PESTICIDE RESIDUES IN FOOD - 1983
Sponsored jointly by FAO and WHO
EVALUATIONS 1983
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, 5 - 14 December 1983
Food and Agriculture Organization of the United Nations
Rome 1985
BITERTANOL
TOXICOLOGY
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Rat
A single oral dose (100 mg/kg) of 14C-phenyl-labelled bitertanol
in propylene glycol was administered by gavage to five male and five
female Wistar rats. Pooled urine and faeces were collected at 4, 8 and
24 h after dosing and then at subsequent 24-h intervals until
sacrifice. In each case, recovered radioactivity exceeded 99 percent
of the administered radioactivity, thus confirming that little, if
any, 14C-respiration occurs. Over seven days, 92.1 percent and
91.9 percent of radioactivity was excreted in the faeces and 7.4
percent and 8.0 percent appeared in the urine of male and female rats,
respectively; 73.2 percent and 71.4 percent of administered
radioactivity appeared in the faeces after 48 h. The urine contained a
number of metabolites, which were not identified. The faeces also
contained numerous metabolites, including two that co-chromatographed
with bitertanol. After hydrolysis, mass spectrometry indicated that
the faeces contained metabolites formed by mono- and di-hydroxylation
of the biphenyl ring system and t-butyl moieties. At sacrifice, seven
days after dosing, tissues contained low levels of radioactivity; the
higher levels, expressed as bitertanol equivalents, occurred in
excretory organs, liver and kidney (male 0.6 ppm and female 3.06 ppm).
Blood contained smaller amounts of radioactivity (male 0.24 ppm and
female 0.32 ppm) while bone, brain, adipose tissue, gonads, heart,
muscle, and spleen each contained less than 0.2 ppm (Puhl et. al.
1979).
TOXICOLOGICAL STUDIES
Special Studies on Embryotoxicity
Rat
Groups of 20 to 22 Long Evans FB 30 rats received daily oral
doses of bitertanol (96.5 percent pure) emulsion by gavage at 0, 10,
30 and 100 mg/kg from day 6 to 15 of gestation. Foetuses were
delivered by Caesarean section on day 20. The body weight gain of the
dams was significantly reduced at 30 and 100 mg/kg during treatment,
and throughout the gestation period at 100 mg/kg. Resorption rates,
foetal deaths, placental weights and sex ratio were unaffected by
treatment. However, foetal weights were significantly reduced at
100 mg/kg and significant foetal stunting occurred at 30 mg/kg and
100 mg/kg. A wide variety of foetal abnormalities occurred at
100 mg/kg, including three litters with cleft palate, one litter with
hydrocephalus and two litters with rib dysplasia. A simple case of
hydrocephalus also occurred at 30 mg/kg, indicating a no-effect level
of 10 mg/kg (Machemer 1977).
In separate experiments, groups of 23 to 25 Long Evans FB 30 rats
were exposed to average concentrations of 0, 2.9, 6.4, 22.4 and 0,
27.6, 60 and 115 mg/m3 of bitertanol aerosol for 4 h daily from day 6
to 15 of gestation. The foetuses were delivered by Caesarean section
on day 20 of gestation. The rate of body weight increase of the dams
was unaffected by treatment. The average foetal weights were reduced
significantly by exposure to 115 mg/m3 and foetuses with stunted
growth were found at aerosol concentrations above 22.4 mg/m3.
Implantation rates, resorption rates, placental weights, skeletal
anomalies, malformation rates and sex ratios were unaffected by
treatment. Treatment-related teratogenic effects were not observed and
6.4 mg/m3 was considered the no-effect level (Machemer & Thyssen
1979).
A suspension of technical bitertanol (95 percent pure) was
administered daily to groups of 25 Sprague-Dawley rats by gavage at
levels of 0, 10, 25 and 65 mg/kg on days 6 to 15 after mating. No
signs of reaction to the treatment were observed. Necropsy was
performed at day 20 of gestation. Body weight gain was unaffected at
10 mg/kg but a significant decrease was observed in dams receiving
25 mg/kg. The 65 mg/kg group displayed a significant reduction in body
weight gain, which persisted after treatment. At necropsy, no effects
were observed on the numbers of corpora lutea, implants, live
foetuses sex ratio, foetal and placental weights, or foetal mortality.
Dose-related increases in the incidences of lumbar (14th) ribs
occurred at 25 and 65 mg/kg. The no-effect level was therefore
established as 10 mg/kg (Nagumo et. al. 1981).
Rabbit
Emulsified bitertanol (96.7 percent pure) was administered daily
to groups of 12 Himalayan rabbits during 6 to 18 days after mating at
0, 10, 30 and 100 mg/kg b.w. Caesarean sections were performed on day
29 of gestation. Although dams treated at 100 mg/kg failed to gain
weight during treatment, and occasionally had reduced feed
consumption, diarrhoea or blood in their urine, pregnancy rates were
unaffected. One dam died. Placental weight, foetal survival and foetal
weight were all reduced at the highest treatment rate. Treatment-
related skeletal malformations were not observed. However, in 12
litters one instance of several pulmonary lobes and another of aplasia
of one lung associated with hypoplasia of the other lung were
observed. The no-effect level determined in this study was 30 mg/kg
(Roetz 1982).
Groups of 15 Himalayan rabbits were treated daily with an
emulsion of bitertanol (93.9 percent pure) at 0, 10, 30 and 100 mg/kg
from day 6 to 18 after mating by gavage. Foetuses were removed on day
29 of pregnancy. Treatment had no effect on behaviour, appearance and
body weight gain of the dams. At 100 mg/kg only, the conception rate
was reduced and the resorption rate increased. Teratogenic effects,
cleft palate and pigeon chest were also observed at the highest
treatment rate. In eight litters, two of the pups had cleft palate
associated with pigeon chest, another had pigeon chest and another had
cleft palate alone. This study confirmed 30 mg/kg as the no-effect
level for bitertanol in the rabbit (Schlueter 1983).
Special Studies on Reproduction
Bitertanol (95.0 percent pure) was fed in the diet to groups of
10 male and 20 female Long Evans PB 30 rats at 0, 20, 100 and 500 ppm.
The animals were maintained on their respective diets prior to mating
for about 70 days. The diet was fed continually throughout three
generations producing two litters in each generation. Pups of the F3b
generation and their F2b parents were necropsied after four weeks
lactation. Although fertility was unaffected by treatment, birth
weight and maternal lactation rate, pup growth and survival were
reduced by treatment at 100 ppm. At 500 ppm, litter size, birth
weights, pup growth rate and viabilities were reduced. At necropsy
maternal liver weight was increased at 100 ppm, confirming 20 ppm as
the no-effect level in rats (Loeser & Eiben 1981).
Special Studies on Mutagenicity
Bitertanol (93.7 percent pure), when tested at 4, 20, 100, 500
and 2 500 µg/plate in Salmonella assays with and without metabolic
activation with 4 LT2 mutants, TA98, TA100, TA1535 and TA1537, was
not found to be mutagenic. Bitertanol was found to be bacteriostatic
above 100 µg/plate in strains TA100 and TA1535 (Herbold 1979).
Bitertanol (95.0 percent pure) was found neither to affect DNA
repair in Bacillus subtilis H17 and M45 nor to be mutagenic
in reverse mutation tests, with or without metabolic activation,
employing Escherichia coli WP2 hcr and Salmonella
typhimurium strains TA1535, TA1537, TA1538, TA100 and TA98 (Shirasu
et. al. 1981).
There was no indication that the cellular DNA of E. coli
strains W3110/pol A+ and p3478/pol A- was modified when bitertanol
was tested with and without S-9 microsome fraction at doses of 100 µg,
333.3 µg, 1.0 mg, 3.3 mg, 10.0 mg and 33.3 mg per plate. However,
precipitation occurred above 333.3 µg/plate (Riach 1981).
Two strains of Sordaria brevicollis, mo-C70 notl+ and mo+ S6
notl-, did not exhibit meiotic aneuploidy when exposed to 0, 0.1,
0.25, 0.5, 1.0 and 2.5 mg/l bitertanol (95.0 percent pure). Spore
maturation was affected at 5 mg/l and spore fertility reduced at
10 mg/l (Bond & McGregor 1981).
Bitertanol did not increase the mutation frequency at the
thymidine kinase gene locus when L5178Y mouse lymphoma cells were
exposed to 10 concentrations ranging from 1.95 to 1 000 µg/ml, with or
without S-9 mix (Bootman & Rees 1983).
In a micronucleus assay, the incidence of Howell-Jolly bodies
among polychromatic erythrocytes was unchanged on treatment of five
male and five female NMRI mice with two oral doses, 24 h apart, of
1 000 and 2 000 mg/kg bitertanol (93.7 percent pure) (Herbold 1978b).
In a dominant lethal assay, male NMRI strain mice in groups of 50
were dosed orally with 1 000 mg/kg bitertanol emulsion and
sequentially mated with a series of 12 virgin females. Fourteen days
after mating, the females were examined for pre- and post-implantation
losses. No effects were observed on fertilization quotas,
preimplantation and postimplantation losses or viable implants
(Herbold 1978a).
Special Study on Carcinogenicity
See under long-term studies.
Special Studies on Skin Sensitization
Guinea pig
A 1 percent emulsion (0.1 ml) of bitertanol was injected
intradermally, with and without Freund's adjuvant, into 20 male and 20
female guinea pigs. After one week, topically applied 25 percent
bitertanol emulsion did not induce a dermal response. Subsequent
dermal challenge after a further two weeks with a 25 percent
bitertanol emulsion failed to provoke an allergic response (Flucke
1981).
Following an initial administration of 0.05 mg/kg, nine repeated
intracutaneous injections of emulsified bitertanol (0.1 mg/kg) over
three consecutive weeks did not produce a significant response.
Intracutaneous injection of an additional 0.05 mg/kg after a further
two-week period also failed to produce signs of dermal sensitization
(Thyssen 1977).
Dog
Oral administration of bitertanol at 35 and 70 mg/kg produced
significant hair loss and reddening of the gums in beagle dogs. After
a six-week withdrawal period, re-treatment with 1.75 mg/kg for 14 days
produced hair loss and gingivitis at an unspecified time towards the
end of the treatment period. Observations on individual animals were
not reported (Hoffman 1977).
Dermal or mucosal irritation were not observed in an inhalational
study in which male beagle dogs were subjected to 15 × 4 h exposures
to bitertanol dust, averaging 28.8 mg/m3. Subsequent re-exposure
after 10 days to dust concentrations averaging 47.1 mg/m3 also failed
to produce signs of dermal irritancy or sensitization (Thyssen &
Kimmerle 1977a).
Special Studies on Potentiation of Acute Toxicity
Since bitertanol can be used in combination with other fungicidal
compounds, acute combination toxicity studies were performed with
Wistar rats. The compounds tested in combination with bitertanol were
captan (Mihail 1982a), triadimenol (Mihail 1982b) and fuberidazole
(Flucke 1980). After determination of the oral LD50 for each
compound, Wistar rats were treated with each test compound in
combination with bitertanol. Groups of 10 rats were used per dose and
the post observation period was 14 days. From the LD50 values for the
individual components, the theoretically expected LD50 was calculated
for each combination. The mixtures were administered in equitoxic
doses, according to their acute toxicity. Slight synergistic effects
were observed for the combination of bitertanol and captan only.
Acute Toxicity
The acute toxicity of bitertanol is generally low. No significant
sex differences were observed. Sheep are the most sensitive to its
oral toxicity but dermal toxicity is uniformly low in those species
tested. Bitertanol is moderately toxic to rats and mice by
intraperitoneal injection. The LD50 in various species by several
routes appear in Table 1.
The principal signs of acute intoxication, altered behaviour,
sedation, motility disturbance, convulsions and dyspnoea, were
consistent with central nervous system toxicity. Signs of
gastrointestinal irritation, vomiting and diarrhoea also occurred and,
in some cases, gastric irritation and mucosal haemorrhage were found
at necropsy.
Table 1 Acute Toxicity of Bitertanol in Animals
Species Route LD50 References
(mg/kg b.w.)
Mouse oral 4 202-4 488 Thyssen & Kimmerle 1977b; Iyatome 1980
Mouse intraperitoneal 520-670 Iyatome 1980
Mouse subcutaneous >1 000->5 000 Thyssen & Kimmerle 1977b; Iyatome 1980
Mouse dermal >5 000 Iyatome 1980
Rat oral 3 300->5 000 Mihail 1982a,b; Iyatome 1980; Thyssen &
Kimmerle 1977b; Flucke 1980; Flucke 1978;
Heimann 1981; Heimann 1983
dermal >5 000 Thyssen & Kimmerle 1977b; Iyatome 1980
intraperitoneal 560-1 160 Thyssen & Kimmerle 1977b; Iyatome 1980
Rabbit dermal >2 000 Hixson 1979
Sheep oral ca 1 000 Hoffmann 1981a
Dog oral >5 000 Hoffmann 1981b
Short-Term Studies
Rat
Groups of 20 male and 20 female Wistar rats were dosed daily by
stomach tube for 28 days at 0, 30, 100 and 300 mg/kg bitertanol
(96.5 percent pure). Half the animals were sacrificed and the other
half were observed for a further 28 days. Although mortality was
unaffected, significant treatment-related effects were observed above
30 mg/kg, particularly in females. Body weight gains were reduced at
100 and 300 mg/kg; at the higher dosage female rats lost hair and had
disturbed behaviour. Also at 300 mg/kg, rats of both sexes had a
moderate leucocytosis and females had reduced haemoglobin and
thrombocyte levels compared with the controls; the males had
relatively increased weight of thyroid, liver and testes while female
rats had increased liver weight but decreased weight of heart,
kidneys, adrenals, ovaries and uterus. Furthermore, four of the female
rats treated at 300 mg/kg showed hyperkeratosis and parakeratosis,
with dilated epithelia of the forestomach and accompanying round cell
and granulocyte infiltration of the epithelial and subepithelial
strata. This study indicated 30 mg/kg as the no-effect level in rats
(Thyssen & Kaliner 1977).
In a subsequent feeding study, groups of 20 male and 20 female
Wistar rats received 0, 150, 600 and 2 400 ppm technical bitertanol
(90.2 percent pure) in their diet for three months. No effects were
observed on behaviour, but food intake in treated females and in males
treated at 2 400 ppm were reduced. Body weight gain was reduced in
treated males and in females treated at 600 and 2 400 ppm. Mortality
was not affected by treatment. At 2 400 mg/kg, haemoglobin
concentration, haematocrit and reticulocyte count were significantly
reduced; also, male rats had reduced erthyrocyte and leucocyte counts
while females had a significant reduction of lymphocytes and segmented
neutrophils accompanying a slightly reduced MCH. Altered liver
function occurred at 2 400 ppm, serum cholesterol and alkaline
phosphatase were elevated and serum protein concentration was reduced.
Male rats had elevated glutamic-oxaloacetic transaminase while female
rats had significantly elevated glutamate dehydrogenase and increased
liver weight at autopsy. The reduced weights of other organs, e.g.
heart, lung, spleen, kidney, adrenal, ovary and testes, corresponded
to the reduced body weight at 2 400 ppm. A no-effect level was not
established in this study (Bomhard & Loeser 1978).
In another feeding study, groups of 15 male and 15 female Wistar
rats received technical bitertanol (purity unspecified) for three
months at 0, 30, 100 and 300 ppm in the diet. The animals were then
sacrificed. At 300 ppm, body weight gain of both male and female rats
was reduced. No toxicologically significant treatment-related effects
were found on serum biochemistry, haematological parameters, serum
cholesterol, blood sugar level or urinalysis. No specific effects were
found at necropsy, indicating 100 ppm in the diet as the no-effect
level (Kroetlinger et al. 1978).
In an inhalational study, groups of 10 male and 10 female Wistar
rats were exposed daily five days per week for three weeks for six
hours to an aerosol of technical bitertanol of unknown purity at an
average concentration of 17.9, 63.3 and 197.9 mg/m3. At the highest
aerosol concentration the male rats had reduced body weight gains but
were without symptoms; the females suffered an impairment of general
condition, however. At necropsy, there were significant increases in
the relative weight of lung in the males and of liver, kidney and
adrenal in females exposed to 197.7 mg/m3; adrenal weights were
slightly but significantly increased at 63.3 mg/m3, indicating
17.9 mg/m3 as the no-effect level for inhalational toxicity of
bitertanol to the rat. Treatment-related histopathological changes
were not observed (Mihail & Kimmerle 1977).
Dog
Encapsulated bitertanol (90.2 percent pure) was administered
orally to groups of four male and four female beagle dogs for 13 weeks
at concentrations of 0, 1, 5 and 25 mg/kg. Water consumption was
unaffected but food consumption was reduced, particularly at 25 mg/kg,
at which dosage treated dogs actually lost weight. Although mortality
was not affected, treatment caused significant effects at 5 and
25 mg/kg, including alopecia, erythema, dermal scale formation,
mucosal irritation, gingivitis, conjunctivitis and lachrymation, as
well as elevation of serum glutamate-pyruvate transaminase and
alkaline phosphatase. Treatment-related changes in haematological and
urinalysis parameters were not observed. At necropsy, increased
hepatic N-demethylase and cytochrome P-450 activities accompanied
increased liver weight at 25 mg/kg. Histologically, at 5 and 25 mg/kg
there was dose-related distension of the dermal stratum epithelium
with some increase in keratinization. In addition, males, which had
dose-related reduction of prostate weight, had corresponding
histopathological changes consistent with reduced maturation at these
doses, indicating 1 mg/kg as the no-effect level (Hoffmann & Schilde
1979).
Long-Term Studies
Mouse
A long-term study was conducted over 24 months to investigate
chronic effects and carcinogenic potential. Four groups of 50 male and
50 female SPF CFI/W strain mice were fed bitertanol (ca. 94 to 95
percent pure) at dietary concentrations of 0, 20, 100 and 500 ppm.
Behaviour, feed consumption, mortality and haematology were not
affected by the treatment. However, at 500 ppm body weight was reduced
and serum alkaline phosphatase was significantly elevated in both
sexes. The latter enzyme concentration was also higher in male mice
treated at 100 ppm, making 20 ppm the level causing no toxicological
effects. Ocular changes were not recorded. At necropsy, hepatic
weights were increased at 500 ppm; the liver was enlarged in females
with an increase in eosinophilic foci microscopically. No dose-related
increase in neoplasia was observed (Bomhard & Loeser 1981b).
Rat
In a combined chronic toxicity/carcinogenicity study, bitertanol
(94 to 95 percent pure) was fed in the diet at concentrations of 0,
20, 100 and 500 ppm to groups of 50 male and 50 female SPF Wistar rats
for 24 months. Rats of both sexes exhibited growth retardation at
500 ppm only, but food consumption, behaviour and physical appearance
were unaffected, making 100 ppm the no-effect level. Ocular changes
were not recorded. Haematological parameters, blood chemistry and
urinalysis were not significantly affected. Mortality was not
adversely influenced by treatment; organ weights, gross pathological
and microscopic examination of the tissues showed no compound-related
effects. There was no indication of an increase in the incidence of
neoplastic lesions (Bomhard & Loeser 1981a).
COMMENTS
After oral administration, the rat excreted radio-labelled
bitertanol and its metabolites, mostly in the faeces. After seven
days, tissues contained low levels of radioactivity. Hydroxylated
metabolites were identified in the faeces but details of the degree of
absorption and the metabolic fate of these compounds of the rat were
not elucidated.
Bitertanol is of low acute toxicity to the mouse, rat, rabbit,
sheep and dog. The symptoms of acute intoxication are consistent with
central nervous system toxicity. Gastrointestinal irritation occurs at
high doses after oral administration.
Subchronic oral administration of bitertanol to dogs induced
significant dermal lesions, including inflammation, scale formation
and hair loss, as well as conjunctival and gingival irritation at
doses above 1 mg/kg/day.
In chronic studies, the rat was less susceptible to bitertanol
toxicity than the mouse. There was no evidence of carcinogenicity in
either species at the doses tested. A battery of short-term
mutagenicity investigations did not indicate any mutagenic potential.
Bitertanol produced maternal toxicity and some evidence of
teratogenicity in rats receiving more than 10 mg/kg/day and in rabbits
at more than 30 mg/kg/day. Clear separation of maternal toxicity and
teratogenicity could not be achieved. Maternal toxicity and
embroyotoxicity, but not teratogenicity, were observed in the rat
multi-generation reproduction study at dietary levels above 20 ppm.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Mouse: 20 ppm in the diet, equal to 3 mg/kg b.w.
Rat: 20 ppm in the diet, equal to 1 mg/kg b.w.
Rabbit: 30 mg/kg b.w./day (based on reproduction)
Dog: 1 mg/kg b.w./day
Estimate of Temporary Acceptable Daily Intake for Man
0 - 0.005 mg/kg b.w.
FURTHER WORK OR INFORMATION
Required (by 1987)
1. Metabolism studies to clarify the metabolic pathway of bitertanol
in mammals.
2. Oral toxicity study in the dog with a minimum duration of one
year.
3. Chronic toxicity and carcinogenicity studies in rats at an
appropriate dosage.
Desirable
Observations in humans.
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See Also:
Toxicological Abbreviations
Bitertanol (Pesticide residues in food: 1984 evaluations)
Bitertanol (Pesticide residues in food: 1987 evaluations Part II Toxicology)
Bitertanol (JMPR Evaluations 1998 Part II Toxicological)