Toxicology Testing

The potential for EBDCs and EBDC-containing formulations to cause adverse health effects has been extensively examined in approved regulatory studies using laboratory animals.

Toxicity testing in animals is performed with the active ingredient and with formulations. Animal studies often involve use of exaggerated doses to fully explore toxic potential.

Acute Toxicity
Short-term (acute) exposure studies are mainly intended to determine the harmful effects that could occur due to an accident, misuse or deliberate ingestion of a large quantity of the product (e.g., suicide attempt). They may also attempt to predict the likelihood of skin and eye irritation and skin sensitization or developmental effects.

Mancozeb has very low acute toxicity by the oral, dermal, and respiratory routes. The World Health Organization (WHO) has classified mancozeb as unlikely to present an acute exposure hazard under conditions of normal use (WHO, 1994). Mancozeb is not irritating to skin on initial contact and only slightly irritating to eyes and mucous membranes; EPA does not classify mancozeb as  a sensitizer.

Absorption, Distribution, Metabolism and Excretion
Studies of the pharmacokinetics and metabolism of mancozeb and other EBDCs in laboratory animals have indicated that the EBDCs are only partially absorbed, then rapidly metabolized and excreted with no evidence of long-term bioaccumulation. Absorption of oral doses is rapid. Only low level residues are found in tissues, principally in the thyroid. ETU is the major metabolite. On average 7.5 percent of an EBDC dose administered is metabolized to ETU on a weight basis.

Genotoxicity
Few materials have been tested for genotoxic potential as extensively as mancozeb and ETU.

A “weight of the evidence” evaluation of the scientifically valid studies shows that, when properly* tested in higher organism test systems, mancozeb and ETU are not mutagenic in the two major endpoints used to assess genotoxicity, gene mutations and chromosomal damage. Further, mancozeb and ETU do not cause adverse effects in ancillary tests of genotoxic damage. Thus, the weight of the evidence indicates that mancozeb and ETU are not mutagenic in mammalian systems.

Short and Long Term Toxicity
The principal target organ upon repeated exposure to all of the EBDCs is the thyroid, which is also the principal target organ of ETU. For example, EBDCs and ETU altered thyroid hormone levels and/or weights at the lowest affected dose after three months of dietary feeding in rats. Most of the other organs affected, such as the liver at generally higher doses or red blood cells usually in dogs, are also common to ETU. Prolonged dietary feeding of ETU produces thyroid and pituitary tumors in rats and mice, and liver tumors in mice.

As normally occurs with toxicological effects due to formation of a metabolite, the long term toxicity of mancozeb is  not as severe as ETU itself. When mancozeb is administered, much higher doses are required to produce adverse effects, and the effects themselves are generally not as pronounced, or may be precluded altogether by high dose limitations.

Cancer Classification
The EBDCs are classified by the U.S. Environmental Protection Agency (EPA) as “likely” human carcinogens (B2) on the basis of the mouse liver tumors and the rodent thyroid tumors observed in chronic ETU studies. In contrast, the International Agency for Research on Cancer (IARC) of the WHO has concluded that ETU is not classifiable as to its carcinogenicity to humans (Group 3) and that evidence from epidemiological studies and from toxicological studies in experimental animals provide compelling evidence that rodents are substantially more sensitive than humans to the development of thyroid tumors in response to thyroid hormone imbalance.

Reproduction and Development
Reproductive outcome is generally unaffected by exposure to mancozeb or ETU. EPA has concluded that mancozeb is not a reproductive toxicant.  EPA did assign an acute reference dose based on the rat developmental study, with a No Observed Adverse Effect Level of 128 mg/kg/day.  However, the developmental effects were only seen in rats at doses that were severely toxic to the mother and in accordance with conventional interpretation of developmental findings, mancozeb is not considered to be a developmental toxicant.

*Care must be taken in evaluating genotoxicity studies since the standard solvent used in these assays is dimethylsulfoxide (DMSO). EBDCs rapidly degrade in DMSO creating liberation of metal ions that would not normally be observed under normal physiological conditions. EBDC studies in which DMSO has been used as a solvent are invalid.

Text Adapted from Hurt, S., Ollinger, J., Arce, G., Bui, Q., Tobia, A.J., and B. van Ravenswaay. 2001. Dialkyldithiocarbamates (EBDCs). in Krieger, R., Doull, J., Ecobichon, D., Gammon, D., Hodgson, E., Reiter, L., and J. Ross. Handbook of Pesticide Toxicology Agents: Second Edition. Academic Press, NY. pp 1759-1779..

References
WHO 1994. Mancozeb TA:Pesticide residues in food - 1993. Toxicology evaluations PG:258-89.