PROMETRYN

PROMETRYN

PROMETRYN 

CAS number: 7287-19-6 

Synonyms: A 1114, EINECS 230-711-3, Prometryne, Promethryne, Caparol, G 34161, Gesagard, Primatol Q, Prometrex, Selectin, 2-Methylthio-4,6-bis(isopropylamino)-s-triazine, N, N’-Bis(1-methylethyl)-6-methylthio-1,3,5-triazine-2,4-diamine. 

Molecular formula: C10H19N5S 

Chemical structure: 

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CAS number: 7287-19-6 

Synonyms: A 1114, EINECS 230-711-3, Prometryne, Promethryne, Caparol, G 34161, Gesagard, Primatol Q, Prometrex, Selectin, 2-Methylthio-4,6-bis(isopropylamino)-s-triazine, N, N’-Bis(1-methylethyl)-6-methylthio-1,3,5-triazine-2,4-diamine. 

Molecular formula: C10H19N5S 

Chemical structure: 

TLV®–TWA, 1 mg/m3, Inhalable Particulate Matter 

A4 — Not Classifiable as a Human Carcinogen  

 

TLV® Recommendation 

A TLV–TWA of 1 mg/m3 measured as inhalable particulate matter is recommended for occupational exposure to prometryn. Beagle dogs were dosed with prometryn as an 80% wettable powder in the diet for 106 weeks. The NOAEL for the study was 3.75 mg/kg per day based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy observed at the high-dose level of 37.50 mg/kg (Woodard et al, 1965 as cited in US Environmental Protection Agency (EPA) 1996). Dogs appear to be the most sensitive of the animal species tested. From a 2-generation reproductive toxicity study, a developmental NOAEL was reported to be 10 ppm (0.65 mg/kg per day). Based on a slight decreased pup weight, the LOAEL was reported to be 750 ppm (50 mg/kg per day) (Giknis and Yau 1990 as cited in US Environmental Protection Agency (EPA) 1996). The doses selected for the study may have artificially lowered the NOAEL. The true NOAEL likely lies between the reported NOAEL of 0.65 mg/kg and the LOAEL of 50 mg/kg. As a result, a NOAEL value of 3.75 mg/kg per day in the 106-week chronic toxicity study was selected as a point of departure. Assuming a 70 kg individual breathes 10m3 of air in an 8-hour workday and total absorption in the lung (rat data indicate significant metabolism and 95% recovery of dose in 7 days), a value of 26 mg/m3 is calculated. Thus, a TLV of 1 mg/m3 should be sufficient to protect against observed adverse effects in the liver, kidney, and bone marrow seen in chronic repeat dose toxicity studies in dogs as well as maternal and fetal toxicity seen in rats.   

Data is available to suggest that a Skin notation is not appropriate (dermal LD50 > 3,170 mg/kg) (Sachsse and Bathe 1976 as cited in US Environmental Protection Agency (EPA) 1996). The NOAEL in a 21-day dermal study in rabbits is > 1,000 mg/kg) (Wolf 1988 as cited in US Environmental Protection Agency (EPA) 1996). Prometryn was negative in a guinea pig maximization test (Werdig 1988 as cited in US Environmental Protection Agency (EPA) 1996) and thus a DSEN notation is not recommended. Sufficient data are not available to provide the basis for recommending RSEN or a TLV-STEL notation. An A4 cancer designation, Not Classifiable as a Human Carcinogen, is recommended based on the lack of tumorigenic activity in mice and rats following chronic oral exposures (Kundzins 1981 as cited in US Environmental Protection Agency (EPA) 1996; Chau et al, 1991 as cited in Grothusen et al. 1996). In addition, the supportive weight of evidence suggests prometryn is non-genotoxic.

TLV Basis 

Liver damage, kidney damage, bone marrow effects, and maternal and fetal toxicity. 

Chemical and Physical Properties 

Technical prometryn is a white crystalline, essentially odorless solid (PubChem 2021a; US Environmental Protection Agency (EPA) 1996) 

  • Molecular weight: 241.37. 
  • Specific gravity: 1.15 g/cc at 20 °C. 
  • Melting point: 118 °C to 120 °C. 
  • Vapor pressure: 1.24 x 10-6 torr at 25 °C. 
  • Saturated vapor concentration: 0.00163 ppm (0.0161 mg/m3) at 25 °C and 760 torr. 
  • Solubility: Soluble at 20 °C in water at 33 ppm and is readily soluble (10 to 30 g/100 mL) in the following organic solvents: acetone, dichloromethane, methanol, octanol, and toluene. 
  • Octanol/water partition coefficient: 3.51. 
  • Conversion factors at 25°C and 760 torr: 1 ppm = 9.87 mg/m3; 1 mg/m3 = 0.01 ppm. 

Major Sources of Occupational Exposure 

Prometryn is a substituted thiomethyl triazine herbicide registered for the control of several annual grasses and broadleaf weeds in terrestrial food and feed crops: cotton, celery, pigeon peas, and dill (US Environmental Protection Agency (EPA) 1996). Occupational exposure potential exists for handlers (mixers, loaders, applicators) using prometryn. There is a potential for exposure to prometryn to persons entering treated sites after the application is complete, especially if the task(s) being performed either disturbs the soil subsurface or a person comes into contact with the area to which the spray was directed (soil incorporation and lay-by treatments, respectively) (US Environmental Protection Agency (EPA) 1996). 

Animal Studies 

Acute/Subacute  

ORAL

Oral LD50 values of 1,802 and 2,076 mg/kg were reported in adult male and female rats, respectively (Kapp, 1975a as cited in US Environmental Protection Agency (EPA) 1996). No further details on these studies are available. The lethal dose of a 50% formulation for rats was 2,250 mg/kg, and signs of salivation, pawing motions, semiprostration, and weight loss were seen in treated rats. The oral LD50 in mice was 2,138 mg/kg, and respiratory depression and muscle weakness were the primary clinical signs (Hydrocarbons, organic nitrogen compounds  2001). 

DERMAL

Technical prometryn was mildly irritating to the skin of rabbits (Kapp 1975b as cited in US Environmental Protection Agency (EPA) 1996). The dermal LD50 in rats was > 3,170 mg/kg (Sachsse and Bathe 1976 as cited in US Environmental Protection Agency (EPA) 1996). 

INHALATION

In a 4-hour exposure inhalation study, the LC50 for an 80% formulation of prometryn in rats was 4.96 mg/L (Shapiro 1992 as cited in US Environmental Protection Agency (EPA) 1996). No further details on the study were available. 

SENSITIZATION

A 44.4% formulation of prometryn was negative in a guinea pig maximization test (Werdig 1988 as cited in US Environmental Protection Agency (EPA) 1996).  

OTHER STUDIES

A 95% formulation of prometryn was mildly irritating to the eyes of rabbits (Grunfeld and Hoverey-Sion 1981 as cited in US Environmental Protection Agency (EPA) 1996).  

Subchronic 

In a 28-day feeding study prometryn (purity not reported) was fed to groups of 5 male and 5 female Charles River CD-1 mice at levels of 0 ppm, 30 ppm, 100 ppm, 300 ppm, 600 ppm, 1,000 ppm, 3,000 ppm, 10,000 ppm, or 30,000 ppm (0, 4.5, 15, 45, 90, 150, 450, 1,500, or 4,500 mg/kg per day) for 28 days. All high-dose animals died by the end of week 2. Macroscopic and microscopic pathological findings in the high-dose animals were limited to the gastrointestinal tract. Clinical signs (i.e., hunched appearance, labored respiration, thinness) and marked decreases in body weights were seen in these animals. Gross findings in the small intestine were observed in some of the mice fed 10,000 ppm (1,500 mg/kg per day). However, the gross findings were not accompanied by histological effects. Clinical signs and moderate to marked decreases in body weights were also noted in these animals. There were no effects of toxicological importance in animals receiving less than 10,000 ppm (1,500 mg/kg per day). The NOAEL (males and females) was 3,000 ppm (450 mg/kg per day), while the LOAEL was 10,000 ppm (1500 mg/kg per day) based on decreased body weights (Piccirillo, 1977 as cited in US Environmental Protection Agency (EPA) 1996). 

In a 21-day dermal toxicity study, technical prometryn was applied to 5 male and 5 female New Zealand white rabbits per dose group at 0, 10, 100, or 1000 mg/kg per day, 5 days per week for 3 weeks. No local or systemic toxicity was observed at these dose levels. The systemic NOAEL was > 1000 mg/kg per day for males and females (Wolfe 1988 as cited in US Environmental Protection Agency (EPA) 1996). 

Three different doses of prometryn were given orally to mice at doses of 185, 375, and 555 mg/kg repeatedly every 48 hours over 28 days. Flow cytometry assay was conducted to record apoptotic and necrotic damage in thymocytes, splenocytes, and lymph node cells. In the spleen, significant changes in the percentage of apoptotic cells were not detected between treated and control groups, respectively. In the thymus gland and lymph node, an increase in the percentage of early apoptosis without any significant increase in necrosis was detected within the lowest dose group (185 mg/kg). Medium dose (375 mg/kg), as well as high dose, triggered an increase in late apoptosis in lymph node while in the thymus gland. Late apoptosis was increased only in animals exposed to the highest dose (555 mg/kg) (Đikić et al. 2009a) 

Chronic/Carcinogenicity  

In a 102-week feeding and oncogenicity mouse study, technical prometryn was fed to groups of 60 male and 60 female Charles River CD-1 mice at dietary levels of 0 ppm, 10 ppm, 1,000 ppm, or 3,000 ppm (0, 1.42, 142, 429 mg/kg per day) for 102 weeks and observed for signs of toxicity, including oncogenicity. Mean body weight gain in the high-dose females was lower than those of controls during the first 48 weeks of the study (statistically significant p ≤ 0.05) There was no significant effect of dosing on clinical signs, mortality, gross pathology, or histopathology. No effects were observed in males. The NOAEL was 1,000 ppm (142 mg/kg per day) for females. The LOAEL was 3,000 ppm (429 mg/kg per day) for females based on decreased body weight gain. Prometryn was not oncogenic under the conditions of the study (Kundzins 1981 as cited in US Environmental Protection Agency (EPA) 1996).  

Technical prometryn was fed to male and female Sprague-Dawley rats for 104 weeks at dietary levels of 0 ppm, 10 ppm, 100 ppm, 750 ppm, or 1,500 ppm (males: 0, 0.38, 3.90, 29.45 or 60.88 mg/kg per day, respectively; females: 0, 0.49, 4.91, 37.25, or 80.62 mg/kg per day, respectively). Decreased body weight and body weight gain were observed in high-dose males and females during the first and second years of treatment. Transient decreases (weeks 1 and 2) in food consumption in both sexes at the high dose and in males at the mid-dose were attributed to decreased palatability of the diet. An increase in the incidence of renal lesions (mineralized concretions) in high-dose males was noted. The LOAEL in males and females was 1,500 ppm, and the NOAEL was 750 ppm (29.45 mg/kg per day and 37.25 mg/kg per day in males and females, respectively). Prometryn was not oncogenic under the conditions of the study (Chau et al. 1991 as cited in US Environmental Protection Agency (EPA) 1996). 

Groups of 3 male and 3 female beagle dogs (4 months to 8 months old) were dosed in the diet for 106 weeks with prometryn 80W (80% wettable powder) as active ingredient concentrations of 0 ppm, 15 ppm, 150 ppm, or 1,500 ppm (0.0, 0.375, 3.75, or 37.50 mg/kg per day). No clinical signs or effects on body weight were observed. No changes in clinical pathology or urinalysis parameters were observed. All of the high-dose males showed slight to moderate renal tubular degeneration, including degeneration of the loops of Henle, cortical congestion, thickening of capsular basement membranes, and hypercellularity of the glomeruli. Slight bone marrow atrophy was observed in 2 of 3 high-dose males, and 1 of 3 males had a congested liver. The NOAEL was 3.75 mg/kg per day and the LOAEL was 37.5 mg/kg per day based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy (Woodard et al. 1965 as cited in US Environmental Protection Agency (EPA) 1996). 

Genotoxicity 

In an Ames Salmonella test, prometryn was negative for gene mutations up to cytotoxic solubility limits (1,000 to 2,000 µg per plate) (Lasinski et al. 1987 as cited in US Environmental Protection Agency (EPA) 1996). In an in vivo Chinese hamster bone marrow test, prometryn was negative for micronuclei when animals were dosed orally up to 5,000 mg/kg (Loos 1984 as cited in US Environmental Protection Agency (EPA) 1996). Prometryn was negative for bacterial DNA repair and gene mutation up to precipitating levels (1,000 g per plate) (Suton 1979 as cited in US Environmental Protection Agency (EPA) 1996). In an unscheduled DNA synthesis test, prometryn was negative in cultured rat hepatocytes up to cytotoxic levels (156.25 g/mL) (Bonas et al. 1984 as cited in US Environmental Protection Agency (EPA) 1996). Prometryn was negative in the Drosophila wing spot test (Kaya et al. 2000). Prometryn administered orally to mice induced DNA damage in leukocytes as measured by the alkaline single cell gel electrophoresis (Comet) assay (Đikić et al. 2009b). 

Reproductive/Developmental Toxicity 

In a rat developmental toxicity study, technical prometryn was administered by gavage to groups of 26 pregnant Sprague-Dawley rats at levels of 0, 10, 50, or 250 mg/kg per day during gestation days 6 to 15. A compound-related increased incidence of clinical signs was noted at 250 mg/kg, as was decreased body weight, body weight gain, and food consumption during the dosing period. Bodyweight was also significantly decreased (p < 0.05) at 50 mg/kg per day, but the decrease was minimal, < 5%, and therefore not of concern. The maternal NOAEL was 50 mg/kg per day and the LOEL was 250 mg/kg per day, based on salivation and decreases in body weight and food consumption. At 250 mg/kg per day, fetal body weight was significantly decreased and incomplete ossification in the sternebrae and metacarpals was observed (p < 0.05) No significant effects were noted at 50 mg/kg per day. The developmental NOAEL was 50 mg/kg per day, and the LOEL was 250 mg/kg per day (Weissenborn et al. 1987 as cited in US Environmental Protection Agency (EPA) 1996).

In a developmental toxicity study, technical prometryn was administered by gavage to pregnant New Zealand white rabbits at 0, 2, 12, or 72 mg/kg per day during gestation days 6 to 19. Decreased food consumption (10% to 36%) was observed in high-dose animals, but a corresponding decrease in body weight parameters was not observed. A slight, not significant increase in abortions was observed. No other toxicity was observed. The maternal NOAEL was 12 mg/kg per day, the LOAEL was 72 mg/kg per day based on decreased food consumption. The developmental NOAEL was 12 mg/kg per day, the LOAEL was 72 mg/kg per day based on increased fetal resorptions (US Environmental Protection Agency (EPA) 1996) 

In a 2-generation reproductive toxicity study, technical prometryn was administered in the diet to groups of 30 male and 30 female Sprague-Dawley rats at levels of 0 ppm, 10 ppm (0.6 mg/kg per day in males, 0.7 mg/kg per day in females), 750 ppm (47.8 mg/kg per day in males, 53.6 mg/kg per day in females) or 1,500 ppm (96.7 mg/kg per day in males, 105.6 mg/kg per day in females). Bodyweight gain in F0 males decreased significantly at 1,500 ppm (11% to 40%) and 750 ppm (11% to 18%). Bodyweight gain decreased in F0 females by up to 50% at 1,500 ppm and 750 ppm. Similar changes in body weight gain were seen in F1 males. Corresponding decreases in food consumption were also observed. The parental systemic toxicity NOAEL was 10 ppm. The LOAEL was 750 ppm, based on decreased food consumption, body weight, and body weight gain. Statistically significant decreases in F1 pup body weights were observed at 1,500 ppm and 750 ppm during lactation. Weight loss was small, ranging from 5% to 12%, and may have been the result of decreased maternal food consumption and maternal weight loss. A similar though less marked profile was seen in F2 generation pups. The developmental NOAEL was reported to be 10 ppm (0.65 mg/kg per day) and, based on decreased pup weight, the LOAEL was reported to be 750 ppm (50 mg/kg per day) (Giknis and Yau 1990 as cited in US Environmental Protection Agency (EPA) 1996). The doses selected for the study may have artificially lowered the NOAEL and the true NOAEL likely lies between the NOAEL of 0.65 mg/kg and the LOAEL of 50 mg/kg.  

Absorption, Distribution, Metabolism, and Excretion 

In metabolism studies, 3 groups of Crl: CD BR rats (5 males and 5 females per group) were given a single oral dose of C-prometryn. Group 1 received 0.46 to 0.47 mg/kg (Maynard, 1989 as cited in US Environmental Protection Agency (EPA) 1996; Maynard et al. 1999). Group 2 received 467 mg/kg (average). Group 3 received 0.5 mg/kg unlabeled prometryn daily for 14 days, followed by 0.46 mg/kg 14C-prometryn on day 15. An additional group, Group 4, was used for metabolite isolation and identification purposes and received 540 mg/kg C-prometryn. Data from these studies indicate that the distribution of prometryn is greatest in the blood, followed by the spleen, and finally in the lungs (the 3 highest tissues measured). Distribution was not dosage-dependent. It was extensively metabolized with < 2% of recovered 14C radioactivity representing the parent compound. Twenty-eight metabolites were identified in the urine, and 28 in the feces. Ten metabolites were identified in both urine and feces. The metabolism of prometryn was shown to occur by N-demethylation, S-oxidation, S-S dimerization, OH substitution for NH(2) and SCH(3), and conjugation with glutathione or glucuronic acid. Rat liver microsomal incubations of prometryn were conducted and compared to the in vivo metabolism. Both in vivo and in vitro phase I metabolism of prometryn was similar, with S-oxidation and N-dealkylation predominating (Maynard et al. 1999). Prometryn metabolism is catalyzed primarily by cytochrome P450 (Grothusen et al. 1996). Prometryn was excreted predominantly in the urine and feces, with slightly higher concentrations in the urine. The 7-day recovery of 14C radioactivity averaged 95% for all 14 dosing groups (Maynard 1989 as cited in US Environmental Protection Agency (EPA) 1996). 

Brain and blood prometryn levels were studied in adult male and female mice after a single oral dose (1g/kg). Prometryn was measured using the GC/MS assay at 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after prometryn administration. Peak brain and blood prometryn values were observed 1 hour after administration and they decreased in a time-dependent manner. Male mice had consistently higher brain and blood prometryn levels than female mice (Đikić et al. 2010). 

Human Studies 

No studies of human exposure to prometryn were found in the literature. 

TLV Chronology 

2020 Proposed: TLV-TWA 1 mg/m3, Inhalable Particulate Matter; A4 
2021 Adopted 

References 

  • Đikić D, Sajli L, Benković V, Knežević A, Brozović G, Lisičić D, Mojsović A, Oršolić N. 2010. Brain Toxicokinetics of Prometryne in Mice. Archives of Industrial Hygiene and Toxicology. 61(1):19-27. 
  • Đikić D, Židovec-Lepej S, Remenar A, Bendelja K, Benković V, Horvat-Knežević A, Brozović G, Oršolić N. 2009a. Effects of prometryne on apoptosis and necrosis in thymus, lymph node and spleen in mice. Environmental Toxicology and Pharmacology. 27(2):182-186. 
  • Đikić D, Židovec-Lepej S, Remenar A, Horvat-Knežević A, Benković V, Lisičić D, Sajli L, Springer O. 2009b. The effects of prometryne on subchronically treated mice evaluated by SCGE assay. Acta Biologica Hungarica. 60(1):35-43. 
  • Grothusen A, Hardt J, Bräutigam L, Lang D, Böcker R. 1996. A convenient method to discriminate between cytochrome P450 enzymes and flavin-containing monooxygenases in human liver microsomes. Arch Toxicol. 71(1-2):64-71. 
  • Hydrocarbons, organic nitrogen compounds. 2001. In: Bingham E, Cohrssen B, Powell CH, editors. Patty’s Toxicology. 5th ed. New York, NY: John Wiley & Sons. p. 1260. 
  • Kaya B, Yanikoǧlu A, Creus A, Marcos R. 2000. Genotoxicity testing of five herbicides in the Drosophila wing spot test. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 465(1):77-84. 
  • Maynard MS, Brumback D, Itterly W, Capps T, Rose R. 1999. Metabolism of [14C]Prometryn in Rats. Journal of Agricultural and Food Chemistry. 47(9):3858-3865. 
  • PubChem. 2021a. Prometryn. Bethesda, MD: National Library of Medicine. 
  • PubChem. 2021b. PubChem Identifier: CID 4929. 
  • US Environmental Protection Agency (EPA). 1996. Prometryn. In: Office of Prevention, Pesticides and Toxic Substances,, editor. Washington, DC. 

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