FENAMIPHOS
EXPLANATION
A full toxicological evaluation of the available data was
performed by the 1974 Joint Meeting (Annex 1, FAO/WHO, 1975a) and an
acceptable daily intake of 0-0,0006 mg/kg b.w. was recommended. A
toxicological monograph was prepared (Annex 1, FAO/WHO, 1975b). Since
then a direct request for reevaluation has been received from a Member
State. Additional data have been received and are reviewed in this
monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical Aspects
Effects on enzymes and other biochemical parameters
Blood samples were extracted from an equal number of male and
female Sprague-Dawley rats and then pooled to compare the in vitro
cholinesterase depression by fenamiphos and five of its metabolites on
plasma and erythrocyte cholinesterases. Substances tested included
fenamiphos, fenamiphos sulfoxide, des-isopropyl fenamiphos sulfoxide,
fenamiphos sulfone, des-isopropyl fenamiphos sulfone, and des-
isopropyl fenamiphos. Samples were incubated for one hour, after which
the cholinesterase (ChE) activity was determined. In vitro
inhibition of plasma and red blood cell (RBC) cholinesterase are shown
below in Tables 1 and 2. Erythrocyte cholinesterase was less sensitive
to fenamiphos and its metabolites than was plasma cholinesterase (Lamb
& Landes, 1978).
Male and female TNO/W74 albino rats were exposed to aerosolized
concentrations of fenamiphos (89.8% purity) four hours per day for
five consecutive days. Concentrations obtained were 0, 0.3, 0.6, 3.3,
4, 9 and 28 mg/m3. Plasma and erythrocyte cholinesterase measurements
were performed pre-exposure, after the 1st, 3rd and 5th exposure, and
72 hours after the 5th exposure. Cholinesterases were depressed in a
dose-related manner, with plasma ChE most significantly depressed and
females the more sensitive sex. Plasma ChE was depressed 32 to 90% in
males at > 3.3 mg/m3 and 31 to 96% in females at > 0.3 mg/m3.
Plasma ChE remained 32 to 46% depressed for 72 hours after the fifth
exposure in females at concentrations of > 9 mg/m3. There was no
effect on erythrocyte ChE in males. However, erythrocyte ChE in
females was depressed 28 to 46% at > 9 mg/m3 (Mihail, 1980).
Table 1. Plasma cholinestrase depression (%) induced
in vitro by fenamiphos and its metabolites
Dose (ppm) in whole blood
6.88 68.8 688 5440 6880
Fenamiphos - 0 10 49 69
F. sulfoxide 18 41 48 - 85
F. sulfone 0 13 50 - 87
Des-isopropyl 6 40 90 - 93
F. sulfoxide
Des-isopropyl 0 20 69 - 90
F. sulfone
Des-isopropyl - 2 13 71 91
fenamiphos
Table 2. Erythrocyte colinesterase depression (%) induced
in vitro by fenamiphos and its metabolites
Dose (ppm) in whole blood
6.88 68.8 688 5440 6880
Fenamiphos - 0 0 0 23
F. sulfoxide 5 0 5 - 52
F. sulfone 8 - - - -
Des-isopropyl 4 0 47 - 50
F. sulfoxide
Des-isopropyl 6 0 32 - 61
F. sulfone
Des-isopropyl - 8 0 32 53
fenamiphos
Toxicological studies
Special studies on teratology
Rabbit
Groups of New Zealand rabbits (20 double-mated females per group)
were administered fenamiphos (88.8% purity) orally in corn oil at
doses of 0, 0.1, 0.3, or 1.0 mg/kg body weight from days 6 to 18 of
gestation. Animals were observed daily for clinical signs of toxicity;
they were weighed initially, periodically during the test and at
terminiation. Pups were delivered by Caesarian section and the dams'
ovaries and uteri examined. Foetuses were examined grossly and
prepared for soft tissue and skeletal evaluations. The number of
corpora lutea, implantations, resorptions, live and dead fetuses, and
anomalies were determined.
Dams administered > 0.3 mg/kg demonstrated decreased body-
weight gain, bloody nasal discharge and white mucoid ocular discharge.
There were no compound-related effects on the number of litters,
number of pups per litter, pregnancy rate, the number of corpora
lutea, implantations or gross abnormalities reported. Mean fetal
weight was slightly depressed at 1.0 mg/kg. One dam at 0.3 mg/kg and
2 dams at 1.0 mg/kg aborted 1 and 8 dead pups, and 7 late resorptions,
respectively. In addition, 1 dead fetus was observed in each of 2
litters at the high dose during Caesarian section.
The most common developmental variation observed was the left
carotid arising from the innominate which occurred in 6 to 8 fetuses
(7 to 9%) in each of 3 litters (25%) at doses of > 0.1 mg/kg. There
was no occurrence in the control group and only 1 of 31 litters (3.2%)
noted in the historical control data from the lab performing the
study. More recent historical control data (through July 1985) reveal
the following:
Fetuses % Litters %
Left carotid 11/336 3.3 9/53 17
arising from
innominate
There is some evidence that the incidence of left carotid
anomalies increases in superovulated or artificially-inseminated
rabbits. Interestingly, the rabbits used in this study were naturally
bred, but the "newer" historical data are from artificially-
inseminated rabbits. Furthermore, historical control data for the same
strain of rabbit, but in different labs (also artificially
inseminated) demonstrate that the left carotid arising from the
innominate is also a frequent finding in that colony with roughly 8%
of the fetuses and 25% of the litters demonstrating this anomaly.
Therefore, the biological significance of this finding in relation to
compound administration is dubious. There were, however, 2 fetuses in
1 litter at the high dose with aortic arches having a common truncus,
a finding considered to represent a major malformation.
The incidence of accessory skull bones was observed in each of
the 3 dose groups (> 0.1 mg/kg) but it did not occur in a dose
related manner. A significant increase in the incidence of chain fused
sternebrae was noted at 1.0 mg/kg, with a finding of 5 fetuses in 3
litters. There was also 1 fetus in 1 litter at 0.3 mg/kg with a
finding of chain fused sternebrae. Other skeletal malformations which
occurred only at > to 0.3 mg/kg included fused ribs, scoliosis,
absent vertebrae (thoracic, lumbar, sacral and caudal), and centra
bipartite/malformed. Although these findings occurred in isolated
incidences of 1 fetus in 1 litter they were not reported in control or
0.1 mg/kg dose groups and, therefore, were considered related to
treatment. Fenamiphos was not maternally toxic or teratogenic at
0.1 mg/kg, but was considered fetotoxic at all levels tested
(MacKenzie, 1982).
Rat
Data submitted were incomplete and illegible, rendering adequate
interpretation and evaluation impossible. Individual animal data, by
dam or by litter, were not provided, and visceral, skeletal, and gross
abnormalities or anomalies were not tabulated (Schluter, 1981).
Special Study on Carcinogenicity
Mice
Groups of 6-week-old CD, outbred strain albino mice (50 per sex
per group) were administered fenamiphos (89.5% purity) in the diet at
dose levels of 0, 2, 10 or 50 ppm for 20 months. Observations for
toxicological effects were conducted daily. Body weights and food
consumption were determined weekly. Haematogical parameters were
analyzed at 6, 12, 18 and 20 months of the study. All animals
underwent complete necropsy, including organ weights of liver, kidney,
heart, lungs, gonads, spleen, brain and adrenals. A full complement of
tissues and organs from all animals were examined histopathologically.
Daily observations were not reported. Survival was comparable in
all groups with only a marginal decrease at the high dose. Survival at
20 months was 32 to 45%. The mean amount of fenamiphos consumed
throughout the study was 0.3 mg/kg b.w. at 2 ppm, 1.4 to 1.8 mg/kg at
10 ppm, and 7.4 to 8.8 mg/kg at 50 ppm. Food consumption and
hematology were unaffected by treatment. Organ weights were variable
with a dose-related decrease, although not significant, in relative
brain weight in both sexes. Relative spleen weights were decreased in
both sexes, but most notably in males at > 10 ppm, Relative weight
of gonads in males was decreased at 50 ppm. Gross and micropathology
evaluation did not identify the reason for these weight changes. The
most frequent pathological finding reported was myocarditis (acute and
chronic) in both sexes in all dose groups but without significant
difference associated with dose. There was also a significant degree
of fatty diffuse change in the liver, again without dose differences.
Amyloidosis was observed in all groups and was uniformly widespread in
many organ systems, including liver, spleen, adrenals and submaxillary
salivary glands. Fenamiphos did not demostrate any oncogenic potential
at doses up to and including 50 ppm (Hayes, 1982).
Special Studies on Mutagenicity
Several mutagenicity tests with different systems have been
carried out on fenomiphos (Table 3). No evidence of a mutagenic
potential was observed.
Acute Toxicity
Several acute toxicity studies have been carried out
administering orally to rats fenamiphos or its metabolites. A few
inhalation studies on fenamiphos are also available. The results are
summarized in Table 4.
Moreover, fenamiphos (91.8% purity) was administered orally to
male Wistar rats together with Curaterr(R) VM75 (2,3-dihydro-2,2-
dimethyl-7-benzofuranyl-N-methylcarbamate) to determine if the
combination produced more than additive acute toxic effects. The acute
oral LD50 (in rats) for fenamiphos and for Curaterr(R) VM75 was 4.6
and 8.1 mg/kg, respectively. The mixture, which was essentially a 2:1
ratio (Curaterr(R):fenamiphos), resulted in an LD50 of 6 mg/kg and
demonstrated the combination was additive, but not synergistic
(Mihail, 1980).
Short-Term Studies
Dog
Groups of 4-month-old Beagle dogs (4M/4F per group) were
administered fenamiphos (89% purity) in the diet at dose levels of 0,
0.6, 1.0 or 1.7 ppm for 100 days. Animals were observed twice daily,
and weekly body weight and food consumption measurements were
recorded. Plasma and erythrocyte cholinesterase values were determined
at 0, 4, 6, 8, 10 and 12 weeks. Brain cholinesterase was determined at
termination of the study. Haematology, clinical chemistry, and
urinalysis were not performed. The tissues/organs were not subjected
to gross or histopathological examination.
Table 3. Results of mutagenicity assays on fenamiphos
Test System Test Object Concentrations Purity Results Reference
of fenamiphos
used
In vitro sister Chinese Activated: ? Negative Chen &
chromatid hamster cell 10, 20, 40, (1) Huang, 1982
exchange assay line V79 & 80 µg/ml
(with metabolic
activation)
CHO/HGPRT Chinese Nonactivated: 85% Negative Yang et
mutation assay hamster ovary 100, 110, 120, (2) al., 1984
(3) cells & 130 µg/ml
(CHO-K1-BH4)
Activated:
170, 190, 210,
& 230 µg/ml
Ames test (3) S. typhimurium, 20, 100, 125, 92.4% Negative Schulz,
TA98, TA100, 250, 500, 1985
TA1535 1,000, 2,000
& TA1537 2,500 &
12,500 µg/plate
dissolved in
DMSO
Ames test (3) S. typhimurium, 4, 20, 100, ? Negative, Herbold,
TA98, TA100, 500, & 2,500 but test 1979
TA1535 µg/plate procedure
& TA1537 dissolved in considered
DMSO unacceptable
Table 3. (Con't)
Test System Test Object Concentrations Purity Results Reference
of fenamiphos
used
Micronucleus Mice (NMRI 0.625, 1.25, 92.5% Negative, Herbold,
test strain) & 2.5 mg/kg but test 1980a
(administered procedure
orally twice, considered
24 hr apart) unacceptable
Dominant lethal Mice (male) 5 mg/kg 92.5% Negative Herbold,
(NMRI strain) (mortality at 1980b
10 mg/kg - 3/5
& at 15 mg/kg
- 5/5)
(1) Positive control (Cyclophosphamide) gave expected positive response at 5 µg/ml.
(2) Positive controls (EMS 0.2 µl/ml; BaP 2 µg/ml) yielded expected positive response.
(3) Both with and without metabolic activation.
Table 4. Results of acute toxicity assays in rats of fenamiphos and its metabolites
Substance LD50 LC50
Tested Sex Route (mg/kg b.w.) (mg/m3) Reference
Fenamiphos M oral 2.7 Lamb & Matzkanin,
(88% purity) F oral 3.0 1975
Fenamiphos (90.2% M oral(l) 5.75 Heiman, 1981
purity) oral(2) 17.2
Fenamiphos M oral(l) 5.8 Heiman, 1984
oral(2) 21.0
Fenamiphos M oral(l) 2.4 Crawford &
(88% purity) F oral(l) 3.3 Anderson, 1974a
Fenamiphos M oral(l) 3.15 Crawford &
(analytical grade F oral(l) 2.38 Anderson, 1973
99.7% purity)
Fenamiphos M oral 2.6 Crawford &
sulfone F oral 2.4 Anderson, 1974b
Fenamiphos M oral 2.4 Crawford &
sulfoxide F oral 2.4 Anderson, 1974b
Des-isopropyl M oral 1.4 Lamb & Matzkanin,
fenamiphos F oral 2.1 1977
Des-isopropyl M oral 4.1 Lamb & Matzkanin,
fenamiphos F oral 3.7 1975
sulfoxide
(95% purity)
Table 4. (Con't)
Substance LD50 LC50
Tested Sex Route (mg/kg b.w.) (mg/m3) Reference
Fenamiphos (89.8% M inhal. 131(3) Thyssen, 1979a
purity) F inhal. 130(3)
Fenamiphos (89.8% M inhal. 100(4) Thyssen, 1979a
purity) F inhal. 100(4)
(1) Fasted animals (3) 1 hr exposure
(2) Non-fasted animals (4) 4 hr exposure
There were no toxicological symptoms or effects on body weight
and food consumption. Erythrocyte and brain cholinesterase were
unaffected by treatment. However, plasma cholinesterase was depressed
28 to 35% in males given 1.7 ppm (equal to 0.358 mg/kg b.w.) in the
diet. Females were not similarly sensitive (Hayes, 1983).
Rabbit - Dermal
An aqueous formulation of technical fenamiphos (89.8% purity) was
applied to the clipped dorsal area of 6 male and 6 female New Zealand
rabbits at 0, 2.5 and 10 mg/kg b.w. for 6 hours/day, 5 days/week for 3
weeks. Two additional groups, dosed at 0 and 0.5 mg/kg b.w. were
treated similar to preceding groups. Half of the animals of each group
were abraded.
No signs of toxicity or mortality were observed. Body-weight
gains were decreased in both sexes at the 10 mg/kg dose level. Slight
erythema was observed in all groups during the initial week for
abraded skin sites only, which cleared by day 7. There were no
apparent differences between test and control groups for hematology,
urinalysis, and clinical chemistry determinations. Gross necropsy,
histopathology, and organ weight measurements were unremarkable in
comparison to control. Plasma and erythrocyte cholinesterase values
were significantly depressed at 10 mg/kg in both male and female
rabbits. However, females were somewhat more sensitive and
demonstrated depressed plasma ChE levels at 2.5 mg/kg as well. Brain
ChE values for females at 2.5 mg/kg and 10 mg/kg were depressed by 19
and 23%, respectively. A dose of 0.5 mg/kg, applied dermally, was
without demonstrated effect on cholinesterase activity (Mihail &
Schilde, 1980).
In a separate study, soil containing up to 200 ppm fenamiphos and
fenamiphos sulfoxide, applied to the shaved skin of New Zealand
rabbits, via either single 24 hr. or 5 consecutive 6 hr. exposures did
not adversely affect plasma or erythrocyte cholinesterase activity
(Hixson, 1981).
Rat - Dermal
Male rats were dosed dermally with 100 to 400 µg/cm› fenamiphos,
25 to 800 µg/cm› fenamiphos sulfoxide or 200 to 1600 µg/cm› fenamiphos
sulfone. Test material in acetone was applied and allowed to dry on
the clipped dorsal area of male rats. After 72 hours the animals were
sacrificed and erythrocyte ChE activity determined. Fifty percent
inhibition of erythrocyte ChE activity was achieved with a dose of
208 µg/cm› for fenamiphos, 262 µg/cm› for fenamiphos sulfoxide and
750 µg/cm› for fenamiphos sulfone (Knaak, 1981).
Rat - Inhalation
Three groups of 10 male and 10 female Wistar TNO/W albino rats
weighing 180 to 220 grams were exposed to technical fenamiphos (92.2%
purity) at 0.0, 0.03, 0.25 or 3.5 µg active ingredient/litre
6 hrs./day, 5 days/week, for 3 weeks. Technical fenamiphos was diluted
with a 1:1 mixture of ethanol and polyethylene glycol 400 for
aerosolization in a dynamic flow inhalation chamber.
There were no toxic signs or effects on mortality, body weight
gain, hematology, urinalysis or clinical chemistry measurements. A
significant decrease in plasma and a slight decrease in erythrocyte
ChE for both sexes was noted at 3.5 µg/litre. Brain ChE activity was
not affected. Ninety-eight percent of the particles were 3 microns or
less. There were no gross or histopathological changes, or effects on
organ weights. (Thyssen, 1979b).
Cattle
Dairy cows (1 control, 3 per test group) were fed fenamiphos
sulfoxide in their diets at 0, 2, 6 or 20 ppm for 29 days. There were
no apparent effects of dosing observed based on behaviour, feed
consumption, milk production and body-weight gain. Determination of
whole blood cholinesterase revealed no adverse effects at 2 and 6 ppm.
However, at 20 ppm, significant depression (51%) was observed (Wargo,
1978).
COMMENTS
Data submitted and evaluated by the 1985 Joint Meeting support
the conclusions of the 1974 Meeting with regard to acute toxicity and
anti-cholinesterase potency. Various purities of technical fenamiphos
(88 to 99.7%) produced the same degree of acute oral toxicity to rats.
The major plant and animal metabolites were equally toxic (e.g. 2 to
3 mg/kg/b.w.).
Fenamiphos and its cholinesterase inhibiting metabolites are
better inhibitors of plasma than erythrocyte cholinesterase.
In a 100-day dog feeding study, fenamiphos inhibited only plasma
cholinesterase in males at 1.7 ppm, but not at 1.0 ppm.
Fenamiphos was not maternally toxic or teratogenic in rabbits at
a dose of 0.1 mg/kg b.w. However, fenamiphos was considered fetotoxic
at all doses administered and was found to cause an increased
incidence of chain fused sternebrae at and above 0.3 mg/kg b.w.
Fenamiphos was not oncogenic in a mouse carcinogenicity study,
nor was it mutagenic in several mutagenicity assays.
The rabbit teratology and mouse oncogenicity studies reviewed in
this monograph addendum are acceptable replacement studies for the
corresponding IBT studies reviewed in 1974 and which were subsequently
determined to be invalid.
Very limited new data were available which were evaluated and
have been included in the monograph addendum. The Meeting determined
that additional studies, including rat oncogenicity, rat reproduction,
rat teratology and rabbit teratology with NOEL for fetotoxicity, are
necessary for estimation of a full ADI.
A full reevaluation was not performed, but the meeting
recommended that such an evaluation be performed when the ongoing rat
oncogenicity study becomes available in 1986. The ADI was converted to
a temporary ADI with an increased safety factor to reflect the concern
of the Meeting for fetotoxicity demonstrated in the rabbit teratology
study.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 3 ppm in the diet, equivalent to 0.17 mg/kg b.w.
Dog: 1 ppm in the diet, equivalent to 0.025 mg/kg b.w.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.0003 mg/kg b.w
FURTHER WORK OR INFORMATION REQUIRED (by 1986)
1. Submission of the results of ongoing rat oncogenicity study.
2. Submission of a full legible report and raw data for the rat
teratology study.
3. New rabbit teratology study to clarify the fetoxicity observed at
low dietary levels.
Desirable
Observations in man.
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