Azocyclotin is an organic tin compound that was reviewed by the
Joint Meeting of Pesticide Residues (JMPR) in 1979 and 1981
(Annex 1, FAO/WHO, 1980a; 1982a). The compound underwent
toxicological evaluation in 1981 and a Toxicological Monograph was
prepared at that time (Annex 1, FAO/WHO, 1982b).
The 1981 JMPR estimated that the acceptable daily intake (ADI)
for man was 0-0.003 mg/kg bw, based upon no-effect observed in
2-year studies in the rat (5 ppm in the diet equivalent to
0.25 mg/kg bw/day) and the dog (10 ppm in the diet equivalent to
0.25 mg/kg bw/day). In addition, further information to permit
adequate evaluation in the future was considered to be desirable.
This information included studies to determine the potential for
central nervous system toxicity.
Azocyclotin has recently been studied for its ability to
produce potential embryotoxic and teratogenic effects after oral and
dermal application to rabbits. The results of these tests are
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Special studies on teratogenicity
In an oral range finding study four groups of 4 artificially
inseminated New Zealand White rabbits received 0 (1% cremophor) 1, 3
or 10 mg/kg bw/day by gavage on days 6-18 of pregnancy (Day 0 of
pregnancy was the day of artificial insemination). No rabbits
carried to term at 3 and 10 mg/kg bw/day, two animals in each group
being killed in extremis, and 2 in each group aborting. Stomach
ulceration in 3/4 at 10 and 2/4 at 3 mg/kg bw/day was noted. One
abortion occurred at 1 mg/kg bw/day attributed to maternal
infection. One animal at this dose lost weight, and 3 showed
reduced food intake. Mean fetal weight was reduced at 1 mg/kg
bw/day. No malformations recorded (Tesh & Rose, 1981).
In the main oral study, 4 groups of artificially inseminated
New Zealand White rabbits received 0 (1% cremophor); 0.1, 0.3 or
1.9 mg/kg bw/day, by gavage of 93.1% pure azocyclotin on days 6-18
of pregnancy (Day 0 was the day of insemination). The incidence of
mortality at these dose levels was 1, 0, 3, and 2, respectively. The
deaths in the control rabbit and in one rabbit at 0.3 mg/kg bw/day
were not compound-related effects.
Compound-related effects (gastrointestinal disturbances) cannot
be ruled out in the remaining animals at 0.3 mg/kg bw/day. Data are
not available on the necropsies of the 1 mg/kg bw/day animals which
died. Decreased body weight gain was observed at 1 mg/kg bw/day,
and slightly reduced at 0.3 mg/kg bw/day. Abortions (2) were
observed at 1 mg/kg bw/day in animals which showed evidence of
gastrointestinal tract disturbances. There were no observed effects
on litter size, number of viable young, resorption incidence, pre-
or post-implantation losses, fetal weight or placental weight. No
major malformations were recorded. However, an increased incidence
of variants (fissures in ovarial boxes, thickened ribs, incomplete
ossification of digits) was observed in pups from the 1 mg/kg bw/day
dose level, which may have been indicative of minimal fetotoxicity.
The NOAEL for maternal toxicity was 0.1 mg/kg bw/day, and for
teratogenicity, 1 mg/kg bw/day (the highest dose tested) (Tesh
et al. 1981).
Groups of female CHBB Himalayan rabbits (15/dose) received
dermal applications of 0, 30, 100, or 300 mg/kg bodyweight
(concentrations of 0, 3, 10, and 30%, respectively) of azocyclotin
(3.9% pure) from days 6 to 18 of gestation (Day 0 = day of mating).
The compound was applied for 6 hours/day to shaved areas on the
backs of the animals using occulusive methods. On gestation day 29,
dams were sacrificed and fetuses delivered by C-section. The
fetuses were dissected and examined for visceral anomalies, and
subsequently cleared and stained for skeletal observations.
One pregnant dam in the 300 mg/kg bw/day group died on day 21
due to unknown causes; the animal had a full, distended gall
bladder and the intestines were filled with gases. Adverse effects
on the skin as well as digestive problems occurred in the dams at
all of the doses tested. The treated skin areas were clearly
injured as indicated by the presence of moderate to severe erythema
and edema, dehydration, and roughened surfaces. Digestive problems
occurred in 9/15 controls, 12/15 low dose, 12/15 mid dose, and 15/15
high dose animals, and were said to be related to stress; there was
a greater incidence (generally dose-related) of reduced nutritional
intake, soft feces, and a smaller amount of feces in all treated
groups compared to the controls. In addition, a few high dose dams
were emaciated, had distended gall bladders and empty intestines
filled with gases, or had diarrhea. Other findings in dams included
the occurrence of hemorrhagic excretions and abortions of placentas
and fetuses (0/15 controls, 1/15 low dose, 0/15 mid dose, and 4/15
high dose) and cysts on the fallopian tubes of ovaries (1/15
controls, 0/15 low dose, 2/15 mid dose, and 4/15 high dose). The
pregnancy rate was reduced at the high dose level as a result of
dams who had completely resorbed (see below); the percentage of
pregnant (expressed as a percentage of those that were fertilized)
was 100% in controls, 85.7% low dose, 92.3% mid dose, and 61.5% high
dose. The weight gain of the dams was reduced at 100 mg/kg/day but
the response did not appear to be dose-related.
Remarkable changes in the fetuses included a dose-related
increase in resorptions in all treatment groups. As a consequence of
this there were reductions in the number of surviving female fetuses
at all 3 dose levels, male fetuses at the high dose level, and
combined male and female fetuses at the two highest dose levels.
There did not appear to be any other changes in the fetuses with
respect to mean fetal and placental weights/litter, number of
corpora lutea, crown-rump length, number of runts/litter, or the
number of fetuses with bone changes or malformations/litter. No
teratogenic effects were observed. A NOAEL could not be determined
for either the dams or the fetuses over the dose range of 30 to
300 mg/kg by dermal application. A dermal dose of 300 mg/kg was a
NOAEL for teratogenicity (Renhof, 1989a).
A second dermal teratogenicity study similar to the one above
was performed in female DHBB Himalayan rabbits (15/dose) using
azocyclotin (94.9% pure) in doses of 0 and 10 mg/kg bodyweight. The
purpose of the study was to determine a NOAEL for the fetuses. The
only treatment-related effect in this study appeared to be injury of
the treated skin areas in the dams as indicated by the presence of
very slight to moderate erythema and edema, dehydration and
roughened surfaces. One death occurred in a pregnant control dam on
day 27. The weight development of the treated dams was reduced
during application but the change was not statistically significant
and was similar in magnitude to that seen with the 30 and 300 mg/kg
bw/day doses of azocyclotin in the above described study. The
weight development of the dams was said to be adversely affected by
the method of compound application. In regard to malformations, one
fetus had a split gall bladder, another had a bifurcated rib, and a
third had fused ribs; all of the fetuses were from different dams.
The malformations were within normal historical control ranges, and
none were seen at doses of 30 to 300 mg/kg bw/day in the first
dermal study except for fused ribs in one fetus at 30 mg/kg bw/day.
No other changes (including digestive problems, hemorrhagic
excretions/abortions, ovarian cysts, changes in the pregnancy rate,
resorptions, or changes in the numbers of surviving fetuses) were
observed after treatment with 10 mg/kg in this study. The NOAEL for
the fetuses was 10 mg/kg bw/day after dermal application (Renhof,
Observations in humans
No information available.
An oral teratology study in New Zealand White rabbits indicated
maternal toxicity at 0.3 mg/kg bw/day and above and no evidence of
teratogenicity at 1 mg/kg bw/day. There was minimal indication of
embryo/fetotoxicity at this dose. The NOAEL for the study was
0.1 mg/kg bw/day.
Estimate of acceptable daily intake for humans
0-0.1 mg/kg bw.
Studies which will provide information valuable in the continued
evaluation of the compound
Further observations in humans.
Renhof, M. (1989a) BUE 1452. Investigations into the dermal
embryotoxic effects on rabbits after dermal administration.
Unpublished Report No. 17698 from Institute of Toxicology, Bayer AG.
Submitted to WHO by Bayer, AG, Wuppertal, FRG.
Renhof, M. (1989b) BUE 1452. Investigations into the embryotoxic
effects on rabbits after dermal administration. Unpublished Report
No. 17686 from Institute of Toxicology, Bayer AG. Submitted to WHO
by Bayer, AG, Wuppertal, FRG.
Tesh, J.M., Rose, F.W. (1981) BUE 1452. Effects of oral
administration upon pregnancy in the rabbit. 1. Dosage range-finding
study. Unpublished Report No. 81/BAG 008/097 from Life Science
Research, England. Submitted to WHO by Bayer AG, Wuppertal, FRG.
Tesh, J.M., Rose, F.W., Secker, R.C., Wilby, O.K. (1981) BUE 1452.
Effects of oral administration upon pregnancy in the rabbit. 2. Main
study. Unpublished Report No. 81/BAG 009/4617 from Life Science
Research, England. Submitted to WHO by Bayer AG, Wuppertal, FRG.