PESTICIDE RESIDUES IN FOOD - 1981
Sponsored jointly by FAO and WHO
EVALUATIONS 1981
Food and Agriculture Organization of the United Nations
Rome
FAO PLANT PRODUCTION AND PROTECTION PAPER 42
pesticide residues in food:
1981 evaluations
the monographs
data and recommendations
of the joint meeting
of the
FAO panel of experts on pesticide residues
in food and the environment
and the
WHO expert group on pesticide residues
Geneva, 23 November-2 December 1981
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
Rome 1982
AZOCYCLOTIN
Explanation
Although this compound was reviewed by the 1979 JMPR*, the
toxicological evaluation was not undertaken at that time.
DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Uptake, distribution and excretion
Studies on rats to investigate uptake, distribution and excretion
of azocyclotin were conducted with both the [113Sn]-labelled and
[1-14C]-labelled compound (Bayer AG 1981; Grubenbecher and Figge
1979a, b). [113Sn] Azocyclotin was administered orally to rats in a
single dose of approximately 8 mg/kg body weight. In the studies with
[1-14C] azocyclotin, possible dependence of elimination kinetics
on dose level was also investigated by comparing a single dose of
10 mg/kg body weight with a single dose of 1 mg/kg body weight.
Labelled azocyclotin was absorbed at a relatively slow rate and
in a small amount. Excretion in urine was slight (1.1% of the
administered radioactivity for the [113Sn]label; 12.6% for the
[1-14C]label.
The amount of radioactivity present in the gastrointestinal
tract after the first 24h was approximately 60% of the administered
radioactivity. Between 24 and 48h, the level of radioactivity
decreased quickly owing to excretion in faeces, with the result that
after 3 days all radioactivity had been virtually completely
eliminated from the animal body.
The radioactivity present in the body less gastrointestinal tract
(3% of administered radioactivity after 3 days, approximately 1% of
administered radioactivity after 10 days) was distributed uniformly
among the organs and tissues.
No radioactivity levels exceeding approximately 1% of the initial
dose were measured in any organ. Somewhat elevated values were
measured at 4h after administration in liver and kidney. Thereafter,
the values decreased continuously in all organs and tissues (Bayer AG
1981).
* See Annex II for FAO and WHO documentation.
TOXICOLOGICAL STUDIES
The acute toxicity of azocyclotin, which was studied in seven
animal species, is reported in Table 1.
TABLE 1. Acute toxicity of azocyclotin
Species Sex Route of LD50 Reference
application (mg/kg)
Rat M oral 99 Thyssen and Kimmerle 1974a,b
Rat F oral 76 ibid.
Rat M oral 180 Iyatomi 1980
Rat F oral 150 ibid.
Rat M oral 102 Flucke 1980
Rat* M oral 93 ibid.
Rat F oral 118 ibid.
Rat* F oral 128 ibid.
Mouse M oral 453 Thyssen and Kimmerle 1974a,b
Mouse F oral 417 ibid.
Mouse M oral 980 Iyatomi 1980
Mouse F oral 870 ibid.
Cat F oral > 25 Thyssen and Kimmerle 1974a,b
Dog F oral < 50 ibid.
Guinea pig M oral 261 Thyssen 1974
Guinea pig F oral 261 ibid.
Quail M oral 144 Thyssen 1979
Quail F oral 195 ibid.
Quail F oral >175 < 250 Kimmerle 1973
Hen oral 250 - 375 ibid.
Rat M intraperitoneal 3.65 Thyssen and Kimmerle 1974a,b
Rat F " 3.54 ibid.
Rat M " 4.6 Iyatomi 1980
Rat F " 5.9 ibid.
Mouse M " 3.6 ibid.
Mouse F " 4.0 ibid.
TABLE 1. (con't)
Species Sex Route of LD50 Reference
application (mg/kg)
Rat M subcutaneous >1000 Iyatomi 1980
Rat F " >1000 ibid.
Mouse M " 250 ibid.
Mouse F " 300 ibid.
Rat M dermal ca. 1000 Thyssen and Kimmerle 1974a,b
Rat F dermal > 1000 ibid.
Rat M " > 5000 Iyatomi 1980
Rat F " > 5000 ibid.
Mouse M " > 5000 ibid.
Mouse F " > 5000 ibid.
* = fasted
Symptoms seen in rats after both oral and intraperitoneal
administration were characterized by impairment of general health,
drowsiness and at elevated dose levels, breathing disorders and
diarrhoea. Onset of these symptoms at the high dose levels were within
one hour of application, and they persisted for up to 14 days.
Following dermal application, the effects seen were local irritation,
increased blood flow and formation of edoema on the ears resulting in
necroses from pressure on the margins of the ears. Subcutaneous
application induced ulcers. Symptoms seen in mice and guinea pigs were
characterized by depression of the general health, drowsiness and
breathing disorders, which persisted for up to 14 and 15 days,
respectively after application. Cats and dogs vomited within one hour
of oral application (Bayer AG 1981).
Single doses of the 25% WP formulation of azocyclotin were also
tested for acute toxicity to rats and mice. The results obtained are
summarized in Table 2.
TABLE 2. Acute toxicity of azocyclotin 25% WP
Species Sex Route of LD50
application (mg/kg) Reference
Rat M oral 631
Rat F oral 611
Mouse M oral 2451 Thyssen and Kimmerle 1974a,b
Mouse F oral 1936
Rat M i.p. 16.7
Rat F i.p. 22.6
The poisoning symptoms seen in the rats following oral and
intraperitoneal administrations were characterized by impairment of
the general health, breathing disorders and body weight depression.
Additional effects observed at the elevated dose levels were diarrhoea
and cyanosis. Symptoms seen in the mice were characterized by
impairment of the general health and breathing disorders.
Short-term studies
Rat
Groups of 15 male and 15 female Wistar rats were orally dosed
with azocyclotin at levels of 0.2, 2 and 20 mg/kg bw, emulsified in
distilled water and Cremophor EL, administered by gavage on 30
consecutive days. A similar control group received the vehicle only.
Male rats tolerated doses of 0.2 and 2 mg/kg bw without any adverse
effects. The female rats tolerated only the lowest dose of 0.2 mg/kg
bw without showing any signs of treatment-related effects. Although
they also tolerated 2 mg/kg bw without showing any noteworthy clinical
symptoms, this dose level caused a slight reduction in their relative
thymus and brain weights. At the 20 mg/kg dose level, some male and
female mortalities occurred. This dose caused an impairment of the
general health and affected the growth rate. Additionally, the
haematological tests showed a tendency towards leucopenia.
Interference with liver function was indicated by increased alkaline
phosphatase activity. Some organ weight alterations were noted at
20 mg/kg, viz. reduction of thymus, heart, lung and kidney weights and
an increase in liver, adrenal and brain weights in males; reduction of
thymus and brain weights and an increase in liver weight in females.
Neither gross pathology or histopathology revealed any variations or
alterations from the physiological norm in the tissues of either sex.
The wet weight of the brains and the weight of freeze-dried brains
provided no indication of the brain having an increased water content
(Thyssen and Luckhaus 1974).
In another study on Wistar rats, groups of 15 males and 15
females were maintained for 3 months on a diet containing azocyclotin
at concentrations of 0, 5, 15, 50 and 150 ppm. Dietary concentrations
of 5 and 15 ppm did not affect physical appearance, behavioural
patterns, growth rate or survival rate of the males and females.
At dietary levels of 50 and 150 ppm, food consumption was less and
body weights were lower than in the control group. The dietary level
of 150 ppm caused mild drowsiness. Clinical chemical tests,
haematological tests and urinalyses performed during and at the end of
the study yielded no indication of any damage to body functions at
dietary levels of up to and including 150 ppm. Gross pathology and
histopathology revealed no indication of any damaging effects from
administration of azocyclotin at dietary levels of up to and including
150 ppm. The dietary level of 15 ppm was tolerated by the rats for 3
months without having any damaging effects whatsoever (Löser and
Luckhaus 1975).
In a subacute inhalational toxicity study, male and female Wistar
rats (10 per sex per group) were exposed for 6h daily over a 3-week
period (total of fifteen 6h-exposures) to azocyclotin aerosols
(ethanol + polyethylene glycol 400; 20 ml/m3) at concentrations
averaging 0.0901, 0.275 and 0.961 mg/m3 air. A control group of
identical composition was exposed to the solvent mixture only. During
the exposure period, the rats were inspected for their behavioural
reactions, and their body weights were measured. At the end of the
study, haematological tests, clinical chemical tests, urinalyses,
macroscopic tissue examinations, organ weight measurements and
histopathological examinations of the major tissues were performed.
The concentration levels of 0.0901 and 0.275 mg/m3 air had no adverse
effects on behavioural patterns, physical appearance and growth rate.
Haematology, clinical chemistry and urinalyses did not reveal any
signs of damage at these concentration levels. Exposure of the rats to
0.961 mg azocyclotin/m3 air caused poisoning symptoms, reduced weight
gain and organ weight alterations. The symptoms were characterized by
impairment of the general health and breathing disorders. One male rat
died after the seventh exposure. Measurement of the organ weights
revealed a reduction of the liver and thymus weights and an increase
in the lung weight at the highest concentration level. The
histological examinations did not reveal any morphological equivalent
of the observed clinical symptoms and organ weight alterations
(Kimmerle 1974).
Dog
In a 13-week feeding experiment, groups of 4 male and 4 female
beagle dogs were maintained on a diet containing azocyclotin at
concentrations of 0, 5, 50 and 500 ppm. In this study, the no-toxic
effect dietary level of azocyclotin was 5 ppm. Higher dietary
concentrations caused slow and reduced food intake, slow weight gain,
diarrhoea and vomiting, in a dose-related manner. The dogs fed dietary
levels of 50 and 500 ppm also had an ungroomed appearance. The dogs of
the 500 ppm group had a slightly drowsy appearance, particularly
during the first phase of the treatment. This was associated with the
depression of their general health. However, all the dogs survived the
treatment. Special haematological tests did not provide any indication
of treatment-related damage at dietary levels of 5 and 50 ppm. At the
dietary concentration of 500 ppm, some male dogs showed signs of
anaemia, manifested by a reduction of the erythrocyte count and
concomitantly by a reduction of the haemoglobin content and the
haematocrit level. Clinical chemistry revealed a slight, treatment-
related increase in serum cholesterol in some female dogs of the 50
and 500 ppm groups at the end of the treatment period. The serum
calcium values showed a slight reduction in comparison with the
initial values in the 50 and 500 ppm groups. One male dog in the
500 ppm group exhibited marked signs of liver damage. The urinalyses
and macroscopic examinations performed at the end of the study
provided no indication of any damage from azocyclotin administration.
Organ weight measurements showed a slight increase in adrenal weights
only in females of the 50 and 500 ppm groups. Histopathology did not
reveal any treatment-related alterations in any tissue in any treated
group (Hoffman and Schilde 1975).
Rabbit
Groups of 3 male and 3 female White New Zealand rabbits were
treated dermally on 5 days per week over a 3-week period (total of
15 applications) with azocyclotin at doses of 0 (vehicle), 5 and
25 mg/kg bw, respectively, applied to either intact or abraded skin
areas. Evaluation of the treated skin areas for reaction to
azocyclotin revealed severe skin reactions (irritations and
corrosions) at both dose levels and on both intact and abraded skin
areas, as compared with the controls. Neither male nor female rabbits
exposed to azocyclotin applied to intact and abraded skin showed any
systematic damage attributable to absorption of azocyclotin. Some of
the rabbits in the highest dose group did not exhibit the same weight
gains as the controls. Since there were no signs whatsoever of
systemic damage, this effect on body weight development was evidently
associated with the severe skin injury and the associated pain.
Therefore, 25 mg/kg body weight applied dermally to rabbits was a no-
effect dose from the systemic toxicity aspect. However, azocyclotin
that was applied emulsified in distilled water and Cremophor EL caused
local intolerance and had strong skin-irritating and skin-corrosive
effects (Thyssen and Kaliner 1978).
Long-term studies
Rat
Azocyclotin was evaluated for potential chronic toxicity and
carcinogenicity in a 24-month study on groups of 50 male and 50 female
Wistar-TNO W74 rats fed dietary levels of 5, 15 and 50 ppm,
respectively. The control group fed a diet without azocyclotin
consisted of 100 male and 100 female rats. For clinical laboratory
tests (haematology, clinical chemistry, urinalyses, enzyme induction
assays) and intermediate necropsies, 10 rats per group and per sex
were used additionally. At the end of the 24-month feeding experiment,
all survivors were sacrificed and necropsied. All major organs were
weighed and histopathologically examined. The tests provided no
indication of azocyclotin causing carcinogenic effects in rats. With
respect to chronic toxicity, the no-effect dose was 5 ppm for both
males and females. Although the two higher dietary levels tested, viz.
15 and 50 ppm, caused retarded growth in both sexes, they did not have
any specific effects on organs and organ functions (Bomhard, Löser and
Vogel 1979).
Mouse
Azocyclotin was evaluated for potential chronic toxicity and
carcinogenicity on groups of 50 male and 50 female CF 1 mice fed the
compound for 24 months at dietary concentrations of 0 (control), 5,
15 and 50 ppm, respectively. For intermediate tests and intermediate
necropsies at 6 and 12 months, 10 male and 10 female mice per group
were used additionally. Clinical inspections, body weight
measurements, food intake measurements, macroscopic examinations and
comprehensive histological examinations were performed.
The study revealed no indication of carcinogenic effects, as the
nature, localization and incidence of tumours, as well as the time of
their occurrence, were comparable in all groups. No chronic toxic
effects were seen at the two lower dietary levels of 5 and 15 ppm. At
the dietary level of 50 ppm, male mice showed less weight gain,
particularly in the first half of the feeding experiment, whereas the
females showed weight gain similar to that of the controls. However,
specific effects on organs or on organ functions were not seen either
in female mice or in males at any of the dietary levels up to and
including 50 ppm (Krötlinger and Löser 1981).
Dog
In a chronic toxicity study, azocyclotin was fed to groups of
4 male and 4 female beagle dogs for 104 weeks at dietary levels of
0, 10, 30, 100 (up to week 53), 200 (week 54 to 82) and 400 ppm (week
83 to 104) respectively. Clinical inspections, haematological tests,
clinical chemical tests and urinalyses were performed. At the end of
the feeding experiment, the dogs were sacrificed and necropsied, organ
weights were measured and tissues were histopathologically examined.
Azocyclotin at a dietary level of 10 ppm was tolerated by both
males and females throughout the two-year period without causing any
untoward effects. Dietary levels of 30 ppm, 100 ppm and above caused
increased diarrhoea. At the highest concentration, which was raised
from 100 ppm through 200 ppm to 400 ppm in order to obtain an effect,
body weight gain was also seen to have been affected, especially in
the second half of the study. However, clinical laboratory tests,
gross pathology and histopathology did not provide any indication of
specific damage to tissues (Hoffman and Schilde 1979).
Special studies on reproduction
Rat
Azocyclotin was evaluated for its potential effect on
reproduction in a three-generation study on Wistar rats. There were
two matings per generation and azocyclotin was fed to groups of 10
male and 20 female rats throughout the study at dietary concentrations
of 0 (control), 5, 15 and 50 ppm, respectively. The treated rats were
studied for the effects of oral azocyclotin on behavioural pattern,
growth rate, mortality, fertility, lactation performance (ability to
successfully nourish the resulting offspring) and development of
offspring. The F0 generation was about 30 to 35 days old at the start
of the study and was treated for 70 days before the first mating. The
pups of the F3b generation were sacrificed at an age of 4 weeks,
dissected, and 17 major tissues were examined histopathologically.
Dietary concentrations of 5 and 15 ppm had no adverse effect on the
reproductive performance of the rats, and 50 ppm in the diet resulted
in lower fertility rates after only one of six matings and usually
caused body weight depressions in the pups during the lactation
period and also in the parent rats. Azocyclotin did not cause any
malformations in the young at any of the tested dietary levels.
Histopathological examination of the major tissues from the 4-week old
pups of the F3b generation did not reveal any alterations. Therefore,
15 ppm was tolerated in the three-generation study without having any
untoward effects (Löser 1980).
Special studies on mutagenicity
Microorganisms
Azocyclotin was tested for mutagenicity by the
Salmonella/microsome test (Ames test) using strains TA 1535, 1537, 100
and 98 and metabolic activation with S-9 microsomal fraction of adult
male rat livers. Azocyclotin was tested at doses of 4, 20, 100, 500
and 2 500 µg per plate; four agar plates were used per dose. Doses of
up to and including 100 µg per plate did not cause any bacteriotoxic
effects, while higher dose levels caused inhibition of bacterial
growth. There were no mutagenic effects found in any of the test
strains used (Herbold 1979b).
In a rec-assay (repair test), azocyclotin was tested for
potential DNA-damaging effects on two Bacillus subtilis strains at
concentrations ranging up to and including, 5 000 µg per plate.
Reversion assays were conducted by the Ames test on the Salmonella
typhimurium strains TA 1535, 1537, 1538, 98 and 100 and on
Escherichia coli WP 2. In these assays, azocyclotin was tested
at concentrations ranging up to and including a maximum of
5 000 µg/plate, with and without metabolic activation. Azocyclotin
induced neither DNA-damage nor any point mutations.
Azocyclotin was evaluated for potential genetic activity
(recombinogenic activity) on two B; subtilis strains and for
potential point mutation activity in a reverse mutation induction
assay (eukaryotic test) employing two S. cerevisiae strains (S 138
and S 211) in comparison with negative (solvent) and positive
controls, with and without metabolic activation. Azocyclotin had
no mutagenic activity at concentrations of up to toxic levels
(100 µg/plate) (Jagannath and Hoorn 1980).
Mouse - micronucleus test
Azocyclotin was evaluated for mutagenicity in a micronucleus test
using the procedure of Schmid (1973) on groups of 10 NMRI mice dosed
orally with the test compound at levels of 2 × 50 mg/kg bw. The study
included a negative control group and a positive control group dosed
with cyclophosphamide. The two applications of azocyclotin were made
at an interval of 24h, and the femoral marrow was prepared 6h after
the second application. Polychromatic erythrocytes, 1000 per mouse,
were analysed; the number of normochromatic erythrocytes per 1 000
polychromatic erythrocytes was counted. No indication of mutagenicity
was found in the mouse at oral doses of up to and including
2 × 100 mg/kg. Erythropoiesis, as measured by the ratio of
polychromatic to normochromatic erythrocytes, was not adversely
affected (Herbold 1979a).
Azocyclotin was tested by the same procedure in male Swiss mice
at oral dose levels of 2 × 50 mg/kg, 2 × 100 mg/kg and 2 × 150 mg/kg
bw. The control group and the lowest dose group each consisted of 10
mice; the middle dose group comprised 15 mice; the highest dose group
consisted of 5 mice. No indication of mutagenicity of azocyclotin was
found. However, some of the doses were toxic; 4 of the 15 mice died at
an oral dose of 2 × 100 mg/kg bw, and 1 of the 5 mice died in the
group dosed orally with 2 × 150 mg/kg bw (Siou 1979).
Mouse (male) - Dominant lethal test
A group of 50 male NMRI mice each received a single oral dose of
2.5 mg/kg bw; a control group of 50 male mice received the vehicle
only. The 2.5 mg/kg dose is within the toxic range (Thyssen and
Kimmerle 1974a). The treated mice exhibited transient drowsiness on
the day of administration, but they all survived. After administration
of the test compound, each male was mated with a fresh untreated
virgin female every 4 days, this procedure being repeated for a total
of 12 matings. The pre-implantation and post-implantation losses and
the fertility data were tested for statistically significant
differences between the treated groups and the controls. Azocyclotin
was not mutagenic in this test system (Machemer 1977a).
Special studies on teratogenicity
Rat
Azocyclotin was tested on Long Evans rats at oral doses of 3, 10
and 30 mg/kg bw/day and, in another experiment, at oral doses of 0.3,
1.0 and 3.0 mg/kg bw/day. Each experiment included a control group.
Twenty fertilized females, which were used per group, were tested
daily from day 6 to 15 post coitum. On gestation day 20, the foetuses
were removed by caesarean section. Doses of up to and including
3 mg/kg had no damaging effects on the dams. Doses of 10 mg/kg and
above depressed dam weight gain. The 30 mg/kg dose level also caused
toxic symptoms and the death of 2 dams. Embryonic and foetal
development were not affected by doses of up to and including
10 mg/kg. Although the dose level of 30 mg/kg had a marked embryo-
lethal effect and caused an increase in the frequency of stunted
foetuses, there were no indications of azocyclotin having any
teratogenic or primary embryotoxic effects at any of the tested dose
levels of up to and including 30 mg/kg; even the maternal toxic dose
of 10 mg/kg did not have any damaging effects on embryonic and foetal
development. Only the dose level of 30 mg/kg, that was markedly toxic
and lethal to dams, increased lethality in embryos (Machemer 1977b).
Special studies on liver and kidney function
Rats
Ten male Wistar rats each received 50 mg azocyclotin/kg bw
administered orally in an aqueous formulation. Ten control males
were dosed with the formulating aids only. The rats were sacrificed
24h after administration, and blood for tests was obtained by
cardiopuncturc. Liver function was assessed by measuring the following
parameters: GOT, GPT, alkaline phosphatase, GLDH, SDH and bilirubin.
Kidney function was assessed by measuring the urea and creatinine
levels in plasma. No evidence was found of liver and kidney function
having been adversely affected by administration of azocyclotin
(Thyssen 1974).
Special studies on haematology
Guinea pig
Ten male and ten female Pirbright guinea pigs received a single
dose of 100 mg azocyclotin/kg bw administered orally in an aqueous
formulation. A control group of the same animal composition received
the formulating aids only. The guinea pigs were sacrificed 4 days
after applications and the blood for the haematological tests was
obtained by cardiopuncture. There was no indication of the treatment
having had any adverse effects on the red blood cells or the while
blood cell differential count (Thyssen 1974).
Special studies on effect on liver enzymes
Rat
Groups of 5 male Wistar rats were treated with a single dose of
25 mg azocyclotin/kg bw administered orally in an aqueous formulation.
The groups were then sacrificed at different intervals, viz. at 24h,
48h, 3 days, 5 days and 7 days, respectively, and the activities
of the EPN-oxidase (enzyme system which oxidises O-ethyl-O-
(4-nitrophenyl)-phenylphonothioate), the O-demethylase and the
N-demethylase in the liver tissue of the rats were then measured. The
results showed that azocyclotin had an inhibitory effect on the
activities of the EPN-oxidase and the N-demethylase in liver tissue.
The activity of O-demethylase was only minimally depressed. While the
activity of the EPN-oxidase was still inhibited 7 days after
administration of azocyclotin, the activity of the O-demethylase was
again within the physiological range only 5 days after administration.
The activity of the N-demethylase corresponded to the physiological
norm at 7 days post-administration (Thyssen 1974).
Special studies on blood clotting
Rats
Azocyclotin applied in an aqueous formulation at a dose of
250 mg/kg bw to the clipped dorsal skin of each of 5 male Wistar rats
for a contact time of 7 days had no effect on the thromboplastin time,
as compared with the results obtained for a control group of similar
composition (Thyssen 1974).
EVALUATION
COMMENTS
Azocyclotin is poorly absorbed from the rat gastro-intestinal
tract. The small amount of absorbed material is evenly distributed
throughout the body tissues and is excreted relatively slowly.
There were no indications of azocyclotin having mutagenic
effects, primary embryo-toxic effects, teratogenic effects or adverse
effects on reproductive performance.
There was no indication that azocyclotin has a cumulative toxic
effect of any significance. No histological changes were observed in
short-term or long-term studies. The highest no-effect dose in a
30-day oral experiment on rats was 0.2 mg/kg bw/day. In a 2-year
feeding experiment on rats, the no-effect dietary level was 5 ppm. The
no-effect dietary level in a 2-year feeding experiment on dogs was
10 ppm (0.25 mg/kg bw/day), and the no-effect dietary level in a
2-year feeding study on mice was 15 ppm (2.0 mg/kg bw/day). Two-year
feeding studies in rats and mice did not indicate any carcinogenic
potential.
As it is known that some organic tin compounds affect the immune
system, and as thymus weight was decreased in some studies, further
investigation of possible immune effects was felt to be desirable.
Level causing no toxicological effect
Rat : 5 ppm, in the diet equivalent to 0.25 mg/kg bw/day
Mouse : 15 ppm, in the diet equivalent to 2.0 mg/kg bw/day
Dog : 10 ppm, in the diet equivalent to 0.25 mg/kg bw/day
Estimate of acceptable daily intake for man
0 - 0.003 mg/kg bw
FURTHER WORK OR INFORMATION
Desirable
1. Studies to determine the potential for central nervous system
toxicity.
2. Studies to examine the possibility of effects on the immunal
system.
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Toxikologie. Report submitted by Bayer, AG. (Unpublished)
1979 BUE 1452 (Peropal) - Guide for Physicians, 20 April 1979.
Bayer AG, Institut für Toxikologie. Report submitted by
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Schmid, W. Chemical mutagen testing on in vivo somatic mammalian
1973 cells. Agents Actions, 3: 77-85.
Siou, G. Recherche de l'action mutagene du Peropal par la technique
1979 des crops de Howell-Jolly (micronucleus test) 6 Fevrier,
1979. C.E.R.T.I., Versailles. Report submitted by Bayer AG.
(Unpublished)
Thyssen, J. BUE 1452/special toxicity studies, 30 September 1974.
1974 Report No. 4949, Bayer AG, Institut für Toxikologie. Report
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1979 BUE 1452/Akute toxikologische Untersuchungen an Wachtteln,
August 22, Bayer AG, Institut für Toxikologie. Report
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Thyssen, J. and Kaliner, G. BUE 1452/subacute dermal cumulative
1978 toxicity study on rabbits, 11 May 1978. Report No. 7513,
Bayer AG, Institut für Toxikologie. Report submitted by
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Thyssen, J. and Kimmerle, G. BUE 1452/acute toxicity studies, 1 April
1974a 1974, Report No. 4617, Bayer AG, Institut für Toxikologie.
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1974b Formulation 6734/Toxicity Studies, 27 November 1974. Report
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1974 July 1974. Report No. 4827, Bayer AG, Institut für
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