Isazophos

SECTION 2: Hazards identification

CHEMWATCH HAZARD RATINGS Min Max Flammability: 1 Toxicity: 4 Body Contact: 3 Min/Nil=0 Low=1 Reactivity: 1 Moderate=2 High=3 Chronic: 2 Extreme=4 CANADIAN WHMIS SYMBOLS EMERGENCY OVERVIEW RISK Very toxic by inhalation. May cause SENSITISATION by skin contact. Harmful: danger of serious damage to health by prolonged exposure through inhalation. Toxic in contact with skin and if swallowed. Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

Potential Acute Health Effects

SWALLOWED Toxic effects may result from the accidental ingestion of the material; animal experiments indicate that ingestion of less than 40 gram may be fatal or may produce serious damage to the health of the individual. Ingestion may produce nausea, vomiting, depressed appetite, abdominal cramps,and diarrhea. Symptoms may be nausea, headache, giddiness, blurred vision, contractionof pupils, vomiting. Aromatase inhibitors (including triazoles and azoles) 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. Thiophosphates (phosphothioate esters) do not generally produce the same degree of cholinesterase inhibition associated with other organophosphates. They may however react with a range of compounds to produce such inhibitors. EYE There is some evidence to suggest that this material can causeeye irritation and damage in some persons. Direct eye contact can produce tears, eyelid twitches, pupil contraction, loss of focus, and blurred or dimmed vision. Dilation of the pupils occasionally occurs. SKIN Skin contact with the material may produce toxic effects; systemic effectsmay result following absorption. The liquid may be miscible with fats or oils and may degrease the skin, producing a skin reaction described as non-allergic contact dermatitis. The material is unlikely to produce an irritant dermatitis as described in EC Directives . There may be sweating and muscle twitches at site of contact. Reaction may bedelayed by hours. 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 vapors or aerosols (mists, fumes), generated by the material during the course of normal handling, may be harmful. The material is not thought to produce respiratory irritation (as classified using animal models). Nevertheless inhalation of vapors, fumes or aerosols, especially for prolonged periods, may produce respiratory discomfort and occasionally, distress. Poisoning due to cholinesterase inhibitors causes symptoms such as increased blood flow to the nose, watery discharge, chest discomfort, shortness of breath and wheezing. Other symptoms include increased production of tears, nausea and vomiting, diarrhea, stomach pain, involuntary passing of urine and stools, chest pain, breathing difficulty, low blood pressure, irregular heartbeat, loss of reflexes, twitching, visual disturbances, altered pupil size, convulsions, lung congestion, coma and heart failure.

Potential chronic health

Harmful: danger of serious damage to health by prolonged exposure through inhalation. This material can cause serious damage if one is exposed to it for long periods. It can be assumed that it contains a substance which can produce severe defects. 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. . Exposure to the material may cause concerns for humans owing to possible developmental toxic effects, on the basis that similar materials tested in appropriate animal studies provide some suspicion of developmental toxicity in the absence of signs of marked maternal toxicity, or at around the same dose levels as other toxic effects but which are not a secondary non-specific consequence of other toxic effects. Repeated or prolonged exposures to cholinesterase inhibitors produce symptoms similar to acute effects. In addition workers exposed repeatedly to these substances may exhibit impaired memory and loss of concentration, severe depression and acute psychosis, irritability, confusion, apathy, emotional liability, speech difficulties, headache, spatial disorientation, delayed reaction times, sleepwalking, drowsiness or insomnia. 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 oestrogens. The importance of androgens and oestrogens 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 oestrogen-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 Some azoles have been associated with prolongation of the QT interval on the electrocardiogram. . Triazole pesticides all contain a triazole ring with nitrogen atoms at the 1,2 and 4 positions. 1,2,4-Triazole (1,2,4-T) and its conjugates, triazole alanine (TA), triazole acetic acid (TAA), triazole pyruvic acid, and triazole lactic acid are the metabolic products of plant, fungal and animal bioconversion. These compounds all possess potentially significant toxicological properties. Following application of a triazole-derivative fungicide, biological and/or chemical processes may cause the triazole ring to be released from the parent compound. In rats and livestock, 1,2,4-triazole is relatively stable and is the terminal form of the triazole ring. In plants, the 1,2,4-triazole molecule may become conjugated to serine. The resulting compound, triazole alanine, may be oxidised to form triazole acetic acid. Triazole alanine and triazole acetic acid are the primary terminal forms of the triazole ring in plants, though some 1,2,4-triazole may remain. The degree of formation of any given form of the triazole ring is highly dependent on the nature and properties of the parent compound. Although other triazole conjugates such as triazole lactic acid and triazole pyruvate have been observed in plant metabolism studies, TA and TAA are the predominant conjugates that need to be included in the dietary risk assessment. Although for most pesticides, mammals convert only a small proportion to free triazole (less than 25%), two compounds (tetraconazole and flusilazole) demonstrate relatively high conversion (68-77%) in rat metabolism studies. Available acute data indicate that 1,2,4-triazole is slightly toxic by the oral route (with oral LD50 values ranging from 666 mg/kg in rabbits to 3650 mg/kg in mice) and slightly to moderately toxic by the dermal route (dermal LD50s were less than 2000 mg/kg in rabbits, and 3000-4000 mg/kg in rats). Limited available information indicates that 1,2,4-triazole is slightly irritating or non-irritating to the skin, but severely irritating to the eye. Based on the limited acute toxicity data, as well as the available developmental toxicity data (see below), it appears that rabbits may be substantially more susceptible to 1,2,4-triazole than are rats or mice Studies indicate that 1,2,4-triazole affects the central and peripheral nervous systems, reproductive tissues of both sexes, and the hematological system. Developmental and reproductive effects have been noted for this compound. Based on the available metabolism data from rats and livestock, 1,2,4-triazole may form in humans following exposure to parent triazole compounds. Relative to triazole alanine, fewer studies are available depicting the toxicological effects of the other triazole conjugates. It is assumed that the triazole conjugates are all toxicologically equivalent to triazole alanine. The available studies found developmental skeletal effects, decreased body weight and body weight gain, and decreased leukocytes and triglycerides. A number of target organs and critical effects have been identified. 1,2,4-triazole targets the nervous system, both central and peripheral, as brain lesions (most notably in the cerebellum) were seen in both rats and mice, and peripheral nerve degeneration was also seen in the subchronic neurotoxicity study in rats. In addition, brain weight decreases were seen in several studies, including in the offspring in the reproductive toxicity study. In the subchronic/neurotoxicity study, there is evidence that effects progress over time, with an increase in incidence of clinical signs (including tremors and muscle fasciculations) during weeks 8 and 13 that were not seen during earlier evaluations. There is no evidence that exposure to triazole alanine results in neurotoxicity. No clinical signs of neurotoxicity, changes in brain weights, changes in brain gross or microscopic pathology, or any other neurotoxic effects were observed in the short-term rat studies, the subchronic rat and dog feeding studies, the rat developmental toxicity study, or the two-generation reproduction study Effects were also seen on reproductive organs in both sexes, most notably ovaries (in rats) and testes (in rats and mice), in both the reproductive toxicity and subchronic toxicity studies. Hematological changes, including slightly decreased hemoglobin and/or hematocrit, have also been seen in multiple studies and species (in rats at doses of 33 mg/kg/day and above, and in mice at doses of 487 mg/kg/day and above). 1,2,4-triazole also causes developmental toxicity in both rats and rabbits, including malformations, at doses similar to those inducing maternal toxicity (decreased body weight gain in rats and clinical signs and mortality in rabbits). Developmental toxicity was also seen in the reproductive toxicity study, with offspring showing adverse effects on multiple endpoints (including decreased brain and body weight) at doses lower than those at which effects were seen in parents. In addition, reproductive toxicity was seen in both sexes: at the highest dose (3000 ppm), only two F1 litters (one pup/litter) were produced, and neither survived to adulthood. Triazole alanine showed increased incidences of skeletal findings in the offspring at the mid and high doses, while no treatment-related effects were seen in the dams up to the limit dose. The skeletal findings included unossified odontoid processes at 300 and 1000 mg/kg/day, with partially ossified transverse processes of the 7th cervical vertebra (bilateral), unossified 5th sternebra, and partially ossified 13th thoracic centrum observed only at 1000 mg/kg/day. Available mutagenicity data are limited but negative. A large number of parent triazole-derivative pesticides have been classified as carcinogens (most also non-mutagenic), but the relevance of that finding to expected effects of free triazole may be limited. The types of tumors associated with exposure to the parent chemicals are most commonly hepatocellular adenomas/carcinomas in mice. Other tumor types vary considerably (including liver tumors, thyroid tumors, ovarian tumors, testicular tumors, and bladder tumors). None of the tumor types are clearly associated with the proportion of free triazole formed in available rat metabolism studies. Evidence indicates that the parent triazole compounds appear to result in a tumor response subsequent to perturbation of liver metabolism, specifically xenobiotic and fatty acid metabolic pathways. In addition the thyroid response appears to be secondary to perturbation of thyroid homeostasis. Thus, the conazoles appear to drive a tumor response secondary to epigenetic effects and not from direct interaction with the DNA. An epigenetic mode of action would be consistent with a nonlinear process. BE AWARE: Repeated minor exposures with only mild symptoms may have serious cumulative poisoning effect.