Is 3-Amino-1,2,4-Triazole harmful?

3-Amino-1,2,4-Triazole, a widely used herbicide found to produce thyroid and liver tumors in rodents and classified as possibly carcinogenic to humans, was investigated to acquire further information about its mechanism of action. A 20-hr exposure to 3-Amino-1,2,4-Triazole concentrations ranging from 5.6 to 18 mM did not induce DNA fragmentation, as measured by the alkaline elution technique, in primary cultures of human thyroid follicular cells and of human liver cells. Under the same experimental conditions a minimal frequency of DNA breaks was detected in primary cultures of rat hepatocytes, but this event was presumably the unspecific consequence of a cytotoxic effect. In rats given 3-Amino-1,2,4-Triazole with drinking water for 12 successive days at a daily dose of approximately 200 mg/kg, plasma levels of triiodothyronine and thyroxine displayed a progressive reduction, and a concurrent increase of both the mitotic index and frequency of S-phase cells revealing a clear-cut follicular cell hyperplasia was observed. In a group of these rats euthanized after 8 days of treatment any evidence of DNA fragmentation was absent in both thyroid and liver cells. Taken as a whole these results provide further evidence that the mechanism of 3-Amino-1,2,4-Triazole carcinogenic activity is most likely nongenotoxic but due to hormone imbalance.[1]

Cancer Studies in Experimental Animals

3-Amino-1,2,4-Triazole caused tumors in two rodent species, at two different tissue sites, and by two different routes of exposure. 3-Amino-1,2,4-Triazole caused cancer of the thyroid gland (follicular-cell carcinoma) and liver tumors (hepatocellular tumors) when administered to rats of both sexes in the feed or drinking water and to 7-day-old weanling mice of both sexes by stomach tube for three weeks and in the diet starting at four weeks of age. It also caused liver and thyroid-gland tumors in rats (of unspecified sex) when administered by subcutaneous injection. Since 3-Amino-1,2,4-Triazole was listed in the Second Annual Report on Carcinogens, additional studies in rodents have been identified. Dietary administration of 3-Amino-1,2,4-Triazole caused cancer of the thyroid gland (follicular-cell carcinoma) in rats of both sexes and marginally increased the incidence of benign pituitary-gland tumors (adenoma) in female rats. Dietary administration of 3-Amino-1,2,4-Triazole to female mice nursing pups and then to the weaned offspring caused liver cancer (hepatocellular carcinoma) in the male offspring.[2]

Cancer Studies in Humans

The data available from epidemiological studies are inadequate to evaluate the relationship between human cancer and exposure specifically to 3-Amino-1,2,4-Triazole. A small cohort study of Swedish railroad workers who had sprayed herbicides found a statistically significant excess of all cancers among those exposed to both 3-Amino-1,2,4-Triazole and chlorophenoxy herbicides, but not among those exposed mainly to 3-Amino-1,2,4-Triazole.

Properties and Uses

3-Amino-1,2,4-Triazole is a triazole compound that is a colorless to white crystalline solid at room temperature. It forms salts with most acids and bases and is a powerful chelating agent. It is soluble in water, ethanol, methanol, chloroform, and acetonitrile; sparingly soluble in ethyl acetate; and insoluble in acetone. 3-Amino-1,2,4-Triazole is stable under normal temperatures and pressures, but decomposes on exposure to light. 3-Amino-1,2,4-Triazole was first registered for use as an herbicide in the United States in 1948 but was not commercialized until the 1950s (EPA 1996). In 1958, food-crop use was limited to post-harvest application to cranberries (EPA 1996; IARC 2001). Registrations for use on food crops were cancelled by the U.S. Environmental Protection Agency in 1971, after which 3-Amino-1,2,4-Triazole was used primarily as a non-selective terrestrial post-emergent herbicide in outdoor industrial areas, non-agricultural rights of way, and non-agricultural uncultivated areas to treat vines, shade trees, ornamental shrubs and trees, and soil. 3-Amino-1,2,4-Triazole has a wide spectrum of activity against annual and perennial broad-leaf and grass-type weeds. Approved uses on soil were for non-crop land prior to sowing and for inter-row weed control in tree and vine crops, where contact with food plants was avoided (IPCS 1994). Limitations on the use of 3-Amino-1,2,4-Triazole included not feeding or grazing animals on land treated with 3-Amino-1,2,4-Triazole and not applying it directly to water or wetlands. 3-Amino-1,2,4-Triazole was usually applied by fixed-boom sprayers attached to tractors, trucks, or railroad wagons.

Production

3-Amino-1,2,4-Triazole was first synthesized in 1898 (IARC 2001). At one time, 40 registered pesticide products contained 3-Amino-1,2,4-Triazole as an active ingredient; however, no active registered products in the United States now contain 3-Amino-1,2,4-Triazole (EPA 2009). 3-Amino-1,2,4-Triazole was not reported to be produced commercially in the United States in surveys conducted in 1978 and 1982 (HSDB 2009). In 2009, 3-Amino-1,2,4-Triazole was produced by one manufacturer in Europe and two manufacturers in East Asia (SRI 2009) and was available from 34 suppliers, including 23 U.S. suppliers (ChemSources 2009). Reported U.S. imports of 3-Amino-1,2,4-Triazole were 1.2 million pounds in 1978, but had declined to 465,000 lb by 1982 (HSDB 2009). No data on U.S. imports or exports after 1985 were found. A report filed in 1990 under EPA's Toxic Substances Control Act Inventory Update Rule indicated that U.S. production plus imports of 3-Amino-1,2,4-Triazole totaled 10,000 to 500,000 lb (EPA 2004); no inventory update reports were filed for 3-Amino-1,2,4-Triazole in 1994, 1998, or 2002.

Exposure

The routes of potential human exposure to 3-Amino-1,2,4-Triazole are inhalation, dermal contact, and ingestion (HSDB 2009). Exposure of the general population could occur through ingestion of contaminated drinking water. Because 3-Amino-1,2,4-Triazole is not registered for food-crop uses, there is no known dietary exposure. In 1958 and 1959, 3-Amino-1,2,4-Triazole residues were found on cranberries (EPA 1996; HSDB 2009). No 3-Amino-1,2,4-Triazole residues were detected in food or water when recommended use practices were followed (IPCS 1994). Exposure could previously have occurred through inhalation near herbicide manufacturing or spraying areas. Large quantities of 3-Amino-1,2,4-Triazole previously were used as an herbicide in the United States. In California alone, 82,000 kg (180,000 lb) was used in 1970 and 64,000 kg (141,000 lb) was used in 1972 (IARC 1974). EPA estimated that annual use was 500,000 to 800,000 lb in 1984, declining to between 50,000 and 100,000 lb in 1989 and between 40,000 and 60,000 lb in 1990 (EPA 1996). One death from ingestion of a weed killer containing a mixture of 3-Amino-1,2,4-Triazole and ammonium thiocyanate was reported; 3-Amino-1,2,4-Triazole was measured in the blood of the victim at 13 mg/L over 12 hours after ingestion (Legras et al. 1996).[3]

According to EPA's Toxics Release Inventory, 176 lb of 3-Amino-1,2,4-Triazole was released to the environment in 1999, mostly to off-site facilities, and slightly over 100 lb was released in 2007, to off-site facilities. The largest total annual releases were of 265 lb to off-site landfills in 2001 (TRI 2009). When 3-Amino-1,2,4-Triazole is released to air, it reacts with photochemically produced hydroxyl radicals, with a half-life of 3 days (EPA 1996; HSDB 2009). It was measured in the air near a manufacturing facility at concentrations as high as 100 μg/m3 (IPCS 1994). In water and soil, 3-Amino-1,2,4-Triazole is not expected to hydrolyze, but it is readily biodegraded by soil microorganisms; it is not likely to bioaccumulate in aquatic organisms. 3-Amino-1,2,4-Triazole is moderately persistent under aerobic conditions, with half-lives of 57 days in water and 22 to 26 days in soil, but it is more persistent under anaerobic conditions, with a half-life of over 1 year in water (EPA 1996; HSDB 2009). 3-Amino-1,2,4-Triazole is highly mobile in alkaline or neutral soils and leaches into groundwater, but it can be bound moderately by cation-exchange reactions in acidic soils, resulting in moderate mobility (EPA 1996; IPCS 1994). Concentrations of 3-Amino-1,2,4-Triazole in a river downstream from a production plant ranged from 0.5 to 2 mg/L (IPCS 1994).

References

[1] Axelson O, Sundell L, Andersson K, Edling C, Hogstedt C, Kling H. 1980. Herbicide exposure and tumor mortality. An updated epidemiologic investigation on Swedish railroad workers. Scand J Work Environ Health. 6(1):73–79.

[2] Legras A, Skrobala D, Furet Y, Kintz P, Forveille E, Dequin PF, Perrotin D. 1996. Herbicide: Fatal ammonium thiocyanate and aminotriazole poisoning. J Toxicol Clin Toxicol. 34(4):441–446.

[3] Marston RB, Schults DW, Shiroyama T, Snyder LV. 1968. Amitrole concentrations in creek waters downstream from an aerially sprayed watershed sub-basin. Pestic Monit J. 2(3):123–128