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Description of key information

A basic toxicokinetics literature search and assessment was performed for the toxicokinetics profile of Monuron (given below in additional information and as attachment to this record). This includes absorption and distribution, metabolism, excretion and enzyme induction properties. Monuron-related compounds are well absorbed via both the gastrointestinal and respiratory tract

(considered at 100% absorption from conservative viewpoint), whereas dermal absorption is lower (considered at 50% absorption from conservative viewpoint). Based on the experimental results of phase I (mainly by oxidative N-demethylation and aromatic hydroxylation) and phase II (conjugation to D-glucoside, glucuronides or ester sulfates) metabolic reactions, Monuron is excreted mainly as water soluble metabolites in the urine and no bioaccummulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

A literature search was performed for the toxicokinetics profile of Monuron. Summarized information was available in the Initial scientific and miniectonomic review of monuron (US EPA, 1975), which served as a starting document to collect further information.

 

Absorption and distribution

·       Monuron is absorbed after oral exposure. After administration of 17 mg/kg for 60 days or 0.1-20.0 mg/ kg for 6 months, monuron-related compounds were found mostly in the lungs with decreasing amounts in the heart, liver,brain, and kidneys (IARC, 1976).

·     Monuron-related compounds are well absorbed via both the gastrointestinal and respiratory tracts; however, it is not known whether they are also absorbed from the skin (Wang et al, 1993).

 

Metabolism

·       In a study on the metabolic fate of urea herbicides, rats were each fed 4.8 g of monuron in 8 days; the urine was then collected and analyzed. The analyses determined that the majority of the metabolites retained the urea structure and that the chief pathway was a step-by- step demethylation, with a minor step leading to hydroxylation of the benzene nucleus. Monuron and its corresponding dechlorinated analog were the only urea herbicides of those studied in which a total demethylation occurred without simultaneous hydroxylation (Ernst, 1969). The metabolic pathways proposed for monuron included following metabolites: (I) N-(4-chlorophenyl) methyl urea, (II) N-(4-chlorophenyl) urea, (III) N-(2-hydroxy-4- chlorophenyl) urea, (IV) N-(3-hydroxy-4- chlorophenyl) -urea.

·       From the results of their studies, Geissbuhler and Voss (1971) concluded that, in animals and in plants, degradation of urea herbicides to the corresponding anilines does not represent a major pathway of transformation for the urea herbicides. From their survey of the literature, they also concluded that the formation of azobenzene from metabolically-formed anilines does not represent significant terminal residues of urea herbicides.

·       Monuron is metabolized mainly by oxidative N-demethylation and aromatic hydroxylation, but some chlorinated aniline derivatives are also produced (Ernst & Bohme,1965; Ernst, 1969). The metabolite yields indicate that hydroxylation favors the 2-position rather than the 3-position. Phenolic metabolites were excreted in the urine as conjugates. 4-Chloro-2-hydroxyaniline was excreted as the N-acetyl conjugate. The detection of 4-chloroaniline-haemoglobin adducts by gas chromatography-mass spectrometry (estimated to be equivalent to 0.56% of the dose in rats given 1 mmol/kg monuron orally) confirms the availability of an aromatic amine metabolite in vivo (Sabbioni & Neumann, 1990).

·       There is indirect evidence that the N-demethylation reaction occurs via a relatively stable N-hydroxyethyl intermediate, which has been identified from mouse hepatic microsomal incubates in vitro and as conjugates from mouse urine in vivo (Ross et al., 1981).

 

Excretion

·       Determinations of quantitative proportions indicated that the metabolites were distributed so that about (see Figure 1) 15% excretion was in the form of (II) N-(4-chlorophenyl) urea, about 7% excretion as (III) N-{2-hydroxy-4- chlorophenyl) urea, and about 2.5% as (IV) N-(3-hydroxy-4- chlorophenyl) –urea ((Ernst, 1969)

·       Geissbuhler and Voss (1971) suggested that hydroxylated animal metabolites of urea herbicides could be eliminated mainly in the urine as glucuronides or ester sulfates. Formation of these conjugates lead to very water-soluble compounds. It must be emphasized, however, that the chemical structure of these conjugates has not been verified . The authors believed that the conjugates were 6-D-glucoside compounds.

 

Enzyme Induction

·       The enzyme systems responsible for the stepwise demethylation of monuron in rats have not been identified. However, Geissbuhler and Voss (1971) reported that the plant enzyme system involved in N-demethylation is a mixed function oxidase that is located in the microsomal fraction of plant extracts and which requires molecular oxygen and either NADPH or NADH as cofactors .The authors also concluded that the pathways of transformations of urea herbicides in plants , animals, and soils are so similar as to make a separate discussion of each process unnecessary.

·       Monuron and other urea herbicides have been found to be inducers of hepatic microsomal enzyme syntheses (Kinoshita and DuBoise, 1970) in weanling and adult female rats which were fed monuron for 1 week at ,000 ppm, and then the changes in enzymatic activities of 0-demethylase, N-demethylase and the hepatic detoxification system were determined.

·       Monuron was also studied in relation to its effect on enzymes that regulate glycolysis in the liver (Rubenchik, 1970). Enzymatic activity was depressed in liver homogenates from rats fed monuron for 10 weeks when compared to that of rats fed regular diets. However, after 18 weeks of feeding, the activity of the glycolytic systems of monuron-treated animals was increased to levels higher than that of the controls. Phosphofructokinase (PFK) activity in the livers of rats fed monuron (450 mg/kg) for 10 days was also depressed below control values. As with total glycolysis at 18 weeks, the activity of PFK was higher in monuron-treated rats than it was in controls . Hexokinase activity did not appear to change because of monuron treatment. Known carcinogens and monuron were shown to have produced similar changes in the profile of glycolysis activity in the liver , although tumors were found in the livers of the carcinogen-treated animals, but out in the livers of monuron-treated ones.

 


 

References:

-       Ernst, W., Metabolism of Substituted Dinitrophenols and Ureas in Mammals and Methods for the Isolation and Identification of Metabolites," J. S. African Chem. Inst., 22:579-588 (1969).

-       Ernst, W. and Bohme, C.Food Cosmet. Toxicol., 3, 789-797, (1965).

-       Geissbuhler, H., and G. Voss, "Metabolism of Substituted Urea Herbicides,"contained in A. S. Tahori (ed.), Pesticide Terminal Residues: Invited Papers from the International Symposium on Pesticide Terminal Residues, Held at Tel Aviv, Israel, February 17-19, 1971, Butterworth and Company,London (1971).

-       IARC Monographs volume on Monuron 53, 1976

-       Katarzyna M, Bloch et al, 2012, Toxicology Research,Transcriptomic alterations induced by Monuron in rat and human renal proximal tubule cells in vitro and comparison to rat renal-cortex in vivo. J. 2013, 00, 1-3 | 1

-       Kinoshita, F. K. and K. P. DuBois, "Induction of Hepatic Mierasomal Enzymesby Her ban, Diuren, and Other Substituted Urea Herbicides," Toxicol. Appl.Pharmacol. , 17:406-417 (1970).

-       Ross D, Farmer PB, Gescher A, Hickman JA, Threadgill MD.Biochem Pharmacol. 1982 Nov 15;31(22):3621-7.

-       Ross, D., Farmer, P.B., Gescher, A., Hickman, J.A & Threadgil, M.D. (1981) The formation and metabolism of N-hydroxymethyl compounds. 1. The oxidative N-demethylation of N-dirnethyl derivatives of arylamines, aryltriazenes, arylformamidines and arylureas including the herbicide monuron. Biochem. Phannacol., 31,3621-3627

-       Rubenchik, B. L., "Effect of Administration of Hepatocarcinogens and theHerbicide Monuron on Intensity of Glycolysis and Activity of lts Regulating Enzymes in Rat Liver Hyalp1asm," Byull. Eksp. Biel. Med. , 69:61-63 (1970).Sabbioni G, Neumann HG. Quantification of haemoglobin binding of 4,4'-methylenebis(2-chloroaniline) (MOCA) in rats. Arch Toxicol. 1990;64(6):451–458. 

-       US EPA .Initial scientific and miniectonomic review of monuron ENVIRONMENTAL PROTEETION AGENCY OFFICE OF PESTICIDE PROGRAMS CRITERIA AND EVALUATION DIVISION WASHINGTON, O.C. 20460, EPA- 540/1-75-028, NOVEMBER 1975

-       Wang SW , Chu CY, Hsu JD, Wang CJ.Haemotoxic effect of phenylurea herbicides in rats: role of haemoglobin-adduct formation in splenic toxicity.Food Chem Toxicol. 1993 Apr;31(4):285-95.