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EC number: 200-889-7
CAS number: 75-65-0
The reproductive toxicity of tertiary butyl alcohol was investigated in
an enhanced guideline reproductive/developmental screening study. In
this study, Sprague-Dawley rats (12/dose/sex) were administered, via
oral gavage, 0, 64, 160, 400 or 1000 mg/kg bw/day tertiary butyl alcohol
for 4 weeks pre-mating and then until termination: week 9 (males) and
PND 21 (females). Selected pups were then administered tertiary butyl
alcohol directly for a period of seven days before termination on PND 27.
At 1000 mg/kg bw/day, F0 toxicity manifested itself as clinical signs
(unresponsiveness/ lethargy, ataxia, increased vocalisation and rapid
breathing). Body weight was mildly affected in males (non-significant
decreases in male body weight from week one) and during the later stages
of gestation in females. The only effect on feed consumption was a 15 %
reduction in females over the first two weeks of lactation. During
lactation a large increase in female body weight gain was observed. The
significance of this finding is unknown. Increases in both liver and
kidney weight were observed in males. At 400 mg/kg bw/day, lower
incidences of clinical signs (as compared to the high dose) were
observed in females, although only transiently (weeks 2-4). Kidney
weight was increased in males of this dose level and was the only effect
observed at 160 and 64 mg/kg bw/day. This increase was not statistically
significant at the lowest dose and, therefore, is not considered adverse.
There was no effect on mating performance or number of pregnancies
observed in any treatment group. A slight effect on gestation length was
observed; with half the females from the top dose group and almost half
the females in the mid dose with a gestation length greater than 22 (all
but one was a shift to 23 days). The shift was reported to be within the
normal range (21-23 days, although with a distinct node of 22) and is
therefore considered a chance finding.
In the F1 generation, there was no effect on the number of implantations
per pregnancy; however, significant pup mortality was observed at 1000
mg/kg bw/day. Six out of 153 pups were stillborn with a further 32 pups
dying between days 1-4 (the majority were found dead on day 1). The
deaths include one total litter loss. The incidence of still born deaths
is likely to be within the normal variation for this type of effect and
is therefore not considered treatment related. The deaths observed
post-parturition were only observed in the presence of maternal toxicity
(unresponsiveness/lethargy and ataxia) and are considered likely to be a
secondary consequence of this toxicity and not a direct effect of
tertiary butyl alcohol.
In addition to the reduction in pup survival, pup bodyweight gain was
also affected in pups treated with 1000 mg/kg bw/day. Direct treatment
of the pups for 7 days from PND 21 had no further effect on the pups.
No treatment related effects were noted at any other dose.
The parental NOAEL was 64 mg/kg bw/day based on increased kidney weight
in males. The NOAEL for this study for reproductive toxicity is 1000
mg/kg bw/day, the highest dose tested. The NOAEL for this study for
offspring effects is 400 mg/kg bw/day based on increased pup mortality
(mostly post-natal) at the top dose.
Data from a two-generation reproductive toxicity study with methyl
tertiary butyl ether (Bevan, et al., 1997) was also used to evaluate the
potential for tertiary butyl alcohol to cause reproductive toxicity.
Methyl tertiary butyl ether is rapidly and irreversibly metabolized to
tertiary butyl alcohol and significant blood levels of tertiary butyl
alcohol can be found following methyl tertiary butyl ether exposures.
The basis for using methyl tertiary butyl ether data is further
explained in the accompanying “Read-Across” document included within
Methyl tertiary butyl ether and tertiary butyl alcohol have similar
properties of toxicity including central nervous system effects and
decreases in body weight or body weight gain at high exposure
concentrations. In terms of reproductive toxicity, neither chemical
caused any effect on an measures of fertility or reproductive success,
in either male or female rats. In terms of effects on the offspring,
both chemicals cause an increased incidence of postnatal death in pups
born to dams receiving these chemicals. The increase in postnatal deaths
was linked to maternal toxicity and reduced care of the newborn pups.
The severity of the increase in postnatal deaths in more apparent in the
tertiary butyl alcohol study as the dams were receiving the chemical
during the days immediately post-parturition while the methyl tertiary
butyl ether dams and litters were less affected as the inhalation
exposures were (necessarily) discontinued during the period of
parturition and the first four days of lactation. As described in the
“Read-Across” document, the Cmax micromolar concentrations of tertiary
butyl alcohol are similar between these two studies and the NOEC of 400
ppm methyl tertiary butyl ether is expected to be the same NOEC for
tertiary butyl alcohol, with similar effects being reported in terms of
effects on fertility and offspring.
Short description of key information:
No effects on fertility were noted in a screening study conducted with tertiary butyl alcohol or in a two-generation reproductive toxicity study with methyl tertiary butyl ether where significant blood levels of tertiary butyl alcohol would be expected throughout the treatment period. Use of this read-across data is further explained in the “Read-Across” document found in Section 5.1.1. In addition, no effects of concern were noted in either the tertiary butyl alcohol screening study or the methyl tertiary butyl ether toxicity study that would warrant further investigation.
Information on developmental toxicity for tertiary butyl alcohol is available from an oral screening study in rats; a published developmental toxicity study (similar to guideline) in the rat conducted via the inhalation route and two non-standard published dietary studies in mice. No malformations were observed in the only good quality study in rat indicating tertiary butyl alcohol is not developmentally toxic. At the top dose in the screening study, 6 pups were stillborn (compared to 2 in the control) and a further 32 pups died by day 4. At this dose level, maternal toxicity was evident (ataxia, sedation and bodyweight reduction during gestation). It is likely that the deaths observed between days 1-4 may be due to neglect by the dams rather than a direct effect of tertiary butyl alcohol. Reduced fetal weights were also observed at all doses; the extent of the reduction was considered adverse in the top two doses. The available studies in mice and are not considered of sufficient quality to provide any useful information on the developmental toxicity of tertiary butyl alcohol. Overall, tertiary butyl alcohol does not appear to be developmentally toxic.
No standard guideline oral developmental studies are available for
tertiary butyl alcohol. Information on developmental toxicity is
available from an oral reproductive/developmental toxicity screening
study conducted on tertiary butyl alcohol. Moderate to severe maternal
toxicity was noted at the 1000 mg/kg bw/day dose level with mild
toxicity (CNS signs) noted in the dams from the 400 mg/kg bw/day group.
No effects were noted in the dams from the 160 mg/kg bw/day group.
Evidence of developmental toxicity was restricted to the 1000 mg/kg
bw/day group and included increased number of dead pups at birth and
decreased litter size. The NOAEL for maternal toxicity was 160 mg/kg
bw/day and the NOAEL for developmental toxicity was 400 mg/kg bw/day.
The developmental toxicity of tertiary butyl alcohol was investigated
via the inhalation route (whole body) in a study considered to be
similar to guideline (Nelson et al, 1989). Sprague-Dawley rats (15
control and 18 treated/group) were exposed 7 hours/day between days 1-19
to 5000, 3500 or 2200 ppm tertiary butyl alcohol. The equivalent mg/kg
bw/day values have been estimated using the conversion equation in
Appendix 1 of OECD guidance document 39 (temp was 24 ºC); a value of
0.34 m3/kg bw calculated for 7 hour exposure based on the information in
table 8.2 of Chapter 8 of ECHA’s guidance; and an absorption value of 60
% for tertiary butyl alcohol. The resulting values were 1239, 2169 and
3098 mg/kg bw/day for the 2000, 3500 and 5000 ppm groups, respectively.
These exposures were therefore higher than the maximum dose recommended
by current OECD guidelines (1000 mg/kg bw/day).
At the top exposure concentration, in dams, body weight gain and feed
consumption was lower compared to the controls. Clinical signs included
unsteady gait and impaired locomotor activity in the top two tertiary
butyl alcohol concentrations, whereas unsteady gait was observed at the
lowest dose level. In fetuses, body weight gain was reduced in all
tertiary butyl alcohol concentrations (≥ 9 %) compared to controls.
According to the publication there was a slight increase in the number
of “skeletal malformations” at the top exposure concentration. The vast
majority of these “malformations” were rudimentary cervical ribs, a
finding commonly considered a skeletal variation. There were also an
increased number of skeletal variations (top two concentrations) and
visceral variations (top concentration only) reported. Due to clinical
signs in dams and reduced fetal weight at all tertiary butyl alcohol
concentrations, a LOAEC of 2000 ppm (1239 mg/kg bw/day) is derived for
both maternal and developmental toxicity.
Information is available on the developmental toxicity of tertiary butyl
alcohol from two non-standard studies.
The effect of tertiary butyl alcohol on development and post-natal
behaviour was investigated in a non-standard study in Swiss Webster mice
(Daniel and Evans, 1982). These mice were administered with 0.5, 0.75 or
1 % tertiary butyl alcohol via a Modified Lieber and DiCarli liquid
diet, that replaced both water and feed sources between days 6 to day
20. Typical use of these diets in the field of ethanol research
required an acclimation period of two weeks, where the concentration of
the alcohol was slowly increased. However, in this study, the feed and
water were simply replaced with the liquid diets on GD6 without any
acclimation period. Only 4 litters/treatment groups were used in the
Equivalent mg/kg bw/day values were estimated using the body weights of
the mice provided in the paper on day 15 of gestation and default values
for feed and water consumption for pregnant dams (table R.8-17 of ECHA’s
guidance on the Characterisation of dose [concentration]-response for
human health (http://echa.europa.eu/documents/10162/13632/information_
requirements r8_en.pdf)). The resulting dose levels were approximately
0, 2375, 3535 or 4714 mg/kg bw/day.
Maternal weight gain was adversely affected at 1 % (10 % lower than
controls), the top dose. A lesser reduction in body weight was observed
in the 0.75 % dose group (5 % lower than controls). A dose related
reduction in litter size, number, weight and viability was observed.
This is consistent with the effects observed in the rat
reproductive/developmental toxicity screening study. At the top two
doses (0.75 % and 1.0%) there were also behavioral effects observed in
offspring (delayed righting reflex, open field performance differences,
reduced roto-rod performance) suggesting that pups at these doses may be
developmentally delayed, possibly as a result of the maternal toxicity
observed. Given the non-standard nature of the study design,
particularly the small group sizes employed, little confidence can be
attributed to the findings of the study. No NOAEL has been derived for
The pre-natal toxicity of tertiary butyl alcohol was investigated in a
limited reported, non-guideline study in two strains of mice (CBA/J or
C57BL/6J) (Faulkner et al, 1989). The study reported that oral gavage
administration of 10.5 mmoles/kg bw (780 mg/kg bw), twice daily between
gestation days 6 to 18, led to an increased number of resorptions and a
decrease in fetal viability. No information on the dams was provided so
it is not possible to assess maternal toxicity. Although developmental
effects are reported, the small group sizes, the very high dose levels
(1560 mg/kg bw administered in total each day), the limited scope of the
study and limited reporting indicate little confidence can be attributed
to the results. No NOAEL/LOAEL was derived
No adverse effects on fertility were observed in an rat reproductive
screening study conducted up to doses of 1000 mg/kg bw/day tertiary
butyl alcohol. With regards to developmental effects, information from a
good quality study for tertiary butyl alcohol did not show any
developmental toxicity. No classification for reproductive toxicity is
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