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.