Page 605 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

570 SECTION | VII Herbicides and Fungicides

VetBooks.ir the individual compounds. Captan, folpet and captafol glutathione levels are decreased, and renal glutathione
levels are elevated. The depletion of hepatic glutathione
have been in use for more than 55 years. These compounds
is considered a direct consequence of glutathione conjuga-
belong to the chloroalkylthiodicarboximide class of fungi-
cides due to the presence of chlorine, carbon, and sulfur in tion within the liver utilizing tissue resources. The
the side chain. Related compounds associated with this increase in renal glutathione content is more difficult to
fungicide class are dichlofluanid and tolylfluanid. These explain, but it may be a consequence of urinary excretion
two compounds have a fluorine atom substituted for one of of glutathione conjugates (Parsons, 2010).
the terminal chlorine atoms. Another compound, chlor- Captan is rapidly degraded to 1,2,3,6-tetrahydrophtha-
othalonil, which is a halogenated benzonitrile fungicide, limide (THPI) and thiophosgene (via thiocarbonyl chlo-
was first registered for use as an agrochemical in the ride) in the stomach before reaching the duodenum. THPI
United States in 1966. Chlorothalonil also has wider bio- has a half-life of 1 4 s, and thiophosgene is detoxified
cidal applications, including use in paints and lubricant via reaction with cysteine or glutathione and is rapidly
fluids. The benzimidazole fungicides, benomyl, and car- excreted. No captan is detected in blood or urine. It is
bendazim, have been in use for more than 40 years, therefore unlikely that these compounds or even thiophos-
whereas anilinopyrimidines, a new class of fungicides gene would survive long enough to reach systemic targets
(cyprodinil, mepanipyrim, and pyrimethanil), were intro- such as the liver, uterus, or testes. Due to rapid elimina-
duced in 1993 for application on cereal grains (Ollinger tion, meat, milk, or eggs from livestock/poultry would be
et al., 2010). devoid of the parent materials. Humans appear to metabo-
lize captan in a similar manner to other mammals (Krieger
and Thongsinthusak, 1993; JMPR, 2004; Gordon, 2010).
TOXICOKINETICS
Cyprodinil, an anilinopyrimidine class fungicide, is
Toxicokinetic studies provide important data on the rapidly absorbed from the GI tract into systemic circula-
amount of toxicant delivered to a target as well as tion in rats. Approximately 48% 68% of the adminis-
species-specific metabolism. Animals are exposed to fun- tered dose is excreted in the urine, whereas 29% 47% is
gicides through ingestion or they are absorbed through the found in the feces. Total excretions reach 92% 97% of
skin or the respiratory system. Different factors regulate the administered dose within 48 h. Cyprodinil is almost
their absorption, distribution, metabolism, and excretion. completely metabolized. No unchanged parent molecule
In general, the liver is the primary site for biotransforma- is found in urine, whereas minor amounts of unchanged
tion and may include detoxification as well as activation cyprodinil are found in feces. Most of the administered
reactions (Gupta, 1986). Some fungicides do not undergo cyprodinil is metabolized by sequential oxidation of the
any metabolism and bind with other active binding sites. phenyl and pyrimidine ring (Fig. 45.1). In urine and feces,
The aryl organomercurials methyl- and ethylmercury there is no difference in the metabolite patterns of the
chloride are poorly excreted and tend to accumulate in phenyl or pyrimidyl labeled cyprodinil. Seven urinary,
muscle, brain and other tissues, whereas the aryl organo- two biliary, and two fecal metabolites have been identi-
mercurial phenylmercury is more readily excreted via the fied, which in total account for 65% 80% of the adminis-
kidney and less likely to accumulate in brain and muscles. tered dose. Cyprodinil is absorbed in goats to a lesser
Similarly, HCB possesses all the properties of chemical extent and more slowly than in rats. The major route of
stability, slow degradation and biotransformation, envi- excretion is in urine and feces, whereas excretion via milk
ronmental persistence and bioaccumulation in adipose tis- is minimal. In laying hens, cyprodinil is rapidly and
sue and organs containing a high content of lipid completely eliminated. Residues in eggs and edible tis-
membranes (Costa, 2008). The newly introduced class of sues are very low. The metabolic pathways of cyprodinil
fungicides are rapidly absorbed, metabolized and excreted in lactating goats and laying hens are similar to those
and do not accumulate in tissues, but some of them are observed in rats (Waechter et al., 2010).
partially absorbed from the gastrointestinal (GI) tract. For Carbamic acid derivative fungicides, such as EBDCs,
example, absorption of chlorothalonil from the GI tract is are only partially absorbed, and then are rapidly metabo-
on the order of 30% 32% of the administered dose. At lized and excreted with no evidence of long-term bioaccu-
least 80% of the administered dose is excreted in feces mulation. Absorption of oral doses is rapid, and doses are
within 96 h. The highest concentrations are observed in excreted within 24 h with approximately half eliminated in
the kidneys—approximately 0.1% of the dose. Gut micro- the urine and half in the feces. Their common metabolite is
flora plays a role in the disposition and metabolism in ethylenethiourea (ETU). Only low-level residues are found
rats. Glutathione conjugation plays a central role in the in tissues, particularly the thyroid. Another compound in
metabolism and subsequent complex metabolic processing this class, propamocarb, is rapidly and nearly completely
of these conjugates, resulting in selective renal uptake and absorbed and distributed with a concentration reaching peak
urinary excretion of thiol-derived metabolites. Hepatic levels within 1 h. Elimination from tissues is rapid; with a