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EC number: 206-108-6
CAS number: 301-10-0
Stannous chloride and 2-ethylhexanoic acid [hydrolysis products of tin
bis(2 -ethylhexanoate)] have been tested in 90 day toxicity studies in
rats and mice and there were no effects noted on reproductive organs.
Reproductive and developmental toxicity studies are not available for
tin bis(2 -ethylhexanoate). Tin bis(2-ethylhexanoate) has not been
evaluated for potential adverse effects in OECD 422 screening studies.
Rats were exposed to 2-ethylhexanoic acid in a one generation study, via
0, 100, 300, or 600 mg/kg bw/day. No mortality was observed. The
relative epididymal weights in high-dose males were significantly
increased, but no histologic changes were noted. A slight, but not
statistically significant, increase in the number of abnormal sperm was
reported in the two highest dose groups; however, the incidence per
animal was not provided. A dose dependent delay in fertility was observed,and
the mean litter size in high-dose females was significantly reduced. The
mean pup weights in the high-dose group were significantly lower on
postnatal day 7 and 14.
of the eyes, teeth and hair appeared to be slightly later in the pups
from the high-dose groups; the significance of this finding is unclear
since no data were presented on the length of gestation in treated and
control dams. The high-dose of 600 mg/kg bw/day significantly reduced
overall water consumption and body weights in female animals. The NOEL
for reproductive effects in parental animals was 300 mg/kg-bw/day; this
effect occurred in the presence of maternal toxicity. The NOEL for F1
offspring was 100 mg/kg-bw/day.
Short description of key information:
Data are considered to be fulfilled by studies on hydrolysis
products. No effects were noted on reproductive organs.
Rats were exposed to 2-ethylhexanoic acid in a one generation study. EHA
induced increased epididymal weights, but no histological changes were
observed. A dose-dependent delay in fertility was observed, and the mean
litter size in high-dose females was significantly reduced. The parental
NOAEL was 300 mg/kg bw/day; this effect occurred in the presence of
Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studied in
Wistar rats. The animals (24 animals per sex per group) were given 2-EHA
as a sodium salt in drinking water at
daily doses of 100, 300, or 600 mg/kg. Control animals received plain
water. Male rats were exposed to 2-EHA for 10 weeks and females for 2
weeks prior to mating, both sexes during the mating period and females
during the entire gestation and lactation period. 2-EHA caused a slight
but dose-dependent decrease in fertility, time to mating increased at
300 and 600 mg/kg and even total infertility ensued. 2-EHA slightly
decreased sperm quality in males. The spermatozoa were significantly
less motile at 100 and 600 mg/kg and abnormal sperm occurred more
frequently at the two highest dose levels. The average litter size was
reduced by 16% in the dose group receiving 600 mg/kg. The birth weights
of the pups were unaffected but the body weight gain was transiently
slower during lactation at 600 mg/kg. Several pups appeared abnormal
(kinky tail, lethargic, slightly paralyzed legs) and the physical
development assessed by several landmarks (opening of eyes, eruption of
teeth, hair growth) and reflexes (grip reflex, cliff avoidance) was
delayed at 300 and 600 mg/kg. In another experiment, a single dose of
600 mg/kg 2-EHA was given to pregnant females by gavage on Gestational
Day 4, 5, 6, or 7 and the number of implantations were counted on
Gestational Day 10. Administration on Day 6 decreased the number of
implantations and caused resorptions. In conclusion, 2-ethylhexanoic
acid caused impaired fertility in Wistar rats and delayed postnatal
development of pups. The reduced fertility might result from disturbed
implantation in uterus and the retarded development of pups from
teratogenicity and pre- and postnatal toxic effects of 2-EHA.
considered to be fulfilled by studies on the hydrolysis products of tin
bis(2-ethylhexanoate), tin(II) and EHA:
In a reliable
prenatal development study (Pennanen, 1992) in Wistar rats 100, 300 and
of EHA was administered via drinking water to pregnant dams from
gestational days 6 to 19. On gestational day 20, the fetuses were
examined for external, visceral, and skeletal malformations and
variations. Skeletal malformations (clubfoot, absence of fibula,
polydactyly) were observed in all treatment groups, with the incidence
increasing in a dose-dependent way. Also visceral malformations were
noted at all dose levels, however, severity and incidence was less
pronounced than the skeletal effects. At the highest dose tested (600
mg/kg), a 5 to 8% decrease in the mean fetal body weight both in males
and females was noted in presence of a near-term body weight decrease of
dams of 11 %. Due to the skeletal malformations at 100 mg/kg, a NOAEL
could not be established. Benchmark dose analysis provided a lower
confidence limit (BMDL) of 35 mg/kg, based on total skeletal
malformations per litter.
supporting prenatal development study (Hendrickx, 1993), slight
fetotoxicity (reduced ossification and increased incidence of skeletal
variations) was noted in the offspring of rats exposed to gavage doses
of EHA in oil of 250 mg/kg/d and above (NOEL = 100 mg/kg/d) and also in
the offspring of rats exposed to EHA in the drinking water at an
equivalent doses of 300 mg/kg/d and above (NOEL= 100 mg/kg/d).
chloride and EHA [hydrolysis products of tin bis(2-ethylhexanoate)] have
been tested in 90-day toxicity studies in rats and mice and there were
no effects noted on reproductive organs. Further, stannous chloride has
been evaluated for potential adverse developmental effects in studies in
four species (US FDA 71 -33). No adverse effects on development were
found at doses up to and including 50 mg/kg/d during gestation in these
2-EHA affected development of the embryos/fetuses at all dose levels.
The number of affected fetuses (having skeletal or visceral
malformation) increased in a dose-dependent manner (p < 0.001) being
4.9, 8.9, and 15.3% per litter in 2-EHA groups vs 2.4% in the control
The developmental toxicity of 2-ethylhexanoic acid (2-EHA), a wood
preservative and a mammalian metabolite of di-(2-ethylhexyl) phthalate
was examined in Wistar rats (20-21 pregnant females/dose). Mated animals
were exposed to 2-EHA in their drinking water at doses of 100, 300, or
600 mg/kg/day on Days 6-19 of gestation. Control animals received
vehicle water. The
fetuses were examined (on Gestational Day 20) for external, visceral,
and skeletal malformations and variations.
2-EHA was marginally toxic to the dams at 600 mg/kg, but not at lower
doses, since the mean near term body weight was reduced by 11%. This
dose level was also slightly fetotoxic as indicated by a 5 to 8%
decrease in the mean fetal body weight both in males and females. No
treatment-related effects were observed in the number of implantations
or live fetuses. At doses of 100 mg/kg and above, 2-EHA caused skeletal
malformations (clubfoot, absence of fibula, polydactyly), while the
development of visceral tissues was less affected. The number of
affected fetuses increased in a dose-dependent way (4.9,8.9, and 15.3%
of treated offspring at 100, 300, and 600 mg/kg/day, respectively, vs
2.4% control). See attachment Pennanen 1992 - Table 2 and Table 3.
These results indicate that 2-EHA is teratogenic in rats already at
doses which are not yet maternally toxic. The skeleton appears to be the
main target of 2-EHA in developing rats. With regard to teratogenicity,
the lowest-observed-adverse-effect-level (LOAEL) was 100 mg/kg and the
NOAEL (no-observed-adverse-effect level) was lower than the lowest dose
-Ethylhexanoic acid has been tested in 90 day toxicity studies in rats
and mice, and there were no effects
noted on reproductive organs.
visceral malformations were noted in the offspring of rats exposed to
gavage doses of EHA in drinking water of 100 mg/kg/d and above (LOAEL =
100 mg/kg/d). Based on this effect on development, a classification as
toxic to reproduction Category 2 (repr. 2) is
applied. This classification is already a harmonised classification, as
it is derived from the harmonised classification of the hydrolysis
product 2-ethyl hexanoic acid.
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