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EC number: 200-661-7
CAS number: 67-63-0
The reproductive toxicity of isopropanol (IPA) was assessed in a
GLP-compliant study equivalent to the OECD test guideline 415
(one-generation reproduction toxicity study). Wistar
rats were administered IPA at concentrations of 0 (tap water), 1.25, or
2.0% in drinking water (Faber, 2008). Based on water
intake, these dose concentrations corresponded to IPA dose levels of
383, 686, and 1107 mg/kg bw/day during the premating period; and 347,
625, and 1030 mg/kg bw/day for 18 weeks of treatment in males. In
females, IPA intake was calculated to be 456, 835, and 1206 mg/kg bw/day
during the premating period; 668, 1330, and 1902 mg/kg bw/day during the
gestation period; and 1053, 1948, and 2768 mg/kg bw/day during the post
partum phase. F0 Generation: There were no
mortalities, abortions, or early deliveries reported. Adult
male food consumption was decreased in all dose groups compared to
controls. This corresponded with decreased body
weights in the 2.0% dose group, and a transient slight decrease in body
weight in animals treated with 0.5 and 1.0% IPA. Water
intake was decreased in male rats treated with IPA; however, intake
returned to normal levels in the 0.5% group. Food
consumption also was decreased in adult females treated with 1.0 and
2.0% IPA; however, decreases noted in the 1.0% group had recovered by
the second day of gestation. Body weights in
IPA-treated adult females were lower than those reported for the control
group at the start of gestation, but had recovered during gestation
except in the 2.0% group. Following parturition, body
weights for all dose groups were initially similar to controls; however,
decreased body weights were noted in the 2.0% dose group on and after
post-natal day 4. Water consumption was initially
decreased in females treated with 1.0 and 2.0% IPA, but had returned to
control levels in the 1.0% IPA group by the third day of treatment.
A slight-dose dependent decrease in red blood cells in the 2.0% group
adult males and 1.0 and 2.0% adult females was noted. For
males, a slight increase in mean cell volume in the mid- and high-dose
groups was observed. Increased absolute and relative
kidney weights, and relative liver and spleen weights were noted in
high-dose F0 males. Statistically
significant increased absolute liver and kidney weight, and relative
liver weight were noted in the 2.0% F0 females.
There were no effects of IPA exposure on fertility. The
number of pups per litter on post-natal day 1 was decreased in the 2.0%
group. This increase was attributed to the cannibalism
of the pups by the Dam and decreased pup survival, as a decrease in
litter size was not observed in the embryotoxicity study. In
the embryotoxicity study, increased preimplantation loss, a decrease in
mean litter weight, and a decrease in mean fetal body weight was noted
in the 2.0% group.
F1 Generation: Average pup weight was decreased in the 2.0% group on
post-natal day 7. Increased mean relative liver weight
was reported in F1 males and females at the 2.0% dose level. High-dose
F1 males also had higher relative kidney weights. Slight
increases in absolute brain weight and increased relative empty caecum
weight were noted in high-dose F1 males and females. There
were no gross abnormalities noted in the F1 generation at
Based on a review of the data it is proposed that the NOAEL for parental
toxicity be considered to be 347 mg/kg bw/day (based on the lowest
calculated parental IPA intake for 0.5% IPA in drinking water). The
proposed NOAEL for reproductive toxicity is 853 mg/kg bw/day (based on
the lowest calculated maternal IPA intake for 1.0% IPA in drinking
water) on the basis of effects noted on pre-implantation loss, mean
litter and fetal body weight, and fetal survival at the 2.0% dose level.
A supportive oral gavage, GLP, multi-generation study equivalent to the
OECD test guideline 416 (Beyer, 1992) reported a NOAEL for
parental toxicity of 500 mg/kg bw/day due to increased organ weights at
1000 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg
bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day due to
reduced body weights and increased mortality at 1000 mg/kg bw/day.
A GLP prenatal development study in rats, equivalent to OECD Test Guideline 414, identified an oral NOAEL of 0.5% (596 mg/kg bw/day) for maternal and developmental toxicity. There were no teratogenic effects reported. Supportive GLP developmental toxicity studies, similar to OECD Guideline 414, in New Zealand White rabbits and rats showed that isopropanol was not teratogenic at the dose levels administered. In rabbits, the reported maternal and developmental NOAELs were 240 and 480 mg/kg bw/day, respectively. In rats, the NOAEL for maternal and developmental toxicity was considered to be 400 mg/kg bw/day.
A NOAEL was not reported by the study authors. It is
proposed that the NOAEL for maternal toxicity be considered to be 0.5%
(596 mg/kg bw/day) due to decreased food and water consumption, and
corresponding effects on body weight at higher dose levels. The
NOAEL for fetal toxicity is proposed to be 0.5% (596 mg/kg bw/day) on
the basis of reduced body weights at higher dose levels.
The substance does not meet the criteria for classification and
labelling for this endpoint, as set out in Regulation (EC) No. 1272/2008.
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