PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
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
Rome, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Rome 1985
METHOPRENE
Chemical name: Isopropyl (E-E)-(RS)-11-methoxy-3,7,11-
trimethyldodeca-2,4-diednote
Synonyms: Altosid; Diacon; Dianea; Apex; Kabat
Structural Formula:
CH3 CH3 CH3 o CH3
' ' H / " /
CH3 - C - CH2 - CH2 - CH2 - CH - CH2C = C - C = C - C = OCH
' H H \
OCH3 CH3
Empirical Formula: C19H34O3
Other information on identity and properties:
Molecular weight: 310
State: A pale yellow liquid with faint fruity
odor
Boiling pont: 100°C at 0.05 mm Hg
Vapour pressure: 2.37 × 10-5 mm Hg at 25°C
1.60 × 10-4 mm Hg at 40°C
Solubility: All organic solvents - infinite; water -
1.39 ppm
Stability: "good"
Cis-trans ratio: >8.92
Flash point: 187°C - open cup method
Octanol/water
partition coefficient: >10,000
Specification of technical material: No data
EVALUATION OF ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution, Elimination and Bio-transformation
Mouse
Mice (eight males and two females) intubated with an alcoholic
solution of tritiated methoprene at 7.7 µ cui/g b.w. eliminated 63.6
percent of the administered radioactivity in urine (labeled at the
C-10 position) and 12.3 percent in faeces within 24 hours of dosing.
Total cumulative recovery of tritium radioactivity at the end of 96
hours was 82 percent (68 percent in urine and 14 percent in faeces).
Autoradiographic studies of single animals sacrificed at various
intervals after the dose of tritiated methoprene showed a high
concentration of radioactivity in the stomach and small amounts in the
liver and kidneys at 0.5 hours post-treatment. At 6 hours,
radioactivity occurred primarily in the small intestine, descending
colon and rectum. By 12 hours, radioactivity had essentially been
eliminated from the body and no residual radioactivity was found at 48
hours. Placental transfer of radioactivity was not evident in two
pregnant mice. (Cohen & Trudell, 1972).
Rat
In male and female rats (25 rats of each sex) given a single oral
dose of 25 mg [5-14C]-methoprene/gk b.w., a total of 43.7% of the
applied radioactive dose was excreted within 24 hours in urine (13%),
faeces (5.2%) and expired air (25.5%). During the next 48 hours, an
additional 5.6%, 9.6% and 10.1% (i.e. a total of 20.3%) was
eliminated in the corresponding routes. By the end of a 5-day
collection period, the cumulative 14C recovery from all 3 routes
amounted to 76.4% of the administered dose (19.6% in urine, 18% in
faeces and 38.8% in expired air). The maximum biological half-life for
about 60% of the radioactivity was stated to be about ten hours and
107 hours for a further 15%. Plasma concentration of 14C in these
rats peaked at 6 hours post treatment and then declined slowly with a
half-life of about 48 hours during the second to the fifth day after
dosing. A sex difference in the rate of eliminiation of radioactive
methoprene was not evident. Total amount of radioactivity in the
plasma at 6 hours was 1.63% of the administered dose. Rats with
cannulated bile duct excreted an average of about 27.4% of a single
oral dose of 25 mg [5-14C]methoprene/kg b.w. in bile during the first
48 hours with the rate of biliary elimination being most rapid during
the first 24 hours after dosing. Analyses of tissues from male rats
sacrificed at various intervals after a single oral dose of
[5-14C]-methoprene at 25 mg/kg b.w. showed highest -14C levels in
liver, plasma, kidney and lung during the first 6-12 hours post
dosing. Significant levels of -14C residues were later found also in
heart, adipose tissue and adrenal glands. At all time intervals
studied, 14C levels were low in brain, eyes and testes. Whole-body
autoradiography showed that much of the -14C was located in organs
concerned with absorption, biotransformation and excretion. A
relatively high concentration of radioactivity was found in the
adrenal cortex, lacrimal glands and adipose tissue after 48 hours.
A number of unidentified metabolites were excreted in urine,
faeces and bile of rats treated with a single oral dose of 25 mg
[5-14C]-methoprene/gk b.w. Unchanged methoprene was found only in the
faeces and accounted for only a small proportion of the applied
14C-dose. (Chasseaud, et al., 1974).
Guinea-pig
A guinea-pig given a single oral dose of approximately 49 mg
[5-14C]-methoprene/gk b.w. eliminated a total of about 50% of the
administered dose in urine (24%), faeces (9%) and expired air (17%)
within 24 hours of dosing. In untreated urine, 95-99% of the
radioactivity recovered was glucuronic acid conjugates and other polar
compounds. In urine treated with H-1 glucuronidase, the major
identifiable components were 11-hydroxy-3,7,11-trimethyl-dodeca-2,
4-dienoic acid (ZR-724) and 11-methoxy-3,7,11-trimethyl-dodeca-2,
4-dienoic acid (ZR-725). These two compounds together amounted to
about 70% of the radioactivity in the urine. Other urinary metabolites
identified included isopropyl 11-hydroxy-3,7,11-trimethyl-2,
4-dodecadienoate (ZR-669), 7-methoxy citronellic acid (ZR-1945).
Unchanged methoprene accounted for about 77-79% of the radioactivity
recovered in the faeces. ZR-669, ZR-725 and ZR-724 were also found as
faecal metabolites (Chamberlain, et al., undated a; Chamberlain,
et al., undated b).
TOXICOLOGICAL STUDIES
Special Studies on Reproduction
Rat
Groups of 20 male and 20 female weanling rats (Long Evans) were
fed technical methoprene (86.9-87.5% purity) at 0, 500 or 2500 ppm
until at least 100 days of age prior to mating to initiate a three-
generation (one litter/-generation) reproduction study. Pups (F1,
F2) to become parents were selected at weaning and, following a
70-day growth and feeding period, were mated to produce the successive
generations. In the parental generations, no compound-related effects
were observed on mortality, food consumption during the growth period,
maternal growth rate during gestation and lactation periods, mating
performance, pregnancy rate and duration of gestation period. Total
weight gain during the growth period was slightly decreased at
2500 ppm in Fo and F1 animals (both sexes). At the top dosage level,
mean pup weight was reduced in F2 litters on day 21 and in F3
litters on days 14 and 21. Additionally, the mean number of pups born
dead per litter was elevated in F3 litters of this dosage group.
There were no treatment-related effects on the other tested parameters
including litter size (live pups) at birth, survival of pups over the
lactation period, sex ratio of pups and necropsy findings of F3
weanlings. The no-effect level on reproduction appeared to be at least
500 ppm (Killeen & Rapp, 1974).
Special Studies on Teratogenicity
Mouse
Groups of 30 mated mice of "ICR lineage" were intubated with
technical methoprene (purity 95.7%) in olive oil at 0, 50, 200 or
600 mg/kg b.w./day from days 7 to 14 of pregnancy. The pregnant dams
(20-23 mice in each group) were sacrificed on day 18 of pregnancy and
the foetuses were removed for external, internal and skeletal
examination. There were no compound-related deaths. Pregnancy rate
(66.7-76.7%) and food or water consumption during the gestation period
were comparable in all groups. An increase in body weight (compared to
controls) was noted in pregnant dams at both 200 and 600 mg/kg b.w. on
day 18. The mean number of implantations and the mean number of live
foetuses were both elevated at the top dosage level. Body weight of
female foetuses of all treated groups was increased. No treatment-
related effects were seen on the mean number of dead embryos or in the
sex ratio of foetuses. No internal or external abnormalities were seen
in foetuses of control and treated groups. (Specific information was
not available on the number of foetuses per control or treated group
examined for such abnormalities). Foetuses of all treated groups
displayed a statistically significant increase in the number of caudal
vertebrae, as compared to controls.
These remaining pregnant mice were allowed to litter and rear
their young until weaning prior to sacrifice. Pups from five litters
per dosage group were sacrificed at weaning and those from the
remaining litters were observed for seven additional weeks. No
mortality or abnormal signs were noted in the dams. Maternal body
weight change was stated to be unaffected during gestation or after
parturition. Compound-related effects were not apparent on the mean
number of implantations, duration of gestation period, mean litter
size and survival rate of pups at birth or at weaning. No adverse
effects were noted on the rate of physical development in pre-weaning
pups as judged by auricle development, hair growth and opening of eye
lids. In weaned pups, no dose-related effects were seen on the time
when descent of testis or opening of vagina was observed. Behaviour of
pups during the ten-week post partum period was normal. Pups
necropsied at three or ten weeks of age showed no gross or skeletal
abnormalities. A non-dose-related decrease in organ/body-weight ratio
of testis was noted in pups of all treated groups sacrificed at 21
days and in those of mid-and low dosage groups sacrificed at 70 days.
Other variations from control values in the weight of a number of
organs (such as the spleen and the kidney) were also observed but
these were not dose-related, or only confined to the top dosage group.
Histological examination of ovaries and testes of pups reportedly
revealed a single case of atrophy of seminiferous tubules at
50 mg/kg b.w. (Nakasawa, et al., 1975a).
Rabbit
Groups of 10 pregnant Japanese rabbits were treated orally with
technical methoprene (purity 95.7%) in olive oil at 0, 50, 200 or
2000 mg/kg b.c./day on days 7-18 of pregnancy. The does were
sacrificed on day 28 of pregnancy and the foetuses were removed by
caesarian section for examination for external, internal and skeletal
abnormalities. There was no mortality or abnormal symptoms. In the top
dosage group, two does aborted and maternal weight gain was depressed.
An increase in the incidence of foetal deaths and in the proportion of
female foetuses also occurred at the top dosage level. Foetuses at
both 200 and 2000 mg/kg exhibited a non-dose-related decrease in tail
length. No compound-related effects were observed with respect to the
mean number of implantations, litter size (live foetuses), body weight
or body length of foetuses or frequency of foetal abnormalities. The
study demonstrated methoprene to be non-teratogenic under the
conditions of the experiment (Nakasawa, Matsumia & Ishikawa, 1975).
Special Studies on Mutagenicity
See Table 1 for summary of mutagenicity tests.
Special Studies on Carcinogenicity (Also see under "Long Term
Studies")
Mouse
Groups of 50 male and 50 female mice (Charles River CD-1 strain)
were fed dietary levels of technical methoprene (86.9-87.5% purity) at
0, 250, 1000 or 2500 ppm for 78 weeks. All animals in the study were
subjected to gross pathological examination. At termination,
histopathological evaluation was conducted on a set of about 20
tissues plus any grossly abnormal tissues from all terminal survivors
of control and top-dosage groups, brain, heart, liver, lung, kidney,
adrenal gland and urinary bladder from ten male and ten female
terminal survivors of the two lower dosage groups and gross lesions
from all animals dying during the study and from the other terminal
survivors of the two lower dosage groups.
Mortality was not increased by treatment. Survival in all groups
was comparable except for females at 1000 ppm where survival rate was
40% at 72 weeks when animals in that group were sacrificed for
necropsy compared to 45-50% in the other groups. Clinical signs, food
consumption and body weight were comparable between control and
treated groups. No gross pathological findings attributable to the
compound were observed. Histopathologically, a dose-related increase
in incidence and severity of liver lesions characterized by pigment
deposition in cytoplasm of liver parenchymal cells and focal
accumulations of macrophages with brownish foamy cytoplasm was found
in terminal survivors (both sexes) at 1000 ppm and above. An elevated
frequency of amyloidosis of the small intestine in females was also
seen at 2500 ppm. There was no compound-related increase in incidence
of any particular type of tumour. Under the conditions of the
experiment, there was no evidence suggestive of carcinogenic activity
of the compound (Wazeter & Goldenthal, 1975a).
Special Studies on Eye and Skin Irritation
A primary eye irritation study in New Zealand White rabbits
indicated that technical methoprene was not an irritant to eyes
(Hallesy & Hill, 1973a).
Technical methoprene was found to have a low irritant potential
to skin in a primary dermal irritation study using New Zealand White
rabbits (Hallesy & Hill, 1973b).
Special Studies on Skin Sensitization
Results of a skin sensitization study in guinea-pigs showed that
technical methoprene was not a skin sensitizer. (Zoecon, 1975a).
Special Studies on Endocrine Activity in Mammals
Immature female mice (19-21 days of age) subcutaneously treated
with methoprene at 0.015 or 0.15 mg/kg b.w./day for three days
exhibited no increase in uterus/body weight ratio. When given
subcutaneously to castrated male rats (21 days old) at 0.37 or
3.7 mg/kg b.w./day for seven days methoprene did not induce an
increase in organ/body weight ratio of seminal vesicles, ventral
prostate or levator ani. In bilaterally adrenalectomized male rats
(21 to 23 days old), daily subcutaneous doses of 0.9 or 9 mg/kg b.w.
of methoprene for six days resulted in no decrease in thymus/body
weight ratio.
Results of the above studies suggest methoprene to be without
estrogenic, androgenic, anabolic and glucocortical activity. (Rooks,
undated).
Special Studies on Toxicity of Metabolites of Methoprene
See Table for metabolite toxicity studies.
Eye and Skin Irritation
In a primary eye irritation study with New Zealand rabbits,
ZR-1564 (technical 97.7%) was found to be slightly irritating to the
eyes (Wazeter & Goldenthal, 1973).
Results of primary skin irritation study in New Zealand rabbits
indicated that ZR-1564 (technical 97.7%) has a low potential for skin
irritation (Wazeter & Goldenthal, 1973).
Table 1. Special Studies on Mutagenicity
Concentration of
Test System Test Object Methoprene used Purity Results Reference
Ames' Test S. typhimurium 0.2 to Not Negative in Hsia,
(with and strains TA 98, 20 ug/plate specified the presence et al.
without TA 100, TA 1535, of metabolic 1979
metabolic TA 1537, TA 1538 activation
activation)
Dominant Rat a) single i.p. doses Not Negative Johnston
lethal up to 2000 mg/kg bw specified 1973
prior to mating
weekly for 8 consecutive
weeks
b) daily i.p. doses up
to 200 mg/kg bw for
5 days prior to mating
weekly for 7 consecutive
weeks
Table 2. Acute oral toxicity in rats: methoprene metabolites
LD50
Metabolite Sex (mg/kg b.w.) Reference
ZR-724 Tech. M + F > 6810 Knott & Johnston, 1972a
ZR-725 Tech. M > 6810 Knott & Johnston, 1972b
F 4870
ZR-669 Tech. M 8910 Zirzow & Johnston, 1972
F 8260
ZR-1945 M > 10,000 Olson, 1973
F 5763
ZR-1602 M + F > 5000 Jorgenson, 1973a
ZR-1564 M + F > 5000 Jorgenson, 1973b
ZR-724: 11-hydroxy-3,7,11-trimethyl-dodeca-2,4-dienoic acid
ZR-725: 11-methoxy-3,7,11-trimethyl-dodeca-2,4-dienoic acid
ZR-669: isopropyl 11-hydroxy-3,7,11-trimethyl-2,4-dodecadienoate
ZR-1945: 7-methoxy citronellic acid
ZR-1602: 7-hydroxy citronellic acid
ZR-1564: 7-methoxy citronellal
Acute Toxicity
The acute toxicity of methoprene to several animal species is
given in Table 3.
Table 3. Acute toxicity of methoprene in animals
LD50
Species Sex Route (mg/kg b.w.) Reference
Rat M oral > 34,600 Jorgenson & Sasmore, 1972a
Rat ? i.p. 4800 Jorgenson & Sasmore, 1972a
Rat M inhalation > 210 mg/*l air Hiddemen, 1972
(4-hour
exposure)
Dog M+F oral > 5000 Hallesy, Shott & Hill, 1972
Dog M+F inhalation ** Zoecon, 1975b
* LC50 in terms of nominal chamber concentration of the test material as an aerosol
** No mortality resulted when dogs were exposed over a 6-hour period to a mist (particle
size: 2 to 5 microns) of technical methoprene as a 2% aqueous ethanol solution at
estimated total amounts of up to 29.9 mg/kg b.w. (males or 19.4 mg/kg b.w. (females)
Short-Term Studies
Oral
Rat
In a range finding study, groups of Sprague-Dawley rats (five
males and five females per group) were fed a diet containing technical
methoprene (68.9%) at 0, 1000, 5000, 10,000, 20,000 or 40,000 ppm for
two weeks and then maintained on a control diet for an additional
week. No mortality occurred. Dose-related growth depression, noted at
20,000 ppm and above on weeks 1 and 2, was still evident on week 3,
although less marked. These effects were attributed to palatibility
problems with the test material. Food consumption, decreased on weeks
1 and 2 at both 20,000 and 40,000 ppm, was not significantly different
from controls on week 3. Gross pathological examination of all animals
in the top-dosage group reportedly revealed no abnormalities
(Jorgenson & Sasmore, 1972a).
Groups of 15 male and 15 female Sprague-Dawley rats (approx 28
days old) were fed technical methoprene (68.9%) in their diet at 0,
250, 500, 1000 or 5000 ppm for 90 days. There was no compound-related
mortality. Behaviour was normal. Weekly body weight, food consumption
and haematology at weeks 4, 8 and 13 were comparable to controls.
Terminal blood chemistry values were not affected in any dose-related
pattern. Urinalysis results at 13 weeks were normal. At termination,
animals of the top-dosage group showed an increase in organ/body
weight ratio of liver (both sexes) and of kidney (males only).
Microscopic evaluation of kidney and liver from all animals of control
and top-dosage groups and from animals at 1000 ppm and a number of
selected tissue from ten males and ten females per control and top-
dosage group revealed a slightly higher incidence in males at 5000 ppm
than in controls of a kidney lesion characterized by vacuoles within
swollen convoluted tubules. In addition, renal tubular regeneration,
not seen in concurrent controls or in the females, was present in
three males at 1000 ppm and seven males at 5000 ppm. A no-effect level
could not be determined because no animals below 1000 ppm were
subjected to histological evaluation of the kidney (Jorgenson &
Sasmore, 1972b).
Dog
Groups of three young adult male beagles were fed dietary levels
of technical methoprene (68.9% purity) at 0, 1000, 5000, or 20,000 ppm
for two weeks and then placed on control diet for an additional week
in a range-finding study. There was no mortality. Actual weight loss
occurred at 10,000 ppm and above on weeks 1 and 2, and growth
depression was seen at both 1000 and 5000 ppm on week 2. Food
consumption was reduced at both 10,000 and 20,000 ppm during the
first two weeks. Terminal sacrifice of all dogs at the end of three
weeks showed a dose-related increase of liver/body weight ratio in all
treated groups. Morphologic changes of the liver (swelling and
vacuo-lation of hepatocytes) were found at both 10,000 and 50,000 ppm.
No treatment-related histological lesions in adrenal glands, kidney or
spleen were evident (Jorgenson & Sasmore, 1972a).
Groups of four male and four female beagles (about 19 weeks old)
were fed diets containing technical methoprene (68.9%) at 0, 250, 500
or 5000 ppm for 90 days. No mortality occurred. Behaviour, body
weight, food consumption and haemotology were not adversely affected.
Urinalysis at weeks 4, 8 and 13 and eye examination at termination
reportedly showed no abnormal findings. Serum alkaline phosphatase
level was elevated at 5000 ppm in both sexes at weeks 4, 8 and 13. At
terminal sacrifice, organ/body weight ratio of liver was increased in
both sexes at 5000 ppm. Gross pathological examination of all animals
in the study and microscopic evaluation of a number of selected
tissues, including the liver, from all animals of control and top-
dosage groups failed to show any treatment-related changes. The study
demonstrated 500 ppm as a no-effect level (Jorgenson & Sasmore,
1972b).
Dermal
Rabbit
Groups of five male and five female Japanese Albino rabbits
were exposed dermally to undiluted technical methoprene (purity
not specified) at 0, 100, 300, 900 or 2700 mg/kg b.w./day for 30
consecutive days. No mortality was observed. Food and water
consumption during the study and terminal urinalysis and blood
chemistry were not affected. Erythema at the application site was
noted at and above 300 mg/kg b.w. Males at 300 mg/kg b.w. and above
and females of all treated groups exhibited an increase in neutrophil
counts at termination and actual weight loss or growth depression over
the course of the experiment. Terminal leucocyte counts were elevated
in all treated groups (both sexes). Variations from control values
were seen in the weight of liver at the top dosage level and of kidney
at the two high dosage levels. Gross and histopathological examination
of the animals indicated the only compound-related findings being
confined to the treated skin sites (Nakasawa, et al., 1975b).
Inhalation
Rat
Groups of ten male and ten female rats were exposed by inhalation
to an aerosol of technical methoprene (purity 68.9%) at nominal
chamber concentrations of 0, 2 or 20 mg/l air, four hours/day, five
days/week for three consecutive weeks. No animals died. Animals at
20 mg/l air had a nasal discharge during each exposure. Weekly body
weight and terminal haematological values were comparable to controls.
Blood chemistry studies at the end of study showed variations from
control values in a number of parameters such as serum alkaline
phosphatase, total bilirubin, etc., in both dosage groups but did not
indicate a consistent pattern of toxicity. Gross necropsies and
histological evaluation of liver, lung, kidney and trachea showed no
treatment-related changes (Olson & Willigan, 1972).
Dog
Groups of three male and three female beagles were exposed via
inhalation to technical methoprene (in 2% ethanol solution) as an
aerosol at 0.0125, 0.0250 or 0.0625 mg/kg b.w./day, six days/week for
four weeks (particle size of aerosol = 0.5 - 2.5 microns). Vehicle
control and untreated control groups had two males and two females
each. There was no mortality. Salivation was noted in two animals of
the top-dosage group during exposure the first day. No
compound-related effects were reported in any of the tested parameters
measured: body weight, food and water consumption, haematology, blood
chemistry, urinalysis and gross histopathological finds (Masao &
Hiroyuki, 1975).
Long-Term Studies
Rat
Groups of 50 male and 50 female rats (Charles River CD strain)
were fed technical methoprene (86.9% purity) in their diet at 0, 250,
1000 or 5000 ppm for two years. Survival rate, not influenced by
treatment, was 38-54% in males and 48-68% in females of all groups
including the control at the end of the study. (Fifty to 64% males and
62-72% females in control and treated groups lived at least 96 weeks).
General appearance and behaviour, body weight and food consumption
were not adversely affected. No compound-related effects were noted on
haematological, biochemical and urine parameters measured on five
males and five females per group at five intervals over the course of
the study. Ophthalmoscopic examination revealed no changes related to
treatment. Absolute and relative weight of the liver was elevated at
5000 ppm in females. Gross pathological examination indicated no
findings attributable to inclusion of methoprene in the diet.
Histopathological evaluation of a wide range of tissues revealed an
increased incidence of hepatic lesions such as bile duct proliferation
and portal lymphocyte infiltration in males at 5000 ppm. There was no
significant difference between control and treated groups in incidence
of any particular type of tumour. Based on the data, 1000 ppm was the
no-effect level (Wazeter & Goldenthal, 1975b).
Comments
In mammals, a single oral dose of methoprene is eliminated via
the urine, the faeces and the expired air. Limited data available on a
guinea-pig, a cow and a steer showed degradation of the compound to
primary metabolites and to natural body constituents.
Methoprene and its known metabolites in animals and plants all
appear to have a low order to acute oral toxicity with the LD50
values being over 5000 mg/kg b.w. for the parent compound in both rats
and dogs and for the metabolites in rats.
A three-generation (one litter/generation) reproduction study in
rats demonstrated a no-effect level on reproduction of at least
500 ppm. Teratology studies in both mice and rabbits gave no evidence
of teratogenicity under the conditions of the experiments. It should
be noted, however, that pregnant mice and rabbits were treated with
methoprene from days 7 to 14 and from the days 7 to 18 of gestation,
respectively. The entire period of organogenesis, therefore, was not
covered. The available mutagenicity studies were negative. A 78-week
mouse and two-year rat oncogenicity study were negative.
A minimum no-effect level of 500 ppm for rats was based on a
three-generation study, and a no-effect level of 500 ppm for dogs was
based on a 90-day feeding study. It was not possible to establish a
no-effect level in the 90-day rat feeding study because of a kidney
lesion, although a two-year rat study did not show this renal effect.
Because no dog study longer than 3 months was available, both
teratology studies presented were inadequate, and the three-generation
reproduction study in rats covered only one litter per generation, the
meeting allocated only a temporary ADI.
Level Causing no Toxicological Effect
Rat: 500 ppm in the diet, equivalent to 25 mg/kg b.w.
Dog: 500 ppm in the diet, equivalent to 12.5 mg/kg b.w.
Estimate of Temporary Acceptable Daily Intake for Humans
0 - 0.06 mg/kg b.w.
FURTHER WORK OR INFORMATION
Required (by 1987)
A six-month feeding study in dogs.
A two-generation (two litters/generation) reproduction study in rats.
Adequate teratology studies.
Desirable:
Observations in humans.
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1972b Technical (1) Ninety-day subacute in rats (2) Ninety-
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Jorgenson, T.A. Untitled letter report to Zoecon Corp. on acute oral
1973a toxicity study in rats of ZR-1602. Stanford Research
Institute, USA. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Jorgenson, T.A. Untitled letter report to Zoecon Corp. on acute oral
1973b toxicity study in rats of ZR-1564. Stanford Research
Institute, USA. Submitted by Zoecon Corp. USA to WHO.
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Killeen, J.C. & Rapp, W.R. A three-generation reporduction study of
1974 the AltosidTM in rats. Bio/dynamics Inc., USA.
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Knott, W.B. & Johnston, C.D. (1972). ZR-724 Technical. Acute oral
1972a toxicity to rats. Unpublished report from Woodard
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Knott, W.B. & Johnston, C.D. (1972). ZR-725 Technical. Acute oral
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Masao, N. & Hiroyuki, M. Determination of subacute toxicity to Beagle
1975 dogs resulting from Altosid inhalation. Nomura Research
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WHO. (Unpublished)
Nakasawa, M., Matsumiya, H. & Ishikawa, I. Test of Altosid Toxicity,
1975 III: determination of teratogenic potential of Altosid
administration orally to rabbits. Nomura Research
Institute, Japan. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Nakasawa, M., Nomura, A., Furuhashi, T., Mihori, J. & Ikeya, E.
1975a Determination of teratogenic potential of Altosid
administered orally to mice. Nomura Research Institute,
Japan. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Nakasawa, M., Shimizu, T., Miyoshi, K., Hasegawa, R., Furuhashi, T.,
1975b Ogawa, M. & Mihori, J. Test of Altosid toxicity, II:
rabbit subacute dermal toxicity of Altosid. Nomura
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Olson, W.A. & Willigan, D.A. Three-week inhalation exposure - rats.
1972 Altosid (Technical grade). Hazleton Laboratories, Inc.,
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(Unpublished)
Olson, W.A. Acute oral - Rats. ZR-1945 Final report. Hazleton
1973 Laboratories, USA. Submitted by Zoecon Corp. USA to
WHO. (Unpublished)
Rooks, W.H. II. Report on the mammalian endocrine testing
undated performed on ZR-515. Syntex Research Center, USA.
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Wazeter, F.X. & Goldenthal, E.I. ZR-1564. Acute toxicity studies in
1973 rabbits. International Research and Development Corp.,
USA. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Wazeter, F.X. & Goldenthal, E.I. Eighteen-month oral carcinogenic
1975a study in mice. International Research and Development
Corp., USA. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Wazeter, F.X. & Goldenthal, E.I. Two-year oral toxicity study in rats.
1975b International Research and Development Corp., USA.
Submitted by Zoecon Corp. USA to WHO. (Unpublished)
Zirzow, G. & Johnston, C.D. Sample No.ZR-669 Tech.Acute oral toxicity
1972 to Woodard Research Corp., USA. Submitted by Zoecon
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Zoecon Corp. USA. Test of Altosid toxicity, V: skin sensitization
1975a of Altosid in guinea-pigs. Nomura Research Institute,
Japan. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)
Zoecon Corp. USA. Investigation of AltosidR toxicity, VII:
1975b determination of toxic consequences of acute inhalation
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Institute, Japan. Submitted by Zoecon Corp. USA to WHO.
(Unpublished)