Research Section
Subchronic toxicity of chlorpropham (CIPC) in ICR mice

https://doi.org/10.1016/S0278-6915(00)00043-0Get rights and content

Abstract

Male and female ICR mice were given 0, 1875, 7500 or 30,000 ppm of chlorpropham (CIPC) in the diet for 13 weeks. Methemoglobin levels of male and female mice in the 7500 and 30,000 ppm groups were significantly elevated. Hemoglobin concentration, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and white blood cell count of male and female mice in the 30,000 ppm group were significantly increased. Dose-dependent splenomegaly was observed in male and female mice in the 7500 and 30,000 ppm group. Congestion, increased hemosiderin deposition and increased extramedullary hematopoiesis in the spleen, hematopoietic cell hyperplasia and hemosiderin deposition in bone marrow was observed dose dependently in male and female mice in the 7500 or 30,000 ppm group. Eosinophilic granular cytoplasm of hepatocytes, sinusoidal dilatation, hemosiderin deposition, extramedullary hematopoiesis and necrosis of hepatocytes were observed in the liver of male and female mice in the 30,000 ppm group. Hemosiderin deposition was increased in the kidney of male and female mice in the 30000 ppm group. Administration of CIPC in diet for 13 weeks caused methemoglobinemia and splenomegaly 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)

  • G.J Van Esch et al.

    Long-term toxicity studies of chloropropham and propham in mice and hamsters

    Food and Cosmetics Toxicology

    (1972)
  • B.L Worobey et al.

    Isolation and identification of chlorpropham and two of its metabolites in potatoes by GC-MC

    Chemosphere

    (1987)
  • H Beernaert et al.

    A single and quick gas chromatographic method for the determination of propham and chlorpropham in potatoes

    Zeitschrift für Lebensmittel Untersuchung und Forschung

    (1991)
  • E Beutler

    Chemical toxicity of the erythrocyte

  • B Caporiccio et al.

    Etude de la toxiite aigue de deux phenylcarbamates: le propham et le chlorpropham

    Compte Rendus des Societe de Biologie

    (1981)
  • S.L Eustis et al.

    Liver

  • S.C Gad et al.

    Statistics for toxicologists

  • M.J Gartrell et al.

    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

    (1985)
  • Cited by (7)

    • Assessment of exposure to pesticide mixtures in five European countries by a harmonized urinary suspect screening approach

      2023, International Journal of Hygiene and Environmental Health
      Citation Excerpt :

      Acetamiprid has been reported to mainly target the liver (EFSA, 2016), where it may cause, at least in rodents, oxidative stress leading to mitochondrial dysfunction (EL-Hak et al., 2022; S. Li et al., 2021). Exposure to chlorpropham rather leads to adverse effects on the hematopoietic system (Arena et al., 2017; Fujitani et al., 2000, 2004). Hemotoxicity such as hemolytic anemia, however, is considered to be due to oxidative stress (Rokushima et al., 2007; Sivilotti, 2004).

    • Retrospective mining of toxicology data to discover multispecies and chemical class effects: Anemia as a case study

      2017, Regulatory Toxicology and Pharmacology
      Citation Excerpt :

      Cabagna showed that toads (Bufo arenarum) exposed to pesticides in the acetochlor class displayed evidence of normochromic, normocytic anemia (Cabagna, 2005). Fujitani et al. studied the effects of chlorpropham in rats including splenotoxicity, anemia and methemoglobinemia (Fujitani et al., 1997; Fujitani et al., 2000; Fujitani et al., 2001; Fujitani et al., 2004). They found that some of these effects were reversible, but that hemosiderin deposition and fibrosis in the spleen were not.

    View all citing articles on Scopus
    View full text