Research SectionSubchronic toxicity of chlorpropham (CIPC) in ICR mice
Introduction
Chlorpropham [isopropyl-N-(3-chlorophenyl)carbamate; CIPC] is widely used as a sprout suppressant on potatoes in order to maintain their quality during transport and storage. Residues of CIPC in potatoes were reported (Beernaert and Hucorne, 1991, Gartrell, Craun, Podrebarac and Gunderson, 1985a, Gartrell,Craun, Podrebarac adn Gunderson, 1985b, Nagayama and Kikugawa, 1992, Vojinovic, Peric and Neskovic, 1985, Worobey and Sun, 1987). CIPC is also used as a herbicide in the cultivation of crops, and CIPC was detected in lettuces grown in a field where CIPC was applied (Rouchaud et al., 1987). In Japan, the official permitted level of CIPC is 50 ppm for potatoes or 0.05–0.50 ppm for other crops, and the acceptable daily intake (ADI) is 0.1 mg/kg body weight.
Toxic and genetic effects of CIPC have been found. CIPC is known to be a mitotic disruptor in mammalian (Hoffman and Mullins, 1996) and non-mammalian cells (Hoffman and Vaughn, 1994). Tanaka reported that CIPC has teratogenicity (Tanaka et al., 1997) or developmental and neurobehavioral toxicity (Tanaka, 1997, Tanaka, 1999). The acute oral LD50 of CIPC was 3.7–4.5 g/kg body weight in ICR mice, 3.3–4.4 g/kg body weight in F344 rats (Kabashima and Ichikawa, 1993) and 6.0 g/kg body weight in Wistar rats (Caporiccio et al., 1981). Anemia and enlargement of the spleen were observed after single oral administration of CIPC to F344 rats (Kabashima and Ichikawa, 1993). Chronic toxicity studies of CIPC in the rat, dog (Larson et al., 1960), hamster or mouse (Van Esch and Kroes, 1972) showed no evidence of carcinogenic effects of CIPC.
Subchronic administration of CIPC in the diet at levels of 7500 to 30,000 ppm caused a decrease in red blood cell count, hemoglobin concentration or hematocrit and an increase in mean corpuscular volume or methemoglobin level in male or female F344 rats (Fujitani et al., 1997). In these rats splenomegaly, accompanied with congestion, increased hemosiderin deposition or increased extramedullary hematopoiesis and hyperplasia of hematopoietic cells in bone marrow, were observed dose dependently, suggesting that the erythrocyte is one of the primary targets of CIPC toxicity in rats.
There has been little information on the subchronic toxicity of CIPC in mice. The present study was carried out in order to determine the subchronic toxicity of CIPC in ICR mice.
Section snippets
Chemicals
Chlorpropham (CIPC; lot. no. 1432) was purchased from Hodogaya Chemical Industry (Tokyo, Japan). It had a purity exceeding 99.7% and did not contain m-chloroaniline detectable in HPLC. CIPC was well mixed at the appropriate concentrations with powdered standard diet CE-2 (CLEA Japan, Tokyo) and the mixtures were then made into pellets. All other chemicals used were reagent grade.
Animals and maintenance
Male and female Crj/CD-1(ICR) mice at 4 wk old were purchased from Charles River Japan (Yokohama, Japan) and were
Food consumption, clinical signs and body weight gain
All male and female mice survived to the end of experiment.
There was no significant change in absolute and relative food consumption between control and treated groups (Table 1).
Male and female mice in the 30,000 ppm group appeared markedly pale from wk 1 or 4 after the beginning of the administration, respectively, to the end of the experiment. Male or female mice in the 7500 ppm group appeared pale from wk 4 or 6 after the beginning of the administration, respectively, to the end of the
Discussion
In mice fed CIPC in the diet for 13 wk, methemoglobin levels were markedly elevated. The supply of oxygen to the tissues may be decreased in these mice, because methemoglobin cannot carry oxygen (Beutler, 1985, Smith, Alkaitis and Shafer, 1967). Ou and Smith (1978) reported that rats exposed to high altitude showed increase of hemoglobin concentration and hematocrit as a result of hypoxia. The increase in hemoglobin concentration, mean corpuscular hemoglobin and mean corpuscular hemoglobin
References (36)
- et al.
Excretory and metabolic studies of isopropyl N-(3-chlorophenyl) carbamate in the rat
Food and Chemical Toxicology
(1972) - et al.
Toxicity of p-chloroaniline in rats and mice
Food and Chemical Toxicology
(1990) - et al.
Hemotoxicity of chlorpropham (CIPC) in F344 rats
Toxicology
(1997) Blood and bone marrow
- et al.
Chronic toxicologic studies on Isopropyl N-(3-chlorophenyl) carbamate (CIPC)
Toxicology and Applied Pharmacology
(1960) - et al.
Propanil-induced methemoglobinemia and hemoglobin binding in the rat
Toxicology and Applied Pharmacology
(1990) - et al.
Metabolism of the arylamide herbicide Propanil. I. Microsormal metabolism and in vitro methemoglobinemia
Toxicology and Applied Pharmacology
(1990) - et al.
Propanil (3,4-dichloropropioanilide)-induced methemoglobin formation in mice in relation to acylamidase activity
Toxicology and Applied Pharmacology
(1973) - et al.
Chemically induced methemoglobinemias in the mouse
Biochemical Pharmacology
(1967) - et al.
Developmental toxicity of chlorpropham in mice
Reproductive Toxicology
(1997)
Long-term toxicity studies of chloropropham and propham in mice and hamsters
Food and Cosmetics Toxicology
Isolation and identification of chlorpropham and two of its metabolites in potatoes by GC-MC
Chemosphere
A single and quick gas chromatographic method for the determination of propham and chlorpropham in potatoes
Zeitschrift für Lebensmittel Untersuchung und Forschung
Chemical toxicity of the erythrocyte
Etude de la toxiite aigue de deux phenylcarbamates: le propham et le chlorpropham
Compte Rendus des Societe de Biologie
Liver
Statistics for toxicologists
Pesticides, selected elements, and other chemicals in infant and toddler total diet samples, October 1978–September 1979
Journal of the Association of Official Analytical Chemists
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