which regulate or modify cell division. These precursors of cholesterol have been discovered to moderate the development of male and female germ (sexual) cells. Several metabolites of lanosterol have been regarded only as precursors of cholesterol without any biological function in animals. This view dramatically changed recently with the observation that FF-MAS isolated from human follicle fluid and T-MAS isolated from bull testis as well as the MAS-  412 and MAS-414 induced resumption of meiosis in cultivated mouse oocytes (Byskov et al. 1995).  Aromatase is another target enzyme of azole compounds. In steroidogenesis, it converts androgens into the corresponding estrogens. The importance of androgens and estrogens for the development of reproductive organs, for fertility, and in certain sex steroid-  dependent diseases is well known. Therefore, azole compounds can be directed against aromatase to treat estrogen-responsive diseases. Based on the inhibitory activity of azoles on key enzymes involved in sex steroid hormone synthesis, it is likely that effects on fertility, sexual behavior, and reproductive organ development will occur depending on dose level and duration of treatment of laboratory animals. Several azole compounds were shown to inhibit the aromatase and to disturb the balance of androgens and estrogens in vivo. In fact, the clinical use of azole compounds in estrogen-dependent diseases is based on this effect. Additionally, azole antifungals developed to inhibit the sterol 14[alpha]-demethylase of fungi and yeast in agriculture and medicine are also inhibiting aromatase. Therefore, these antifungals may unintentionally disturb the balance of androgens and estrogens. Until now, it is not clear whether this effect is compensated by an increased expression of aromatase or by other unknown mechanisms.  The broad use of biologically active compounds in human therapy as well as in nonhuman applications may involve some risks, as exemplified by emerging antibiotic resistance. In agriculture, fungi and yeast are well known to develop resistance to azoles, and some molecular mechanisms of resistance development have been described. The significance of the agricultural azole resistance for human clinical antimycotic therapies has been discussed in Europe, but is not clarified yet. The actual target enzyme of azole antifungals, the fungal sterol 14[alpha]-demethylase, is expressed in many species including humans, and it is highly conserved through evolution. Hence, it seems reasonable to assume that most of the azole antifungals used in agriculture and medicine as well as azoles used in management of breast cancer also act as inhibitors on human sterol 14[alpha]-demethylase to an unknown extent. The toxicologic profiles of individual azole fungicides provide evidence for endocrine effects. In fact, many of these fungicides have effects on prostate, testis, uterus, and ovaries as well as on fertility, development, and sexual behavior. The current database does not allow us to establish causal relationships of these effects with inhibition of sterol 14[alpha]-demethylase and/or aromatase, but the overall view strongly suggests a connection with disturbed steroidogenesis.  Zam et al; Environmental Health Perspectives - 3/1/2003    .  Epidemiological studies have associated long-term exposures to triazine herbicides with increase risk of ovarian cancer in female farm workers in Italy and of breast cancer in the general population of Kentucky in the United States. In experiments with female F344 rats, atrazine induced tumours of the mammary gland and reproductive organs. Atrazine also caused lengthening of the oestrus cycle, a dose-dependent increase in the plasma levels of 17beta-oestradiol and early onset of mammary and pituitary tumours in female Prague-Dawley rats.  Investigations into the mechanism of these apparent oestrogenic effects have not been able to demonstrate any consistent interactions with triazine herbicides with the oestrogen receptor or effects on receptor-mediated responses. Atrazine, simazine and propazine have been shown to induce aromatase activity in a human adrenocortical carcinoma cell line. This response was observed at concentrations in the submicromolar range. Aromatase is a circulating enzyme which converts androstenedione (generated in the adrenals) to oestrone in peripheral tissues such as adipose tissues. Oestrone subsequently undergoes conversion to oestradiol which binds to oestrogen receptors in many tissues with induction of tumours. In addition, many human breast cancers contain aromatase. (Breast cancer therapies, based on aromatase inhibitors, are now available.)  The effects of triazine herbicides and some of their metabolites on aromatase activity may provide a partial explanation for the observed increase in plasma oestradiol in rats, together with the observed oestrogen-mediated toxicities in vivo. [1] [1] Sanderson et al: Environmental Health Perspectives, 109, pp 1027-1031, 2001  Suggestive evidence between atrazine (or triazines) exposure and an increased risk of prostate cancer, breast cancer, and ovarian cancer have been reported. Although these data provide a suspicion of carcinogenicity, the limited number of investigations and study limitations preclude drawing conclusions regarding these cancer types.  Extensive structural activity data from the family of triazole pesticides suggests that may induce hepatocellular adenomas in animal models. The significance of this finding in human carcinogenicity is equivocal.  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. Prime symptom is breathlessness; lung shadows show on X-ray.