AGP:1970/M/12/1
WHO/FOOD ADD/71.42
1970 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD
THE MONOGRAPHS
Issued jointly by FAO and WHO
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Working Party of Experts and the WHO Expert
Group on Pesticide Residues, which met in Rome, 9-16 November, 1970.
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
WORLD HEALTH ORGANIZATION
Rome, 1971
PYRETHRINS
Explanation
This insecticide was considered at joint Meetings held in 1966, 1967,
1968 and 1969. In 1969 (FAO/WHO 1970b), the only data considered
related to use, together with piperonyl butoxide, on fish. This 1970
meeting confined itself to a consideration of data relating to the
evaluation of the acceptable daily intake. This consideration is
summarized in the following addendum.
IDENTITY
In this addendum, the term pyrethrins refers to the mixed active
ingredients as present in commercially available extracts of
pyrethrum. Such extracts contain about 30 percent by weight a mixture
of six components in about the following amounts: pyrethrin I (11.4
percent), cinerin I (2.2 percent), jasmolin I (1.2 percent), pyrethrin
II (10.5 percent), cinerin II (3.5 percent) and jasmolin II (1.2
percent) (Head, 1969).
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Biotransformation
Utilizing an in vitro enzyme system from insects in the presence of
NADPH2, Yamamoto and Casida (1966) showed that pyrethrin I was
converted to at least ten metabolites. A major metabolite was
characterized as a product which had undergone oxidation of a methyl
group in the isobutenyl moiety to the carboxylic acid. In a more
comprehensive study, these authors conclude that oxidation rather than
hydrolysis in insects might be the major mode of metabolism of
pyrethroid chemicals (Yamamoto et al., 1969).
Pyrethrins I and II have been shown to be oxidatively metabolized in
rats. Oxidation was found to occur at the trans-methyl group of
pyrethrin I as well as on the pentadienyl side chain to produce two
diols. These metabolites were also found in conjugate form (Casida et
al., 1970).
TOXICOLOGICAL STUDIES
Special studies on reproduction
Rabbit
Two groups of nine rabbits each were administered pyrethrins at 0 and
90 mg/kg body-weight/day, orally, from day 8-16 of gestation. Pups
were delivered by normal parturition or by caesarian section on day 30
of gestation. No apparent effects were noted on the number and weight
of foetuses, implantation sites or on gross external and internal
examination. Two control pups and one pup in the group given
pyrethrins had a club-like deformed front paw, and one pyrethrin pup
had a missing caudal vertebrae. There appears to be no apparent
teratogenic effects elicited by pyrethrins in rabbits (Weir, 1966a).
Special studios on skin sensitization
Guinea pig
Two groups of nine male guinea pigs were used to examine the
sensitizing effect of pyrethrins. The criterion of sensitization was a
comparison of the response following a challenge dose with the
response elicited by previous sensitizing doses. A positive control
(1-chloro-2,4-dinitrobenzene) produced sensitization in all animals of
one group. No sensitization was obtained with a 1 percent formulation
of pyrethrins (Weir, 1966b).
Acute toxicity
LD50 (mg/kg
Species Route body-weight) Reference
Rat (M) oral 710 Weir 1966c
Rat oral 584-900 Malone & Brown, 1968
i.p. 167-798 Malone & Brown, 1968
Mouse oral 273-796 Malone & Brown, 1968
i.p. 172-452 Malone & Brown, 1968
Chick Perivisceral 240-1262 Malone & Brown, 1968
The latter five ranges comprise various grades of pyrethrum, including
crude oleoresins and refined concentrates.
The acute signs of poisoning in rats include: depression, rapid and/or
laboured respiration, ataxia, incoordination, convulsions and muscular
tremors. Necropsy findings include: congestion of the lungs, liver,
kidneys, adrenals and pancreas and slight gastric inflammation (Weir,
1966c; Malone and Brown, 1968).
An acute dermal toxicity test was performed with rabbits using
pyrethrins in combination with a synergist. Typical sprays made with
the synergists, tropital or piperonyl butoxide (1 percent) in
combination with 0.1 percent pyrethrins, exhibited a low order of
toxicity when tested dermally on 6-12 male rabbits. The acute dermal
LD50 of both formulations was >10 gm/kg. At 10 gm/kg with tropital,
three of 12 rabbits died. At 5 and 10 gm/kg, body-weight gain was
reduced and transient signs of toxicity were evident with both
synergist combinations. No effects were noted at a concentration of 2
gm/kg (equivalent to 2 mg/kg pyrethrins and 20 mg/kg synergist)
(Wisconsin, 1965)
Short-term studies
Rat
Two groups of rats (ten male and ten female) were exposed to aerosols
of 1 percent pyrethrins for one hour. The flow was 50 l/min containing
2 mg/l of air. Gross examination of the lung tissue demonstrated the
presence of haemorrhagic pin point lesions in nine of ten male and ten
of ten female rats exposed to pyrethrins (Leong and Martin, 1966).
Microscopic examination of the lungs indicated that the alterations
were typical of those found in murine pneumonitis (Weir and Crews,
1966). No distinguishing pathological observations were reported which
might be attributed to pyrethrins.
Rabbit
A group of rabbits (ten male and ten female) and a control group (five
male and five female) were tested by repeated dermal application to
either abraded or intact skin with a 1.0 percent formulation of
pyrethrins at doses of 0 and 10 mg/kg body-weight/day. Treatments of 1
ml/kg body-weight of the formulation were applied daily (6-8 hour
exposure per day) five days per week for three weeks. No systemic,
clinical or necrotic findings were attributed to the test material.
Repeated dermal applications of a 1 percent formulation of pyrethrins
was not detrimental to rabbits (Weir, 1966d).
Long-term studies
No new information available.
OBSERVATIONS IN MAN
Two hundred human subjects (177 females, 23 males) were patch tested
for skin sensitivity and irritation using pyrethrins at 1 percent in
water simulating formulation levels. Under the conditions of this
patch test, pyrethrins at the 1 percent formulation level was not a
primary irritant and was not a sensitizer to human skin (Weir, 1966e).
COMMENT
Skin sensitization studies using very low levels of pyrethrins have
been negative. Dermal and inhalation toxicity studies of pyrethrins in
combination with synergists, using a commercial formulation, exhibited
a low order of toxicity to rabbits. Further studies of this type,
using especially the methylenedioxy synergists would, however, appear
desirable. A rabbit reproduction study indicated that pyrethrins were
not teratogenic. Some limited information on the mammalian metabolism
of pyrethrins has recently become available. The short-term studies in
the dog and other species requested at the 1966 Joint Meeting with a
view to elucidating the effect on the liver found in a long-term study
in rats, have not been forthcoming. The Committee therefore decided to
retain the acceptable daily intake on a temporary basis.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 200 ppm in the diet, equivalent to 10 mg/kg body-weight/day
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0-0.04 mg/kg body-weight
FURTHER WORK OR INFORMATION
REQUIRED (before June 1973)
Short-term toxicity studies in several species including a non-rodent
mammalian species, with special emphasis on the effects on the liver
and a detailed study of the mammalian metabolism of pyrethrins.
DESIRABLE
Further studies to determine if mammalian toxicity to pyrethrins is
increased when they are used along with synergists, especially with
methylenedioxy compounds such as piperonyl butoxide.
REFERENCES
Casida, J.E., Kimmel, E.C., Elliot, M. and Janes, N.F. (1970)
Oxidative metabolism of pyrethrins in mammals. Unpublished report
submitted to WHO
FAO/WHO. (1967) Evaluation of some pesticide residues in food. FAO.
PL:CP/15; WHO/Food Additives/67.32
Head, S.W. (1969) The composition of pyrethrum extract. Pyrethrum
Post, 10: 1-5
Leong, K.J. and Martin, A.R. (1966) Acute inhalation exposures - Rats.
o/w Emulsion of neopynamin, o/w emulsion of pyrethrin. Unpublished
report from Hazelton Laboratories, Inc. (31 March 1966) to S.C.
Johnson and Son, Inc.
Malone, J.C. and Brown, N.C. (1968) Toxicity of various grades of
pyrethrum to laboratory animals. Pyrethrum Post, 9: 3-8
Weir, R.J. (1966a) Reproduction study - rabbits. Neopynamin and
pyrethrin. Unpublished report (3 August 1966) from Hazelton
Laboratories, Inc. to S.C. Johnson and Son, Inc.
Weir, R.J. (1966b) Skin sensitization study - guinea pigs. Neopynamin
and pyrethrin. Unpublished report (1 June 1966) from Hazelton
Laboratories, Inc. to S.C. Johnson and Son, Inc.
Weir, R.J. (1966c) Acute potentiation study - oral administration,
rats. Neopynamin and pyrethrin. Unpublished report from Hazelton
Laboratories, Inc. (1 June 1966) to S.C. Johnson and Son, Inc.
Weir, R.J. (1966d) Repeated dermal application - rabbits. Neopynamin
and pyrethrin. Unpublished report from Hazelton Laboratories, Inc. (1
June 1966) to S.C. Johnson and Son, Inc.
Weir, R.J. (1966) Human patch test. Unpublished report (3 November
1966) from Hazelton Laboratories, Inc. to S.C. Johnson and Son, Inc.
Weir, R.J. and Crews, L.M. (1966) Supplement to acute inhalation
exposures - rats. Unpublished report from Hazelton Laboratories, Inc.
(1 June 1966)
Wisconsin. (1965) Unpublished report (23 September 1965) from the
Wisconsin Alumni Research Foundation
Yamamoto, I. and Casida, J.E. (1966) 0-demethylpyrethrin II analogs
from oxidation of pyrethrin I, allethrin dimethrin and phthalthrin by
a house fly enzyme system. J. econ. Entomol., 59: 1542-1543
Yamamoto, I., Kimmell, E.C. and Casida, J.E. (1969) Oxidative
metabolism of pyrethroids in houseflies. J. Agr. Fd. Chem., 17:
1227-1236