CYHEXATIN: Addendum
First draft prepared by
A. Moretto
Institute of Occupational Medicine,
University of Padua, Padua, Italy
Explanation
Evaluation for acceptable daily intake
Biochemical aspects
Absorption, distribution and excretion
Toxicological studies
Acute toxicity
Reproductive toxicity
Embryotoxicity and teratogenicity
Observations in humans
Comments
Toxicological evaluation
References
Explanation
The toxicological data on cyhexatin (tricyclohexyltin
hydroxide) were reviewed by the Joint Meeting in 1970, 1973, 1978,
1980, 1981, 1988, 1989 and 1991 (Annex I, references 14, 20, 30, 34,
36, 53, 56 and 62). The 1991 Meeting reviewed draft reports of
several toxicokinetic studies with both technical and micronized
cyhexatin and of a multigeneration study in rats; final reports of a
teratogenicity study in rabbits and a multigeneration study in rats
were also reviewed. An ADI was established at 0-0.001 mg/kg bw on
the basis of the multigeneration study in rats. The 1991 Meeting
recommended that cyhexatin be reviewed again in 1994 when the
following additional information would become available: (i)
observations in humans; (ii) clarification of the influence of
particle size on the toxicokinetics and toxicity of cyhexatin; (iii)
determination of the effect of restricted food intake on
reproduction parameters, preferably by a limited paired-feeding
study in rats during gestation and lactation; and (iv) information
on the particle size of cyhexatin residues in food.
Evaluation for acceptable daily intake
1. Biochemical aspects
Absorption, distribution and excretion
Mice
Absorption of uniformly labelled 14C-cyhexatin applied at 1
mg/kg bw to a 1.2-cm2 area of the skin of the upper back of
7-8-week-old Dublin ICR mice was slow. The geometric mean percentage
dermal penetration was 0.7 after 1 h, 1.4 after 6 h and 5.5 after 24
h (Grissom et al., 1985).
Rats
Two Wistar rats weighing about 200 g were given a single oral
dose of 5 mg of 119Sn-cyhexatin in a gelatin capsule, and urine
and faeces were collected for 10 consecutive days after dosing.
Total radioactivity was recovered quantitatively in excreta; 75-85%
was excreted within the first four days after administration. Most
of the radiolabel (97.5-98.1%) was found in the faeces, suggesting
little absorption from the gastrointestinal tract. This assumption
was confirmed in guinea-pigs given 2 mg of 119Sn-cyhexatin in
gelatin capsules, since little radiolabel was found in the bile
(Smith & Fischer, 1970).
Radiolabel concentrations were measured in 53 Wistar rats fed
diets containing 100 ppm of 119Sn-cyhexatin for 90 days and
sacrificed periodically during treatment and up to 115 days after
the end of treatment. The tissue 119Sn content increased during
the first two weeks of feeding and then remained substantially
unchanged. After 90 days of feeding, kidney, liver, brain, heart,
spleen and muscle had the highest concentrations of 119Sn (0.4-0.8
ppm). After cyhexatin was withdrawn from the diet, the level of
119Sn in the tissues decreased slowly, with a half-life of about
10 days, except in muscle and brain where the half-life was about 40
days. Trace amounts were still present after 115 days. Animals that
received comparable amounts of 119Sn as stannic chloride had much
lower tissue levels of 119Sn. About 60% of total radiolabel in
muscle tissue soon after withdrawal of cyhexatin was 119Sn, but
the level decreased to about 25% after 80 days;
119Sn-dicyclohexyltin oxide represented about 20 and 70% of total
radiolabel, respectively (Smith & Fischer, 1970).
Forty OFA-SD (10PS Caw) female rats were administered 3 mg/kg
bw of technical-grade or micronized cyhexatin (purity, 96%)
suspended in carboxymethylcellulose in 5 mg/ml water by gastric
intubation. Five female rats served as controls. Groups of five
treated rats were bled 0.5, 1, 3, 4, 6, 8, 12 and 24 h after dosing;
controls were bled at 24 h only. Urine and faeces were collected
throughout the 24-h period from five treated animals and the
controls. No deaths or clinical signs were observed. The mean
urinary levels of tin over 24 h were 9.0 µg/l in controls and 69
µg/l in rats treated with technical-grade cyhexatin and 8.5 µg/l in
controls and 85 µg/l in rats treated with micronized compound. The
mean faecal levels were 1.9 µg/g in controls and 177 µg/g in rats
given the technical grade, and 2.4 µg/g in controls and 203 µg/g in
rats receiving micronized compound (Barrow, 1991a,b,c,d).
The most relevant results are reported in Table 1. The
bioavailability and peak blood concentrations (measured as tin) of
micronized cyhexatin were about twice those of technical-grade
cyhexatin, but the bioavailability of both formulations was low (1.2
and 0.5%, respectively). The half-life in blood was about 2 h.
Table 1. Pharmacokinetics of technical-grade and micronized cyhexatin in female OFA-SD rats
after oral and intravenous administration
Treatment Bioavailability Half-life Peak blood Peak time Excretion at 24 h (% of dose)
(% of dose) (h) conc. of tin in blood
(µg/l) (h) Urine Faeces
3 mg/kg bw 0.53 1.16 4.56 2 0.3 14
technical-
grade, oral
3 mg/kg bw 1.2 1.55 8.1 2.5 0.5 25
micronized,
oral
0.5 mg/kg bw (100) 3.35 2019.6a 0.8 35
micronized,
intravenous
From Barrow (1991a,b,c,d); 1 µg of tin corresponds to 3.25 µg of cyhexatin.
a At t = 0
Rabbits
Cyhexatin (purity not reported) was administered by either
gavage (in 0.5% w/v methylcellulose) or topically (in 2.0% w/v
methylcellulose mucilage; 6 h) to groups of six pregnant New Zealand
white rabbits on days 6-19 of gestation at doses of 0.1 or 1 mg/kg
bw per day. On days 6 and 19, 14C-labelled cyhexatin
(radiochemical purity, > 96%) was administered; blood samples were
taken 0, 0.5, 1, 2, 4, 8, 12 and 24 h after treatment on day 6 and
0, 1, 4, 8, 12 and 24 h after treatment on day 18. Samples were than
taken every 24 h. All samples were assayed for total radioactivity.
The animals were killed on day 28 of gestation and their state of
pregnancy assessed. A fifth group of nine pregnant rabbits received
cyhexatin by gavage on days 6-19 of gestation at a dose of 1 mg/kg
per day, a dose of 14C-cyhexatin being administered on day 19 of
gestation only. At that time, five females were killed 1 h after
treatment and four were killed 24 h after treatment; maternal blood,
fetuses, placentae and amniotic fluid were assayed for total
radioactivity.
The maximal blood concentration of 14C-cyhexatin was reached
within 1 h after gavage and within 48-78 h after topical
application, on both days 6 and 19. The mean peak blood
concentrations were 24-31 µg/l after gavage of 1 mg/kg bw, 1.4-2.5
µg/l after gavage of 0.1 mg/kg bw and 2.6-2.8 µg/l after topical
application of 1 mg/kg bw; cyhexatin was not detected after topical
application of 0.1 mg/kg bw. The rate of decay of blood
concentrations was biphasic: the initial half-lives after
administration of 1 mg/kg per day by gavage were essentially similar
on days 6 and 19 of gestation (about 8 h). The levels of cyhexatin
in fetuses and placentae at 24 h were greater (about 1.5 and 3.5
times, respectively) than the corresponding blood levels, while at 1
h they were lower. The levels in amniotic fluid were always lessthan
35% of those in blood (Bailey et al., 1992).
Technical-grade cyhexatin (purity, 96%) in
carboxymethylcellulose was administered by gavage at 0 or 3 mg/kg bw
per day to pregnant Hy/Cr New Zealand white rabbits on days 6-18 of
gestation. Blood samples were taken 2, 3 and 4 h after
administration on day 18 from six treated and six control animals
for determination of tin. These animals were sacrificed the
following day. All surviving animals were sacrificed on day 26 of
gestation, and selected organs and tissues were taken from dams and
fetuses and weighed. The tin levels in maternal blood peaked 3 h
after dosing (day 18), with a mean concentration after subtraction
of control levels of 11.3 µg/l, and had returned nearly to control
levels by 24 h. By day 26, the blood tin levels in treated animals
were only slightly higher than those in controls. Tin was found in
the brain, liver and kidney on days 19 (dams only) and 26 (dams and
fetuses) and in placenta (days 19 and 26) and whole fetuses (day
19). There was no apparent increase in tin levels in treated
animals, but high interindividual variability precluded meaningful
comparisons. In amniotic fluid, the tin levels were about fivefold
higher than those in controls on day 19 but not on day 26 (Woehrle,
1991).
Groups of 20 female Hy/Cr hybrid New Zealand white rabbits were
administered 3 mg/kg bw of technical-grade or micronized cyhexatin
(purity, 96%) by gavage or percutaneously. Blood samples were taken
from two rabbits in each group after 0.25 (only those treated by
gavage), 0.5, 1, 4, 8, 24, 32, 48 and 56 h (the last only for those
treated percutaneously). Urine and faeces were collected from four
animals after 48 (gavage) or 56 h (percutaneous). A further group of
20 animals was given a single intravenous bolus of 0.5 mg/kg bw
micronized cyhexatin. The dose was chosen on the basis of the
results of a preliminary experiment in which all animals given 3
mg/kg bw and one of four animals given 1 mg/kg bw died within a few
hours of treatment (Woehrle, 1992a). Blood samples were taken from
five rabbits 5, 10, 15, 20 and 30 min and 1, 2, 4, 6, 8 and 24 h
after treatment. Urine and faeces were collected from five animals
24 h before and 24 and 48 h after treatment.
Treatment had marked respiratory and circulatory effects: four
animals died after blood sampling, and two died 2-5 min after
dosing. In all of the studies, tin levels were assumed to mirror
cyhexatin concentrations. The most relevant results are reported in
Table 2. Absorption was slower after percutaneous exposure, but
bioavailability was similar after oral and percutaneous
administration (7-10% of the dose). Administration of micronized
cyhexatin resulted more quickly in slightly higher peak blood
concentrations than the technical-grade formulation given by the
same route. The half-life in blood was about 2 h in animals given
micronized cyhexatin orally or intravenously and 9-22 h for the
other preparation, possibly because of slower absorption (Barrow,
1991e,f,g,h; Woehrle, 1992b).
Table 2. Pharmacokinetics of technical-grade and micronized cyhexatin in female New Zealand
white rabbits after oral, percutaneous and intravenous administration
Treatment Bioavailability Half-life Peak blood Peak time Excretion at 24 h (% of dose)
(% of dose) (h) conc. of tin in blood
(µg/l) (h) Urine Faeces
3 mg/kg bw 9.2 9 8.1 5.5 0.4 23
technical-
grade, oral
3 mg/kg bw 7.7 2 11.5 3.5 0.6 27
micronized,
oral
3 mg/kg bw 7.7 22 3.4 11.7 0.2 0
technical-
grade, skin
3 mg/kg bw 6.9 14 4.3 9.1 0.3 0
micronized,
skin
0.5 mg/kg bw (100) 2 316a - 0.6 ?b
micronized,
intravenous
From Barrow (1991e,f,g,h; Woehrle, 1992a); 1 µg of tin corresponds to 3.25 µg of cyhexatin.
a At t = 0
b Severe constipation precluded meaningful analysis.
2. Toxicological studies
(a) Acute toxicity
The LD50 of micronized cyhexatin (purity, 96%) in
Sprague-Dawley CD rats treated by gavage was 265 mg/kg bw (95%
confidence interval, 124-569) in females and 501 (192-1307) mg/kg bw
in males (Denton, 1993a). Higher LD50s were found for
technical-grade cyhexatin, i.e. 654 (446-1454) mg/kg bw in females
and 627 (478-1120) mg/kg bw in males (Denton, 1993b).
The LD50s in CD(SD)BR rats after gavage of technical-grade
and micronized cyhexatin (purity, 95-96%) from another source were
274 (189-397) mg/kg bw for technical-grade and 411 (293-577) mg/kg
bw for micronized cyhexatin in females and 425 (260-693) mg/kg bw
for technical-grade and 407 mg/kg bw (confidence interval not
calculable) for micronized cyhexatin in males (Longobardi, 1994a,b).
(b) Reproductive toxicity
Rats
The following additional information was available from the
multigeneration study in rats that was reviewed by the 1991 JMPR
(Annex I, reference 64): The purity of the micronized cyhexatin was
96%. Analysis of diets at weeks 1, 2, 4 and 6-45 indicates a median
(range) percentage of nominal concentration of 104% (82-120) at 10
ppm, 104% (86-120) at 30 ppm and 101% (89-122) at 100 ppm. Diets
were prepared weekly; in one test for stability, it was shown that
there was no loss of compound over eight days. The mean intakes of
compound before mating were 0.7, 2.1 and 7 mg/kg bw per day for
males and 0.7, 2.4 and 7.5 mg/kg bw per day for females fed 10, 30
and 100 ppm, respectively. The intakes of F0 females during
gestation were 1, 2 and 6.7 mg/kg bw per day, and those during
lactation were 1.7, 4.8 and 12.8 mg/kg bw per day in the same
groups, respectively. The food intakes of the F1 generation before
mating were 0.8, 2.8 and 10.6 mg/kg bw per day for males and 1.0,
2.9 and 10.5 mg/kg bw per day for females, respectively. The intakes
of F1 females were 1, 2 and 7.3 mg/kg bw per day during the first
gestation, 1.7, 4.8 and 11.8 mg/kg bw per day during lactation and
1, 2 and 6.3 mg/kg bw per day during the second gestation. The NOAEL
was 10 ppm, equal to 0.7 mg/kg bw per day.
A draft report describing a one-generation pair-feeding study
of reproductive toxicity in rats was available. Groups of 25 male
and 25 female OFA SD rats were given a diet containing 30 ppm
cyhexatin (purity and formulation not reported) ad libitum for a
four-week period before mating, during mating, during gestation and
during lactation. Pair-fed groups received the same quantity of diet
as that consumed by the treated groups. Diets were prepared weekly.
One test for stability showed no loss of compound over eight days.
Analysis of the diet on day 1 and at weeks 5 and 10 showed
analytical concentrations within 90% of the target, except on one
occasion when it was about 80%. Food consumption was recorded daily,
and animals were observed for signs of toxicity. Body weights were
recorded weekly; those of females were also recorded on days 0, 7,
14 and 20 of gestation and on days 1, 4, 7, 14 and 21 of lactation.
Neither deaths nor signs of toxicity were observed. Mean
body-weight gain was slightly reduced (- 5%) in treated animals and
more so (- 11%) in the group fed only during gestation. The treated
males consumed about 9% less food during the first week of
treatment, and the treated females consumed about 10% less food
during the first two weeks of gestation and, occasionally, during
the last two weeks of lactation. The intakes of cyhexatin were
1.9-2.5 mg/kg bw per day until the end of gestation and had
increased to a maximum of 5.9 mg/kg bw per day by the end of
lactation. Mating performance, fertility, length of gestation and
pup viability were similar in all groups. Pup weight gain was
slightly lower in both the treated (- 19%) and pair-fed groups (-
13%) than in concurrent controls, but was similar to that of
historical controls in the laboratory. The difference between the
treated and control groups was statistically significant on days 14
(females) and 21 (males and females). Physical and functional
development of offspring (assessed by pinna infolding, incisor
eruption and eye opening) was marginally delayed in the treated
group; in general, however, it was comparable in all groups. No
significant observations were made at necropsy in any group. The
weights of the epididymes and testes were not altered by the
treatment. It was concluded that cyhexatin at 30 ppm in the diet has
some effect on pup growth, which cannot be explained solely on the
basis of reduced food intake due to unpalatability of the diet. This
effect was only partially diminished by pair-feeding. The reduced
food intake is likely to be the cause of the reduced body-weight
gain seen in females of the F0 generation (Barrow, 1993).
(c) Embryotoxicity and teratogenicity
Rabbits
Groups of 25-26 pregnant New Zealand white rabbits were
administered 0, 0.5, 1 or 3 mg/kg bw per day of technical-grade
cyhexatin (purity, 95.1%) in 0.5% carboxymethyl-cellulose in a
volume of 0.25 ml/kg on one of six clipped, 30-cm2 sites on the
back during days 6-18 of gestation. The sites were used in rotation.
Solutions were prepared daily. Analyses of the formulations showed
concentrations that were 78-103% of the target at week 1; after
adjustment of the formulating procedures, the concentrations were
91-103% of the target at week 2. Homogeneity was reported to be
within acceptable limits (no data), and the concentration 6 h after
preparation was > 90% of the initial level. Animals were observed
daily for clinical signs and were weighed on days 0, 6-19, 23, 26
and 29; their food consumption was determined daily. On day 18, 3-4
h after treatment, blood samples were taken from three animals
selected randomly from each group, which were then sacrificed to
verify their pregnancy status. Plasma cyhexatin levels on day 18
were below the levels of linearity of the method (0.26 mg/l) in some
samples and undetectable in others. No relevant clinical signs were
observed, except for erythema, oedema, eschar and fissuration
(dose-related) at the application sites. Two of the animals at the
low dose and one at the high dose died, and one at the low dose and
one at the middle dose aborted. The body weight and food consumption
of dams were not affected by treatment, and the findings in females
at necropsy were unremarkable. The numbers of corpora lutea,
implantations, intra-uterine deaths and live young, the percentage
of implantation loss, and litter weights were similar in all groups.
No visceral malformations were recorded, except for spina bifida in
two control fetuses. One fetus of a dam at the middle dose was
missing part of the cerebral hemisphere. Differences in the
incidences of enlargement of the anterior fontanelle of the cranium
and of incomplete or non-ossification of the fifth sternebrae were
not statistically significant. The Meeting concluded that cyhexatin
at percutaneous doses up to 3 mg/kg bw per day had no maternally
toxic effect and was not teratogenic (Jamieson, 1991).
An expert review of a study of teratogenicity in rabbits (Ross,
1990 [reported as Bailey et al., 1990 by the 1991 JMPR]; Annex I,
reference 64) was available to the present Meeting. The observations
are summarized in Table 3. The range of incidence of folded retinas
in control groups in studies performed six months before or after
the period of the reported study during which the animals were alive
was 2.4-33.3% for unilateral and 2.2-18.9% for bilateral folded
retina. Since the folding was classified as slight, artefacts of
fixation could not be ruled out. Given the absence of a clear
dose-response relationship, the historical control data and the
possibility of some fixation artefacts, the Meeting concluded that
the NOAEL in this study was 0.75 mg/kg bw day on the basis of
possible maternal toxicity at higher doses (Tesh, 1994).
Table 3. Incidence (%) of slightly folded retina in rabbits treated with cyhexatin
from two sources
Treatment From Kentucky (USA) From Vlissingen (Netherlands)
(mg/kg per day) (97% pure) (98% pure)
Unilateral slightly folded retina
0 14.3 14.3
0.75 21.1 20.7
1.5 18.2 20.6
3.0 32.3 15.8
Bilateral slightly folded retina
0 11.9 11.9
0.75 21.7 10.3
1.5 31.8 14.7
3.0 16.1 21.1
From Ross, 1990 [reported as Bailey et al., 1990 by the 1991 JMPR]
3. Observations in humans
A study was conducted to evaluate potential exposure to
cyhexatin of people mixing and spraying Plictran 50W Miticide in
orchards and re-entering the treated orchards to pick fruit. The
formulation was applied from commercial two-directional orchard
sprayers towed behind tractors which had either open or enclosed
cabs. Treated orchards were re-entered in order to harvest or thin
fruit 0, 7 and 14 days after application. Operators wore half-face
air-purifying respirators with pesticide cartridges, chemically
resistant gloves, goggles and long-sleeved, long-legged clothing for
both mixing and spraying. The operators of open-cab tractors wore
protective rubber suits, and pickers wore long-sleeved, long-legged
clothing. The average concentrations of cyhexatin measured in the
breathing zone of drivers of open- and enclosed-cab tractors were
0.039 mg/m3 during mixing and 0.027 mg/m3 during spraying.
Potential dermal exposure was assessed by the method suggested in
the US Environmental Protection Agency Pesticide Assessment
Guidelines, on the basis of estimates of surface deposition of
cyhexatin on exposed body surfaces and 16% of surface deposition on
clothed body surfaces. The average potential dermal exposure during
mixing and spraying was 0.7-7 mg/day. Potential dermal exposures
during picking were 21 mg on the day of application to 0.83 mg 14
days after application. The percentage of the potential dermal
exposure that occurred on the hands was 81% on the day of
application and 25% 14 days after application (Scortichini & Bohl,
1988).
Exposure to cyhexatin (determined as tin) was monitored in one
mixer/loader, one tractor driver and two sprayers on three
consecutive working days and two subsequent rest days. Exposure by
inhalation was low (6-1070 µg/day). Dermal exposure was 0.8-19
mg/day. The concentration of tin in blood increased by up to 20
times after exposure; the peak level in one subject was 20.5 µg/l.
There was a poor correlation of blood levels with cutaneous
exposure, except on day 1. Blood tin concentrations had not returned
to normal values two days after the end of exposure, and in one
subject it was normal one day after exposure but much higher the
following day. The authors gave no explanation for this finding.
Sample contamination during blood drawing could not be discounted.
Urinary and faecal levels were not determined (Maroni, 1993).
Medical surveillance of workers exposed to organotin compounds,
including cyhexatin, showed no adverse effects on haematological,
clinical chemical or immunological parameters. The urinary tin
levels of exposed workers were no higher than those of unexposed
controls (Baaijens, 1992).
Comments
Cyhexatin is poorly absorbed after oral administration to rats
and rabbits or dermal application on rabbits. In rabbits, the
bioavailability was similar after treatment by either route,
although a higher peak blood concentration was reached after oral
administration. The bioavailability after oral administration was
much greater in rabbits (7-9%) than in rats (0.5-1.2%). Micronized
cyhexatin had greater bioavailability than the technical formulation
in female rats but not in female rabbits.
The disposition of cyhexatin is slow: 75-85% was eliminated in
rats within four days after treatment, and the administered dose was
recovered completely within about 10 days. After rats were fed diets
containing 100 ppm of 119Sn-cyhexatin for 90 days, the tissue
content of 119Sn reached a steady state within about two weeks.
When cyhexatin was removed from the diet, the half-life of 119Sn
in most tissues was about 10 days, except in the brain and muscle
where it was about 40 days. 119Sn was present in muscles mainly as
cyhexatin and, later, as dicyclohexyltin.
In pregnant rabbits given 14C-cyhexatin either orally or
dermally, peak blood concentrations were found to be higher than
those expected from results obtained in non-pregnant animals.
Contrasting results were obtained in fetus, placenta and amniotic
fluid in two studies.
Comparative studies in rats showed that micronized cyhexatin
has greater acute oral toxicity (LD50 = 265 mg/kg bw) than
technical-grade cyhexatin (LD50 = 654 mg/kg bw) in females but not
in males (LD50 = 501 and 599 mg/kg bw, respectively). This finding
is consistent with data on kinetics from the same laboratory using
the same source of cyhexatin, in which the bioavailability of
micronized cyhexatin was greater than that of technical-grade
cyhexatin in female rats. In studies of acute toxicity in female
rats performed in another laboratory using cyhexatin from another
source, however, lower acute toxicity was seen with micronized
(LD50 = 411 mg/kg bw) than with technical-grade (LD50 = 274
mg/kg bw) cyhexatin. WHO (1992) has classified cyhexatin as slightly
hazardous.
More information has been provided from the multigeneration
study (reviewed by the 1991 Meeting) in rats fed diets containing 0,
10, 30 or 100 ppm of micronized cyhexatin. The NOAEL in this study
was 10 ppm, equal to 0.7 mg/kg bw per day, on the basis of decreased
body-weight gain in pups during lactation and reduced survival of
F0 and F1 offspring at 30 ppm.
A one-generation study of reproductive toxicity was conducted
in pair-fed rats. Animals were given control diet ad libitum, a
diet containing 30 ppm of micronized cyhexatin or the same amount of
control diet as that consumed by the cyhexatin group. Pup growth was
affected by both cyhexatin and the control diet but to a greater
extent by the former. Therefore, reduced food intake accounted only
partially for the effects. In a study of reproductive toxicity
reviewed by the 1991 Meeting, rats were administered diets
containing cyhexatin at concentrations that yielded 0, 0.1, 0.5 or
6.0 mg/kg bw per day. A slight effect on body weight, associated
with reduced food intake, was observed in F0 females at 0.5 mg/kg
bw per day, and the NOAEL was 0.1 mg/kg bw per day. Taking into
consideration the results of the pair-feeding study and the other
multigeneration study in rats, the Meeting considered that the
effect seen at 0.5 mg/kg bw per day might be due to diet
unpalability. The Meeting concluded that the NOAEL was 0.5 mg/kg bw
per day.
In a study of teratogenicity in rabbits given percutaneous
doses of technical-grade cyhexatin of 0, 0.5, 1 or 3 mg/kg bw per
day, neither maternal toxicity nor teratogenic effects were
observed. In another study, rabbits were given 0, 0.75, 1 or 3 mg/kg
bw orally. An increased incidence of folded retinas was found in
treated groups, but a dose-response relationship could not be
demonstrated and fixation artefacts were considered likely. The
NOAEL in this study was 0.75 mg/kg bw per day on the basis of
possible maternal toxicity at higher doses. After taking into
consideration the results of all the studies of teratogenicity in
rabbits, the Meeting concluded that cyhexatin is not teratogenic to
this species.
Two studies have been carried out of occupational exposure to
cyhexatin during mixing and spraying. Average exposure by inhalation
was very low; cutaneous exposure was 0.7-19 mg/day. Cutaneous
exposure during fruit picking in cyhexatin-treated orchards ranged
from 21 mg/day at 0 days to 0.8 mg/kg 14 days after application. No
reliable measurements were reported of tin or cyhexatin in blood or
urine.
No information was available on the particle size of cyhexatin
residues in food because it could not be determined analytically;
however, it is conceivable that residues are of the same sizes as
the applied product.
The Meeting based the ADI on the NOAEL determined in the
multigeneration study in rats (0.7 mg/kg bw per day), applying a
100-fold safety factor.
Toxicological evaluation
Levels that cause no toxic effect
Mouse: 3 mg/kg bw per day (two-year study) (Joint Meeting,
1981)
Rat: 0.7 mg/kg bw per day (multigeneration study)
Rabbit: 0.75 mg/kg bw per day (maternal toxicity in
teratogenicity study)
Estimate of acceptable daily intake for humans
0-0.007 mg/kg bw
Studies that would provide information useful for continued
evaluation of the compound
Further observations in humans
References
Baaijens, P.A. (1992) Medical surveillance of workers exposed to
organotin-compounds. Unpublished report submitted to WHO by ELF
Atochem, Agra SA, Plaisir, France.
Bailey, G.P., Ferguson, E.G.W., Hallifax, D. & Miner, C. (1992)
Tricyclohexyltin hydroxide: absorption study in the rabbit.
Unpublished report No. 91/0929 from Life Science Research Ltd, Eye,
United Kingdom. Submitted to WHO by ELF Atochem Agri SA, Plaisir,
France.
Barrow, P.C. (1991a) Cyhexatin technical. pharmacokinetic
investigation in the rat by the oral route. Unpublished report No.
457059 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Barrow, P.C. (1991b) Cyhexatin micronised. pharmacokinetic
investigation in the rat by the oral route. Unpublished report No.
458059 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Barrow, P.C. (1991c) Cyhexatin technical. Pharmacokinetic
investigation in the rat by the oral route. Amendment No 1.
Unpublished report no. 457059 from Pharmakon Europe, Lyon, France.
Submitted to WHO by Oxon Italia SpA, Milan, Italy.
Barrow, P.C. (1991d) Cyhexatin micronised. Pharmacokinetic
investigation in the rat by the oral route. Amendment No 1.
Unpublished report no. 458059 from Pharmakon Europe, Lyon, France.
Submitted to WHO by Oxon Italia SpA, Milan, Italy.
Barrow, P.C. (1991e) Cyhexatin technical. Pharmacokinetic
investigation in the rabbit by the oral route. Unpublished report
No. 459059 from Hazleton France. Submitted to WHO by Oxon Italia
SpA, Milan, Italy.
Barrow, P.C. (1991f) Cyhexatin micronised. Pharmacokinetic
investigation in the rabbit by the oral route. Unpublished report
No. 460059 from Hazleton France. Submitted to WHO by Oxon Italia
SpA, Milan, Italy.
Barrow, P.C. (1991g) Cyhexatin technical. Pharmacokinetic
investigation in the rabbit by the percutaneous route. Unpublished
report No. 461059 from Hazleton France. Submitted to WHO by Oxon
Italia SpA, Milan, Italy.
Barrow, P.C. (1991h) Cyhexatin micronised. Pharmacokinetic
investigation in the rabbit by the percutaneous route. Unpublished
report No. 462059 from Hazleton France. Submitted to WHO by Oxon
Italia SpA, Milan, Italy.
Barrow, P.C. (1991i) Two generation oral (dietary administration)
reproduction toxicity study in the rat. Unpublished report No.
396039 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Barrow, P.C. (1993) One generation oral (dietary admixture)
reproduction toxicity study in the rat with pair-feeding.
Unpublished draft report No. 1 from Pharmakon Europe, Lyon, France.
Submitted to WHO by Oxon Italia SpA, Milan, Italy.
Denton, S.M. (1993a) Cyhexatin micronised. Acute oral toxicity to
the rat. Unpublished report from Huntingdon Research Centre Ltd.,
Huntingdon, United Kingdom. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Denton, S.M. (1993b) Cyhexatin technical. Acute oral toxicity to the
rat. Unpublished report from Huntingdon Research Centre Ltd.,
Huntingdon, United Kingdom. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Grissom, R.E., Jr, Brownie, C. & Guthrie, F.E. (1985) Dermal
absorption of pesticides in mice. Pestic. Biochem. Physiol., 24,
119-123.
Jamieson, H. (1991) Cyhexatin percutaneous teratology study in
rabbits. Unpublished report No. 737-088-161/T/122/91 from the
Research Toxicology Centre SpA, Pomezia, Italy. Submitted to WHO by
Chemia SpA, Ferrara, Italy.
Longobardi, C. (1994a) Acute oral toxicity study in the albino rat.
Unpublished report No. 271-010/T/140/93 from the Research Toxicology
Centre SpA, Pomezia, Italy. Submitted to WHO by Chemia SpA, Ferrara,
Italy.
Longobardi, C. (1994b) Acute oral toxicity study in the albino rat.
Unpublished report No. 271-011/T/129/93 from the Research Toxicology
Centre SpA, Pomezia, Italy. Submitted to WHO by Chemia SpA, Ferrara,
Italy.
Maroni, M. (1993) Personal and biological monitoring of exposure to
cyhexatin during agricultural use. Unpublished report from the
International Centre for Pesticide Safety. Submitted to WHO by Oxon
Italia, Milan, Italy.
Ross, F.W. (1990) Cyhexatin: Teratology study in rabbit. Unpublished
report No. 89/0161 from Life Science Research Ltd, Eye, United
Kingdom. Submitted to WHO by Elf Atochem SA, Plaisir, France.
Scortichini, B.H. & Bohl, R.W. (1988) Evaluation of tractor/sprayer
operator and orchard worker exposures to cyhexatin during orchard
spraying with Plictran 50W miticide and reentry of treated orchards,
Hartford, Michigan, 28 July 1987. Unpublished report No.
HEH2.1-1-182(72) from Dow Chemical Co., Midland, MI, USA. Submitted
to WHO by ELF Atochem Agri SA, Plaisir, France.
Smith, G.N. & Fischer, F.S. (1970) Metabolism of Plictran miticide.
Observations on the absorption, distribution, and excretion of
tricyclohexyltin-Sn119 hydroxide in white rats. Unpublished report
from Dow Chemical Co., Midland, MI, USA. Submitted to WHO by ELF
Atochem Agri SA, Plaisir, France.
Tesh, J.M. (1994) Tricyclohexyltin hydroxide: teratology study in
the rabbit. Expert review. Unpublished report no. 89/MTC010/0161
from Pharmaco LSR, Ltd. Submitted to WHO by ELF Atochem Agri SA,
Plaisir, France.
WHO (1992) The WHO recommended classification of pesticides by
hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
Available from the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland.
Woehrle, F. (1991) Cyhexatin technical. Blood and tissue level
determination in the pregnant rabbit and its litter after oral
administrations during the organogenesis period. Unpublished report
No. 40890 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
Milan, Italy.
Woehrle, F. (1992a) Cyhexatin micronised. Pharmacokinetic
investigation in the rabbit by the intravenous route. Unpublished
report No. 40790 from Hazleton France. Submitted to WHO by Oxon
Italia SpA, Milan, Italy.
Woehrle, F. (1992b) Cyhexatin micronised. Pharmacokinetic
investigation in the rabbit by the intravenous route. Unpublished
report No. 49890 from Hazleton France. Submitted to WHO by Oxon
Italia SpA, Milan, Italy.
See Also:
Toxicological Abbreviations