DIMETHIPIN EXPLANATION Dimethipin was evaluated by the Joint Meeting in 1985 (Annex I, FAO/WHO, 1986c) and a Temporary Acceptable Daily Intake (TADI) of 0-0.003 mg/kg bw was allocated. Additional information was required concerning the historical control data utilized by that Meeting regarding lung tumours in CD-1 mice and astrocytomas and liver rumours in SD rats. Further pharmacokinetic and metabolism studies in rats and/or a non-rodent mammalian species were required, as well as acute oral toxicity studies on major plant metabolites which were not found in animals. Data have been provided and are considered in this monograph addendum. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Biochemical aspects Absorption, distribution sad excretion Rats In a study designed to examine the absorption, distribution and excretion of dimethipin as a function of dose, time and route, 48 CD Sprague-Dawley rats (24 male/24 female) were divided into separate groups. Group I received a single oral dose of 1.2 mg/kg bw labelled dimethipin; Group II received a single i.v. dose of 1.2 mg/kg bw of labelled dimethipin; Group III received a single oral dose of 50 mg/kg bw of labelled dimethipin; and Group IV received 1000 ppm non-labelled dimethipin in the diet continuously for 14 days followed immediately on day 15 by a single oral radio labelled dose of 50 mg/kg bw dimethipin. Urine, faecal, blood, and tissue samples were analyzed in each group at numerous intervals following compound administration. Urine samples collected and analyzed by HPLC supported previous findings that very little unchanged dimethipin is excreted (0.4-6.5%) in the first 24 hours. During the same time period, the reduced product, the N-acetylcysteine and polar fractions increase, while cysteinylglycine conjugates decrease with time. There were no sex differences identified. These results support the proposed metabolic pathway involving glutathione conjugation. Glutathione levels in liver and blood samples from 3 male and 3 female rats in Group IV were not different from control values (Billings, 1987; McManus et al., 1987a). Toxicological studies Special studies on mutagenicity Dimethipin did not demonstrate mutagenic activity in short-term tests (see Table 1). Special studies on carcinogenicity Rats/mice Additional information was required by the 1985 JMPR concerning the historical control data for rats/mice used at Hazleton Laboratories America, Incorporated. The requested additional information were provided, However, these data were considered not useful for delineating whether the tumour incidence in either rat or mouse study is different from or consistent with historical control incidence. The historical control data differ in study design (e.g. diet vs gavage; use of vehicles: acetone, corn oil, water; number of animals per cage) and in the sources of SD rats and CD-1 mice used in the respective studies. The available data, including that reviewed by the 1985 JMPR, showed that dimethipin caused an increased incidence of lung adenocarcinomas in male CD-1 mice only. Lung adenomas and adenocarcinomas occur commonly in this strain. Dimethipin was negative for oncogenic potential in female CD-1 mice. Table 1. Results of mutagenicity studies on dimethipin Test system Test object Concentration Purity Results Reference of dimethipin (%) Micronucleus Mouse 220 mg/kg 98.9 Negative McManus (1986) (in vivo) Swiss CD-1 In vivo/ Rat 100, 300 or 98.9 Negative McManus (1987b) In vitro UDS Wistar 1000 mg/kg Pathological examination of brain tissues from the Sprague-Dawley rat study showed that the incidence of astrocytomas was not statistically different between control and treated groups. Additional astrocytomas and brain tumours were identified in controls during a pathological re-examination. A review of the data clarified the questions raised in 1985 about the potential oncogenicity of dimethipin in Sprague-Dawley rats. It was concluded that dimethipin did not demonstrate oncogenic potential in this rat study. Further data pertaining to certain organ weight changes in the Sprague-Dawley rat study were provided by the testing laboratory. These data clarified the organ weight changes and demonstrated a NOEL of 200 ppm for relative and absolute adrenal weight decrease in female rats, and a NOEL of 200 ppm for relative and absolute liver weight increase in male rats. Also, a NOEL of 40 ppm was demonstrated for relative and absolute liver weight increase in females, and serves as the NOEL for the study. COMMENTS The Meeting in 1985 requested clarification of the metabolism of dimethipin in plants and animals. Additional data, reviewed by the 1987 JMPR (Annex I, FAO/WHO, 1987c), showed similar metabolic pathways of dimethipin in plants and animals. Additional metabolism data in rats reviewed by the present Meeting support the previous conclusions. Further information reviewed by the Meeting on historical control data were not useful in delineating compound-related effects in rats or mice. The available data, including that reviewed by the 1985 JMPR, showed that dimethipin caused an increased incidence of lung adenocarcinomas only in male CD-1 mice at high dose. The Meeting noted that the lung adenoma and adenocarcinomas occur commonly in this strain. Hence this finding was not considered to be of toxicological relevance. Pathological examination of brain tissues from the study in Sprague-Dawley rats evaluated by the 1985 JMPR showed that the incidence of astrocytomas was not statistically different between control and treated groups. These findings resolved questions raised in 1985 for the potential oncogenicity of dimethipin in Sprague-Dawley rats. The Meeting concluded that this study did not indicate carcinogenicity. TOXICOLOGICAL EVALUATION LEVEL CAUSING TO TOXICOLOGICAL EFFECT Mouse: 80 ppm in the diet, equal to 12.3 mg/kg bw/day Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg bw/day Rat: 40 ppm in the diet, equivalent to 2.0 mg/kg bw/day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.02 mg/kg bw. STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED EVALUATION OF THE COMPOUND Observations in man. REFERENCES Billings, T.J. 1987. A [14C]-Radiolabeled pharmacokinetics and metabolism study in rat. Southwest Bio-Labs, Inc. Project No. 8656r. Submitted to WHO by Uniroyal Chemical Co., Inc., Bethany, CT, USA. McManus, J.P. 1986. Mouse micronucleus test - Dimethipin technical. Life Sciences Research, Rome; Report 180001-M-06886. Submitted to WHO by Uniroyal Chemical Co., Inc., Bethany, CT, USA. McManus, J.P. 1987a. Analysis of urine samples from Dimethipin (Harvade) rat pharmacokinetic study. Submitted to WHO by Uniroyal Chemical Co., Inc., Bethany, CT, USA. McManus, J.P. 1987b. In vivo/in vitro UDS Study in rat. Robens Institute, Report No. 4/86/TX. Submitted to WHO by Uniroyal Chemical Co., Inc., Bethany, CT, USA.
See Also: Toxicological Abbreviations Dimethipin (Pesticide residues in food: 1985 evaluations Part II Toxicology) Dimethipin (JMPR Evaluations 1999 Part II Toxicological)