Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

IMAZALIL SULFATE

NFPA

PRODUCT USE

Systemic fungicide with protective and curative action. Inhibits ergosterol biosynthesis.
For the control of a wide range of fungal diseases on fruit, vegetable, and ornamentals,
e.g. powdery mildew. Formulated as an emulsifiable concentrate.

SYNONYMS

C14-H16-Cl2-N2-O5-S, "1H-imidazole, 1-(2-(2, 4-dichlorophenyl)-2-(2-propenyloxy)ethyl)-,
sulfate", "1H-imidazole, 1-(2-(2, 4-dichlorophenyl)-2-(2-propenyloxy)ethyl)-, sulfate",
"(+/-)-1-(beta-allyloxy)-2, 4-dichlorophenethyl)imidazole sulfate", "(+/-)-1-(beta-
allyloxy)-2, 4-dichlorophenethyl)imidazole sulfate", "1-(2-(2, 4-dichlorophenyl)-2-(2-
propenyloxy)ethyl)-1H-imidazole sulfate", "1-(2-(2, 4-dichlorophenyl)-2-(2-
propenyloxy)ethyl)-1H-imidazole sulfate", R021780, "azole/ fungicide/ pesticide/
antimycotic"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

EMERGENCY OVERVIEW

RISK

Danger of cumulative effects.
May cause SENSITIZATION by skin contact.
Very toxic by inhalation and if swallowed.
Very toxic to aquatic organisms, may cause long- term adverse effects in the
aquatic environment.

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Severely toxic effects may result from the accidental ingestion of the material; animal experiments indicate that ingestion of less than 5 gram may be fatal or may produce serious damage to the health of the individual.  Accidental ingestion of the material may be harmful; animal experiments indicate that ingestion of less than 150 gram may be fatal or may produce serious damage 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

  There is some evidence to suggest that this material can causeeye irritation and damage in some persons.  

SKIN

  Skin contact is not thought to produce harmful health effects (as classified using animal models). Systemic harm, however, has been identified following exposure of animals by at least one other route and the material may still produce health damage following entry through wounds, lesions or abrasions. 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

  Inhalation of dusts, generated by the material, during the course of normalhandling, may be harmful.  The material is not thought to produce respiratory irritation (as classified using animal models). Nevertheless inhalation of dusts, or fume, especially for prolonged periods, may produce respiratory discomfort and occasionally, distress.  

CHRONIC HEALTH EFFECTS

  Repeated or long-term occupational exposure is likely to produce cumulative health effects involving organs or biochemical systems.  Skin contact with the material is more likely to cause a sensitization reaction in some persons compared to the general population.  There is some evidence that human exposure to the material may result in developmental toxicity. This evidence is based on animal studies where effects have been observed in the absence of marked maternal toxicity, or at around the same dose levels as other toxic effects but which are not secondary non-specific consequences of the other toxic effects.  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..  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.  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    .  Imidazole is structurally related to histamine and has been used as an antagonist to counteract the effects of excess histamine found in certain induced physiological conditions (it therefore acts as an antihistamine).  Imidazoles have been reported to disrupt male fertility through disruption of testicular function.  2-Methylimidazole decreased luteinising hormone secretion and tissue interstitial fluid testosterone concentration two hours after injection into Sprague Dawley rats.  Imidazoles bind to cytochrome P450 haeme, resulting in inhibition of catalysis. However, 2-substituted imidazoles are considered to be poor inhibitors. Imidazole is probably an inducer of cytochrome P4502E1. In general, inducers of this isozyme stabilise the enzyme by preventing phosporylation of a serine which leads to haeme loss.  Several drugs containing an imidazole moiety were retained and bound in connective tissue when administered to laboratory animals. The bound material was primarily recovered from elastin (70%) and the collagen. It is postulated that reaction with aldehydes gives an aldol condensation product.