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DICARBOXIMIDE FUNGICIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dicarboximide fungicides are endocrine-disrupting pesticides which bind to the androgen receptor in mammals. Chemically, these fungicides are nitrogen-organic-heterocycles. They have low toxicity by ingestion and inhalation. The dicarboximide fungicides are often used in formulations with other fungicides, particularly carbamate fungicides; thus, poisonings may be a result of a combination of fungicides.
    B) This group of fungicides is considered General Use Pesticides. They are in toxicity class III - slightly toxic. The most commonly used of this group is vinclozolin.

Specific Substances

    A) CHLOZOLINATE
    1) Ethyl 3-(3,5-dichlorophenyl)-5-methyl-2,4-dioxo-5-oxazolidine carboxylate
    2) Oxazolidine-5-carboxylic acid, 3-(3,5-dichlorophenyl)-2,4-dioxo-5-methyl-, ethyl ester
    3) Dichlozolinate
    4) M 8164
    IPRODIONE
    1) 1-Imidazolidinecarboxamide, 3-(3,5-dichlorophenyl)-N-(1-methylethyl)-2,4-dioxo-
    2) 3-(3,5-dichlorophenyl)-N-(1-methylethyl)-2,4-dioxo-1- imidazolidinecarboxamide
    3) FA 2071
    4) Glycophen
    5) Glycophene
    6) Kidan
    7) LFA 2043
    8) MRC 910
    9) NRC 910
    10) Promidione
    11) ROP 500 F
    12) Rovral
    13) RP 26019
    NDPS
    1) N-(3,5-Dichlorophenyl)succinimide
    PROCYMIDONE
    1) 1,2-Cyclopropanedicarboximide,N-(3,5-dichlorophenyl)-1,2-dimethyl-
    2) Dicyclidine
    3) S 7131
    4) SP 751011
    5) Sumilex
    6) Sumisclex
    VINCLOZOLIN
    1) 2,4-Oxazolidinedione,3-(3,5-dichlorophenyl)-5-methyl-5-vinyl-
    2) BAS 352 F
    3) Ornalin
    4) Ronilan
    5) Vinchlozoline
    6) Vinclozoline
    7) Vorlan
    8) FUNGICIDES, DICARBOXIMIDE

    1.2.1) MOLECULAR FORMULA
    1) Chlozolinate: C13-H11-Cl2-N-O5
    2) Iprodione: C13-H13-Cl2-N3-O3
    3) Procymidone: C13-H11-Cl2-N-O2
    4) Vinclozolin: C12-H9-Cl2-N-O3

Available Forms Sources

    A) FORMS
    1) These fungicides are available as a wettable powder, suspension concentrate, dustable powder, smoke tablet, dry flowable, water dispersible granular, and flowable, wettable powder in water soluble bags (HSDB, 2003). Vinclozolin is a colorless or white crystalline solid with a slight aromatic odor. Iprodione is a colorless or white crystal which is odorless (HSDB, 2003).
    B) SOURCES
    1) Vinclozolin is formed synthetically by the reaction of 3,5-dichlorophenyl isocyanate with an alkyl ester of 2-hydroxy-2-vinylpropionic acid; an elevated temperature results in ring closure of the finished chemical(HSDB, 2003).
    C) USES
    1) These chemicals are agricultural, non-systemic fungicides with protective actions. They have been used for the control of several types of fungi in vines, strawberries, vegetables, fruit, ornamentals, and turf grass. They act by preventing spore germination. They have been used as a post-harvest dip, as a seed treatment, or as a dip or spray at planting (HSDB, 2003). Vinclozolin is registered in the United States and Europe for use on agricultural crops (Wong et al, 1995).
    2) Vinclozolin was originally developed to inhibit the production of a fungal steroid, ergosterol (Flynn et al, 2001). This group of fungicides is active against zygomycetes, deuteromycetes, ascomycetes and basidiomycetes; low toxicity is shown against oomycetes and yeasts. Dicarboximides have been used in the control of gray mold of grape and protected vegetable and ornamental crops caused by Botrytis cinerea, and the control of brown rot of fruit due to Monilinia spp. The mechanism of action of these fungicides includes inhibition of spore germination and mycelial growth, inducing leakage of pool metabolites, and causing distortion, bursting, and lysis of cells (Cabral & Cabral, 2000).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dicarboximide fungicides are used as seed treatments and as protectants against mildew, late blight, and other plant diseases. They are endocrine-disrupting pesticides which bind to the androgen receptor in mammals.
    B) TOXICOLOGY: Unknown.
    C) EPIDEMIOLOGY: This is a very uncommon poison with only a handful of cases reported in the literature. Large overdoses produce mild to moderate symptoms with no confirmed fatalities reported in the literature.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Acute toxicity is low or unlikely following acute ingestion and inhalation exposure. Chronic exposure to high doses may result in anti-androgenic effects, similar to those caused by flutamide, although no human cases have yet been reported. All information about overdose is based on a few case reports. One reported dermal exposure produced symptoms of vomiting and diarrhea. In animal studies, in utero exposure to large doses of dicarboximide fungicides is associated with hypospadias and alterations in sexual differentiation of androgen-dependent tissues. The relevance of this finding to human exposure is unknown.
    0.2.20) REPRODUCTIVE
    A) Due to the mechanism of action of endocrine disruptors, it is expected that toxic human exposures could result in antiandrogenic alterations in the reproductive system. Prenatal exposure may be responsible for reductions in human sperm counts and increased incidences of hypospadias, and undescended testes.
    B) These chemicals are harmful to the developing rodent fetus, producing malformations; in contrast, fertility in adult male rats is unaffected after prolonged high-dose exposure (100 mg/kg/day for 25 weeks) of vinclozolin.
    0.2.21) CARCINOGENICITY
    A) Vinclozolin has been classified by the EPA as a Group C chemical, a possible human carcinogen (Flynn et al, 2001).

Laboratory Monitoring

    A) Dicarboximide fungicide plasma levels are not clinically useful or readily available.
    B) Monitor vital signs and mental status following a significant exposure.
    C) Monitor CBC and liver function tests after a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occurs following ingestion of a pesticide formulation, monitor fluid and electrolyte levels.
    E) Women of reproductive potential with a significant exposure to dicarboximide fungicides should have a pregnancy test.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with mild to moderate exposure, through either dermal or oral exposure, are usually asymptomatic. Given the self-limiting and nonlethal effects of overdose, basic supportive care is all that is required. According to case reports any symptoms abate within 6 hours.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity has not been reported from this exposure.
    C) DECONTAMINATION
    1) PREHOSPITAL and/or HOSPITAL: No oral decontamination is indicated. For accidental ingestions in children, rinsing the mouth and dilution with a few sips of water should be sufficient. DERMAL EXPOSURE: Decontaminate with soap and water. EYE EXPOSURE: Rinse with copious amounts of normal saline.
    D) AIRWAY MANAGEMENT
    1) There has never been a report of a patient needing an advanced airway due to the exposure of this chemical. Consequently, airway compromise is not expected.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Symptoms are self-limiting. There has never been a report of a patient needing enhanced elimination.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults can be managed at home. Asymptomatic children with accidental exposures can probably be managed safely at home with telephone follow-up. Any patient with an altered mental status, weakness or syncope should be evaluated at a healthcare facility.
    2) OBSERVATION CRITERIA: A patient with vomiting and diarrhea should be evaluated at a healthcare facility and observed until symptoms are stable or improving.
    3) ADMISSION CRITERIA: If patients have electrolyte abnormalities, ataxia, or other symptoms that prevent them from accomplishing their normal activities, they should be admitted to a medical floor.
    4) CONSULT CRITERIA: Consult a perinatology specialist or a reproductive toxicology expert for a pregnant woman with a significant exposure to dicarboximide fungicides. If patients develop respiratory failure, hemodynamic instability, hepatitis, electrolyte abnormalities, or any other symptoms not expected with this exposure, consult a toxicologist or poison center. The National Pesticide Telecommunications Network (NPIC) provides consultation to poison centers and other health professionals for the management of pesticide poisoning. Calls will be transferred to the Oregon Poison Center in Portland, Oregon for all emergency cases requiring immediate medical response. The National Pesticide Telecommunications Network has a toll-free number, 1-800-858-7378, or they may be contacted via the internet at npic@ace.orst.edu.
    H) PITFALLS
    1) Common errors for managing these patients include failing to recognize a second agent that might be toxic or failing to identify other similar presenting medical conditions.
    I) DIFFERENTIAL DIAGNOSIS
    1) Patients exposed can be easily confused with gastroenteritis effects or other gastrointestinal tract irritants.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Toxic levels for humans have not been established. No human exposure cases have yet been reported.

Clinical Effects

Summary Of Exposure

    A) USES: Dicarboximide fungicides are used as seed treatments and as protectants against mildew, late blight, and other plant diseases. They are endocrine-disrupting pesticides which bind to the androgen receptor in mammals.
    B) TOXICOLOGY: Unknown.
    C) EPIDEMIOLOGY: This is a very uncommon poison with only a handful of cases reported in the literature. Large overdoses produce mild to moderate symptoms with no confirmed fatalities reported in the literature.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Acute toxicity is low or unlikely following acute ingestion and inhalation exposure. Chronic exposure to high doses may result in anti-androgenic effects, similar to those caused by flutamide, although no human cases have yet been reported. All information about overdose is based on a few case reports. One reported dermal exposure produced symptoms of vomiting and diarrhea. In animal studies, in utero exposure to large doses of dicarboximide fungicides is associated with hypospadias and alterations in sexual differentiation of androgen-dependent tissues. The relevance of this finding to human exposure is unknown.

Heent

    3.4.3) EYES
    A) Rats have developed cataracts. No effects have been reported in humans.
    B) ANIMAL STUDIES
    1) Cataracts have been reported in subchronic and chronic vinclozolin feeding studies in rats, but not in other animal species. No ocular effects have been reported in humans (Zober et al, 1995).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) Dicarboximide fungicides are mild mucous membrane irritants and may cause nasal irritation following contact (HSDB, 2003).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) This group of fungicides is considered mild mucous membrane irritants. Contact may result in throat irritation (HSDB, 2003).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER FINDING
    1) LACK OF EFFECT: No evidence of liver injury has been found in personnel following exposure to vinclozolin during synthesis and formulation operations. Increased liver weight was found in experimental animals during subchronic and chronic vinclozolin feeding studies (Zober et al, 1995).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INCREASED HORMONAL ACTIVITY
    1) WITH POISONING/EXPOSURE
    a) Reversible hypergonadism may theoretically occur following prolonged, significant exposures. Because flutamide, a nonsteroidal antiandrogen drug with similarity to the dicarboximide fungicides in structure and biological activity, is known to cause an elevation of serum LH and a slight elevation of testosterone in humans, it is expected that these fungicides may also cause a similar effect. Animal studies have demonstrated hypergonadism following chronic exposures, which was reversible on discontinuation of exposure. There have been no reports indicating that flutamide causes testicular interstitial cell tumor induction in humans and these fungicides are not expected to do this either (Murakami et al, 1995; Hosokawa et al, 1993; Hosokawa et al, 1993a).
    B) UROGENITAL FINDING
    1) WITH POISONING/EXPOSURE
    a) LACK OF EFFECT: No evidence of prostate changes has been found in personnel following exposure to vinclozolin during synthesis and formulation operations. Increased testes weight and decreased prostate, seminal vesicle, and epididymides weights were reported in experimental animals during subchronic and chronic vinclozolin feeding studies (Zober et al, 1995). Further study is warranted of the possible male reproductive effects of these fungicides.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Acute tubular necrosis
    a) A comparative rat study of the acute nephrotoxic potential of 3 dicarboximide fungicides (NDPS, vinclozolin, and iprodione) was reported. Rats were each administered one intraperitoneal injection of a fungicide (0.4 or 1.0 mmol/kg) or a sesame oil vehicle. Characteristic renal effects noted in the NDPS-treated rats included marked diuresis, increased proteinuria, elevated BUN, decreased organic ion accumulation by renal cortical slices and proximal tubular necrosis. Only minor or no renal alterations were noted in the iprodione- and vinclozolin-treated rats. NDPS induces nephrotoxicity via one or more of its metabolites. NDPS was developed in Japan, but its use has been limited due to its potential health hazards (Rankin et al, 1989).
    2) Increased hormonal activity
    a) Animal studies (rats and mice) have clearly demonstrated hypergonadotropism, with elevations in serum and/or organ LH and testosterone, following chronic oral dosing (within 2 weeks) with dicarboximide fungicides. Hypergonadotropism was shown to be a reversible effect. No lesions in gonadal systems were seen on histopathologic examinations. These chemicals react similarly to flutamide, a drug with antiandrogenic activity (Murakami et al, 1995; Hosokawa et al, 1993; Hosokawa et al, 1993a).
    b) When vinclozolin was administered by dermal application (100 mg/kg/day for 5 days per week) to rabbits during male adolescence (during third and fourth month of life), it was reported that the exposed animals had a smaller weight gain. At maturity, the accessory sex glands weighed less than control animals and the pooled sperm count of exposed animals was significantly higher than unexposed animals. It was speculated that vinclozolin blocked the negative feedback mechanism of testosterone on the hypothalamus or pituitary gland, thus allowing for increased gonadotropin release and increasing sperm production (Moorman et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) No evidence of hemolytic anemia has been found in personnel following exposure to vinclozolin during synthesis and formulation operations. Hemolytic anemia has been reported in subchronic and chronic feeding studies in animals (Zober et al, 1995).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Hemolytic anemia
    a) In subchronic and chronic vinclozolin feeding studies in rats, mice, and dogs, signs of hemolytic anemia were reported (Zober et al, 1995).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) These fungicides are moderate skin irritants (HSDB, 2003).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HORMONE LEVEL - FINDING
    1) WITH POISONING/EXPOSURE
    a) Abnormal hormonal profiles may theoretically occur in men and women following prolonged toxic exposures to dicarboximide fungicides (antiandrogenic agents). In men, hormonal changes could include: decreased spermatogenesis, increased luteinizing hormone, follicle stimulating hormone, and testosterone concentrations, decreased testicular size, or gynecomastia. In women, an increase in sex hormone binding globulin and follicle stimulating hormone, an increase in testosterone levels, gynecomastia, galactorrhea and breast tenderness could theoretically occur due to the mechanism of toxicity of these fungicides.
    b) One study found no evidence of any antiandrogenic effects due to vinclozolin in a cross sectional study of 67 men exposed to vinclozolin for one to 13 years during synthesis and formulation operations. However, their follicle stimulating hormone (FSH) concentrations were significantly higher than those of controls (P=0.004)(Zober et al, 1995). Further study is warranted of the possible male reproductive effects of these fungicides.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Hormone level - finding
    a) Subchronic and chronic vinclozolin feeding studies in rats, mice and dogs revealed changes related to antiandrogenic effects, namely increased testes weight and decreased prostate, seminal vesicle, and epididymides weights (Zober et al, 1995).
    2) Decreased thyroxine level
    a) In a thyroid function study of vinclozolin administered to cotton rats for 90 to 100 days, only the higher dosage (up to 610 mg/kg/day) resulted in a significant decrease (25%) in thyroid hormone concentration (T3 and T4). However, this was compensated for by an increase in thyroxine turnover so the thyroxine utilization rate was not different. No difference between treated or untreated animals was noted in any of the metabolic parameters measured (Tomasi et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Due to the mechanism of action of endocrine disruptors, it is expected that toxic human exposures could result in antiandrogenic alterations in the reproductive system. Prenatal exposure may be responsible for reductions in human sperm counts and increased incidences of hypospadias, and undescended testes.
    B) These chemicals are harmful to the developing rodent fetus, producing malformations; in contrast, fertility in adult male rats is unaffected after prolonged high-dose exposure (100 mg/kg/day for 25 weeks) of vinclozolin.
    3.20.2) TERATOGENICITY
    A) ENDOCRINE DISORDER
    1) It is speculated that perinatal exposure to sufficient levels of antiandrogenic environmental chemicals could result in reductions in human sperm counts and increased incidences of hypospadias, and undescended testes as well as other anti-androgen effects (Ostby et al, 1999; Gray, 1998; James , 1997; Kelce & Wilson, 1997). It is possible that environmental antiandrogens could cause male pseudohermaphroditism (incomplete masculinization of the male fetus) to varying degrees dependent on time of exposure and potency of the chemical.
    B) ANIMAL STUDIES
    1) ENDOCRINE DISORDER
    a) VINCLOZOLIN - Administration of vinclozolin to late pregnant and early lactating rat dams at 100 to 200mg/kg/day results in antiandrogenic effects in male pups characterized by reduced anogenital distance, nipple development, cleft phallus, hypospadias, ectopic testes, and a vaginal pouch (Gray et al, 2001; Hellwig et al, 2000; Wolf et al, 2000; Gray et al, 1994; Gray et al, 1993). Isolated inflammation-related deaths due to pyelonephritis were also reported (Hellwig et al, 2000). The doses used were not overtly toxic to the dam and did not impair pup survival. With sexual maturity, exposed males mounted but did not often accomplish intromission (Gray et al, 1994). Social play, which is perinatally organized by androgens, was affected in neonatal male rats given vinclozolin, with social play being significantly reduced (Hotchkiss et al, 2002).
    1) A dose-response to vinclozolin has been shown on reproductive development in experimental rats. Varying doses (from 3 to 100 mg/kg/day) administered during sexual differentiation (GD 14 to day 3 of lactation) resulted in dose-dependent alterations of numerous androgen-dependent tissues. At relatively low dosages, a reduction in male rat anogenital distance and induction of areolas was noted. In the mid dosage range, hypospadias, agenesis of the sex accessory tissues and retained nipples were noted. At the highest dosages, undescended testes and epididymal agenesis were seen (Gray et al, 2001).
    2) The mechanism of toxicity appears to be antagonism at the androgen receptor by vinclozolin metabolites (Kelce et al, 1994), and does not appear to involve interference with the androgenic activity of epidermal growth factor or inhibition of 5 alpha-reductase (Wolf et al, 1999; Gray et al, 1993). Female pups with exposure during late gestation and early lactation showed transient alterations in anogenital distance at maternal doses of up to 200 mg/kg/day but no effects on puberty or fertility (Gray et al, 1994).
    b) IPRODIONE and CHLOZOLINATE- When evaluated for possible adverse endocrine effects during development, neither iprodione nor chlozolinate produced any signs of maternal or fetal endocrine toxicity at 100 mg/kg/day (Wolf et al, 1999).
    c) PROCYMIDONE - At exposures of 100 mg/kg/day, procymidone produced demasculinization and feminization of male rat offspring, similar to that seen following vinclozolin dosing. Male offspring displayed reduced anogenital distance, areolas, permanent nipples, reduced sex accessory gland size, and hypospadias with a vaginal pouch (Wolf et al, 1999). Other investigators have replicated these results in male rat studies with doses up to 200 mg/kg/day (Ostby et al, 1999). Malformations reported include hypospadia, cleft phallus, exposed os penis, vaginal pouch, hydronephrosis, occasional hydroureter, epididymal granulomas, and ectopic, undescended testes.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) VINCLOZOLIN - At oral doses of 200 mg/kg/day to rats throughout pregnancy, the pregnancy was not affected by the treatment. Food consumption and body weight gain were reduced only during lactation (Hellwig et al, 2000).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS72391-46-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS36734-19-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Vinclozolin has been classified by the EPA as a Group C chemical, a possible human carcinogen (Flynn et al, 2001).
    3.21.3) HUMAN STUDIES
    A) TESTIS NEOPLASM MALIGNANT
    1) It has been proposed that increases in human testicular cancers and hypospadias, as well as a reported decline in human sperm counts, may be due to exposures to endocrine disruptor fungicides. This has not yet been substantiated in human studies (Gray et al, 2001; Gray, 1998).
    2) Because flutamide, a nonsteroidal antiandrogen drug with similarity to the dicarboximide fungicides in structure and biological activity, has not caused testicular testicular interstitial cell tumor induction in humans following chronic therapy, the dicarboximide fungicides are not expected to cause this effect either (Murakami et al, 1995).
    B) BREAST CARCINOMA
    1) Although not substantiated by any studies or statistics, it may theoretically be possible for environmental antiandrogens to exacerbate breast cancer among females. Antiandrogens may interfere with normal androgen-induced growth suppression leading to hypertrophy. Androgen receptor is expressed in about 85% of breast cancers, with androgen therapy benefiting 20% to 50% of these patients. Studies are warranted of the possible carcinoma effects of these fungicides (Kelce & Wilson, 1997).
    3.21.4) ANIMAL STUDIES
    A) TESTIS DISORDER
    1) In rat and mouse studies, rats appeared to be uniquely sensitive to procymidone's hormonally mediated effect on testicular Leydig cell tumors, with hypergonadotropism associated with an increase of interstitial cell response. A sustained response of the Leydig cells to stimulation resulted in chronic hyperplasia and subsequent benign tumor formation only in the rat. This is not expected to occur in humans since humans do not appear to respond to elevated levels of gonadotropins with the production of interstitial cell tumors (Murakami et al, 1995; Hosokawa et al, 1993a).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Dicarboximide fungicide plasma levels are not clinically useful or readily available.
    B) Monitor vital signs and mental status following a significant exposure.
    C) Monitor CBC and liver function tests after a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occurs following ingestion of a pesticide formulation, monitor fluid and electrolyte levels.
    E) Women of reproductive potential with a significant exposure to dicarboximide fungicides should have a pregnancy test.
    4.1.2) SERUM/BLOOD
    A) Monitor CBC and liver function tests after significant exposures or in symptomatic patients.
    B) Monitor fluid and electrolyte levels if severe vomiting and/or diarrhea occurs.
    4.1.3) URINE
    A) Biomonitoring for all dicarboximide fungicide exposures in the workplace is based on determination of urinary metabolites containing a 3,5-dichloroaniline (3,5-DCA) moiety. 3,5-DCA is a marker for exposure to these fungicides. Urine samples were collected before the end of the work shift. Analytical detection of urinary metabolites containing a 3,5-DCA moiety has been accomplished by high performance liquid chromatography (HPLC). This method detected concentrations down to about 5 mcg/liter of urine (Zober et al, 1995). Other methods for determining dichloroanilines in urine include GC-MS, GC-MS-MS, and GC-ECD (Wittke et al, 2001).
    B) It has been suggested that androgen disruption in humans can be assessed noninvasively by assay of urine samples once a pertinent ratio of androgen-dependent 6 alpha- and 15 alpha-hydroxylase activities has been established. The 6 alpha- and 15 alpha-hydroxylase ratio is a biomarker of androgen disruption. In mice, treatment with vinclozolin significantly increased the 6alpha/15alpha-hydroxylase ratio as serum testosterone levels decreased. However, the hydroxylase ratio was much less variable and more sensitive than serum testosterone levels (Wilson et al, 1999).

Methods

    A) CHROMATOGRAPHY
    1) Gas chromatography with electron capture detection and tandem mass spectrometry method was developed for the analysis of vinclozolin in human serum. The limit of quantification was 0.161 and 1.5 mcg/liter, respectively, using the GC-ECD and GC-MS-MS method (Moreno-Frias et al, 2001).
    2) A high performance liquid chromatography (HPLC) method combined with UV spectrophotometry was described for the analysis of vinclozolin and its two metabolites in rat serum (Kelce et al, 1994).
    3) A HPLC with diode array detection method was described for the quantitation of procymidone and iprodione in groundwater and soil samples (Martinez-Galera et al, 1997).
    4) An analytical method using gas chromatography-mass spectrometry and whole body dosimetry was described for assessing potential dermal exposure to procymidone. The limit of detection for procymidone was 4 mcg while the limit of quantification was 13 mcg (Egea-Gonzalez et al, 1999a).
    B) IMMUNOASSAY
    1) A competitive assay which was has been described similar to a radioimmunoassay/enzyme linked immunosorbent assay (RIA/ELISA), with the exception that the capture antibody was substituted by sex hormone-binding globulin (SHBG) from human pregnancy serum. This assay was developed for the purpose of determining potential estrogenic effects of environmental pollutants at the level of binding proteins in blood. It was found that the endocrine disruptor, vinclozolin, showed moderate displacement of tritiated estradiol, indicating an affinity for SHBG and, consequently, an estrogenic activity (Meulenberg, 2002).
    C) SAMPLING
    1) An analytical method based on personal air sampling and use of solid sorbents (connected to personal samplers) has been described for measuring vinclozolin and procymidone in greenhouse air for potential inhalation exposure of applicators and re-entry workers (Egea-Gonzalez et al, 1999; Egea-Gonzalez et al, 1997). The selected sorbent, polyurethane foam, was used with the personal samplers, with GC-ECD analysis and MS confirmation of the chemicals.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) If patients have electrolyte abnormalities, ataxia, or other symptoms that prevent them from accomplishing their normal activities, they should be admitted to a medical floor.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults can be managed at home. Asymptomatic children with accidental exposures can probably be managed safely at home with telephone follow-up. Any patient with an altered mental status, weakness or syncope should be evaluated at a healthcare facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a perinatology specialist or a reproductive toxicology expert for a pregnant woman with a significant exposure to dicarboximide fungicides. If patients develop respiratory failure, hemodynamic instability, hepatitis, electrolyte abnormalities, or any other symptoms not expected with this exposure, consult a toxicologist or poison center.
    B) The National Pesticide Telecommunications Network (NPIC) provides consultation to poison centers and other health professionals for the management of pesticide poisoning. Calls will be transferred to the Oregon Poison Center in Portland, Oregon for all emergency cases requiring immediate medical response. The National Pesticide Telecommunications Network has a toll-free number, 1-800-858-7378, or they may be contacted via the internet at npic@ace.orst.edu.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) A patient with vomiting and diarrhea should be evaluated at a healthcare facility and observed until symptoms are stable or improving.

Monitoring

    A) Dicarboximide fungicide plasma levels are not clinically useful or readily available.
    B) Monitor vital signs and mental status following a significant exposure.
    C) Monitor CBC and liver function tests after a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occurs following ingestion of a pesticide formulation, monitor fluid and electrolyte levels.
    E) Women of reproductive potential with a significant exposure to dicarboximide fungicides should have a pregnancy test.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Exposure to dicarboximide fungicides is generally NOT expected to result in significant toxicity. Gastrointestinal decontamination should only be needed after large ingestions. For accidental ingestions in children rinsing the mouth and dilution with a few sips of water should be sufficient.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Exposure to dicarboximide fungicides is generally NOT expected to result in significant toxicity. Gastrointestinal decontamination should only be needed after large ingestions. For accidental ingestions in children, rinsing the mouth, washing exposed skin and dilution with a few sips of water should be sufficient.
    B) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Patients with mild to moderate exposure, through either dermal or oral exposure, are usually asymptomatic. Given the self-limiting and nonlethal effects of overdose, basic supportive care is all that is required. According to case reports any symptoms abate within 6 hours. Dicarboximide fungicides are of low order toxicity in mammals. Insecticide formulations may also contain surfactants, solvents, or other ingredients which may be more toxic than the dicarboximide itself. It is important to elucidate which other toxic substances may be involved and treat accordingly.
    2) MANAGEMENT OF SEVERE TOXICITY: Severe toxicity has not been reported from this exposure. Following a massive ingestion, antiandrogen effects may occur.
    B) DILUTION
    1) Irrigate the mouth with water rinses.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    C) ENDOSCOPIC PROCEDURE
    1) Consider endoscopy in patients with signs or symptoms of mucous membrane irritation following ingestion of formulations containing corrosive solvents.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

Range Of Toxicity

Summary

    A) TOXICITY: Toxic levels for humans have not been established. No human exposure cases have yet been reported.

Maximum Tolerated Exposure

    A) SUMMARY
    1) Dicarboximides are considered one of the safest pesticides (Meister, 2012).
    B) ADULT
    1) IPRODIONE
    a) The ADI (acceptable daily intake), reported by WHO, is 0.2 mg/kg body weight for iprodione (Lu, 1995).
    2) PROCYMIDONE
    a) The ADI (acceptable daily intake), reported by WHO, is 0.1 mg/kg body weight for procymidone (Lu, 1995).
    3) VINCLOZOLIN
    a) Exposure guidelines: RfD: 25 mg/kg/day. This is approximately equivalent to 260 mcg/L in urine of 3,5-dichloroaniline (3,5-DCA).
    b) The ADI (acceptable daily intake), reported by WHO, is 0.07 mg/kg body weight for vinclozolin (Lu, 1995).
    c) In developmental toxicity studies, a no observable adverse effects level (NOAEL) in rats given oral doses is reported as 2.5 mg/kg body weight/day (Zober et al, 1995).
    d) In developmental toxicity studies, the lowest observable adverse effect level (LOAEL) in rats given oral doses is reported as 50 mg/kg of body weight/day. Antiandrogenic effects were the most sensitive changes seen in these studies (Zober et al, 1995).
    e) When vinclozolin is used on food crops with human exposure, it is estimated that approximately 2 mcg/kg/day may be ingested (Flynn et al, 2001). Occupational exposure is expected to be much greater.

Workplace Standards

    A) ACGIH TLV Values for CAS72391-46-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS36734-19-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS72391-46-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS36734-19-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS72391-46-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS36734-19-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Iprodione
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS72391-46-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS36734-19-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CHLOZOLINATE
    1) LD50- (ORAL)MOUSE:
    a) Greater than 10 g/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) Greater than 4500 mg/kg (RTECS, 2003)
    3) LD50- (SKIN)RAT:
    a) 5 g/kg (RTECS, 2003)
    B) IPRODIONE
    1) LD50- (ORAL)MOUSE:
    a) 4 g/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 3500 mg/kg (RTECS, 2003)
    C) PROCYMIDONE
    1) LD50- (ORAL)MOUSE:
    a) 7800 mg/kg (RTECS, 2003)
    2) LD50- (SKIN)MOUSE:
    a) 7800 mg/kg (RTECS, 2003)
    3) LD50- (ORAL)RAT:
    a) 7 g/kg (RTECS, 2003)
    4) LD50- (SKIN)RAT:
    a) Greater than 2500 mg/kg (RTECS, 2003)
    D) VINCLOZOLIN
    1) LD50- (ORAL)MOUSE:
    a) Greater than 10 g/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 10 g/kg (RTECS, 2003)
    3) LD50- (SKIN)RAT:
    a) Greater than 2 g/kg (RTECS, 2003)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The dicarboximide fungicides have been found to bind human androgen receptors and block androgen-induced gene expression in vitro and in vivo. These fungicides exhibit low to moderate affinity for androgen receptors and act as type I antagonists, preventing androgen receptor DNA binding (Gray, 1998; Kelce & Wilson, 1997; Hosokawa et al, 1993). It was found that the endocrine disruptor, vinclozolin, showed moderate displacement of tritiated estradiol in human serum, indicating an affinity for SHBG and, consequently, an estrogenic activity in a competitive assay, designed similar to a RIA/ELISA. Disturbances in the equilibrium between bound and free steroid hormones may result in clinical symptoms and diseases (Meulenberg, 2002). Procymidone appears to have about half the potency of vinclozolin in in vivo studies of animal prostate androgen-receptor binding and induction of malformations (Kavlock, 2001; Ostby et al, 1999). Procymidone has been shown to have a relative binding affinity to androgen receptors that is of the same order as that of flutamide in rats and mice (Hosokawa et al, 1993).
    B) The mechanism of toxicity, in reproductive animal studies, appears to be antagonism at the androgen receptor by vinclozolin metabolites (Kelce et al, 1994); it does not appear to involve interference with the androgenic activity of epidermal growth factor nor is it due to an inhibition of 5 alpha-reductase (Wolf et al, 1999; Kelce et al, 1994). Competition of vinclozolin with androgen for binding to the androgen receptor is very weak. However, binding of its metabolites, M1 and M2, to the androgen receptor is 10 and 100 times more effective than vinclozolin, respectively. This would suggest that detrimental effects of significant human exposures to vinclozolin are mediated via the formation of the antiandrogenic metabolites, M1 and M2 (Wong et al, 1995; Kelce et al, 1994).

Physicochemical

Physical Characteristics

    A) Iprodione is a colorless or white crystalline solid, which is odorless. It is soluble in water (13.9 mg/liter at 25 degrees C), ethanol, methanol, acetone, dichloromethane and dimethylformamide (HSDB, 2003).
    B) Vinclozolin is a colorless or white crystalline solid at room temperature, with a slight aromatic odor. It is almost insoluble in water, but is readily soluble in most organic solvents (HSDB, 2003; Zober et al, 1995).

Ph

    A) Vinclozolin: pH 6.5 in water at 22 degrees Centigrade (Zober et al, 1995)

Molecular Weight

    1) Chlozolinate: 332.15
    2) Iprodione: 330.17
    3) Procymidone: 284.15
    4) Vinclozolin: 286.12

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