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EC number: 203-988-3
CAS number: 112-59-4
In an oral reproductive toxicity study in the OECD 422 design, groups of
12 male and 12 female CD rats were administered the test subatcne via
the diet at concentrations supplying 0, 100, 300 and 1000 mg/kg/day for
at least 33 days. The NOAEL for general toxicity was found to be 300
mg/kg/day in male and female rats. The NOAEL for reproductive and
neurological effects was 1000 mg/kg/day.
Body and Organ Weight Effects
from control mean by Dunnett's test, Alpha = 0 .05. •
different from control mean by Wilcoxon's test, Alpha = 0 .05 .
Bold type indicates the
effects judged to be treatment related .
Italics type indicates
the effects that were reflective of the treatment-related decrease in
Identified Clinical Chemistry Parameters
*Statistically different from control mean by Dunnett's test, Alpha = 0
Bold type indicates the effects judged to be treatment related .
Treatment related Histopathological
Bold indicates effects were considered to be treatment related .
In a Combined Repeated Dose Toxicity Study
with the Reproduction/Developmental Toxicity Screening Test (OECD 422),
groups of 12 male and 12 female CD rats were administered the test
substance via the diet at concentrations supplying 0, 100, 300 and 1000
mg/kg/day. Females were dosed daily for two weeks prior to breeding,
through breeding (up to two weeks), gestation (three weeks), and through
post-partum day 4. Females were necropsied on post-partum day 5. The
males were dosed for two weeks prior to breeding and continuing through
breeding (two weeks) up until necropsy (test day 34). Effects on
reproductive and neurological function as well as general toxicity were
evaluated. In addition, post-mortem examinations included a gross
necropsy of the adults with collection of organ weights and extensive
histopathologic examination of tissues.Litter size, pup survival,
sex, body weight, and the presence of gross external abnormalities were
Dietary administration of the test substance
to CD rats resulted in slight treatment-related decreases in body
weights of males and females given 1000 mg/kg/day. Decreased maternal
body weights persisted throughout the gestation and lactation phases of
the study. Females given 1000 mg/kg/day had treatment-related increases
in serum ALT and ALP activities, along with increases in relative liver
weight. These effects corresponded with treatment-related
histopathologic changes in the liver that consisted of very slight
panlobular hepatocyte hypertrophy. Males given 1000 mg/kg/day had
treatment-related increases in relative liver weight, which corresponded
with the histological alteration of very slight periportal hepatocyte
hypertrophy. At 1000 mg/kg/day, other findings of lesser significance
included slightly increased blood urea nitrogen and decreased absolute
thymus weights in females, decreased urine pH and increased relative
kidney weights in males. Additional histopathologic findings of minor
toxicological significance at 1000 mg/kg/day included very slight
diffuse acinar hypertrophy of the submandibular salivary gland in males,
and very slight atrophy of the mesenteric adipose tissue in females. No
adverse effects of the test substance on neurological function were
There were no treatment-related
effects at any dose level on mating, conception, fertility and gestation
indices, time to mating, gestation length, post-implantation loss, pup
survival or pup sex ratio. In addition, there were no adverse gross or
histopathological findings in the reproductive organs of males or
females at the highest exposure level, despite the presence of
treatment-related maternal toxicity at this dose.
on the results of this test, NOAELfor general toxicity was 300
mg/kg/day. The NOAEL for reproductive and neurological effects was 1000
mg/kg/day, the highest dose level tested.
were also no effects on reproductive parameters in three one-generation
studies and one study to assess the estrous cycle in rat with the read
across substance DEGBE up to 2000mg/kg after dermal exposure and up to
1000mg/kg after oral (gavage or drinking water exposure).
OECD 414, rats, vapour: NOAEL = 500 mg/m³ (highest dose tested), Dow
1987, RA substance EGHE
OECD 414, rats, diet: NOAEL = 633 mg/kg (highest dose tested), Ema 1988,
RA substance DEGBE
Timed-pregnant Fischer 344 rats, 25 per
group, were exposed to ethylene glycol hexyl ether vapor for six
hours/day on gestational days (gd) 6 through 15 for rats at target
concentrations of 0, 20, 40 or 85 ppm (analytical concentrations of 20.8
± 0.90, 41.1 ± 1.77 and 79.2 ± 10.80 ppm for the 20, 40 and 85 ppm
groups, respectively). Eighty-five ppm was close to the saturated vapor
concentration of the material at 20°C. Maternal body weights were
measured on gd 0, 6, 9, 12, 15 and 21 (rats). Food and water consumption
was measured, for rats only, for three-day intervals throughout
gestation. At scheduled sacrifice on gd 21 (rats), maternal body weight,
gravid uterine weight, and liver weight were taken. Maternal blood
samples were taken examined for hematologic changes including
differential leukocyte counts. Ovarian corpora lutea of pregnancy were
counted and all uterine implantation sites were identified and recorded:
resorptions (early or late), dead fetuses and live fetuses.All live
fetuses were examined for external malformations, including cleft
palate, and variations. About 50% of the rat fetuses in each litter were
examined for visceral malformations and variations, 50% of the fetuses
in each litter were examined for craniofacial defects and the other 50%
(intact fetuses) were examined for skeletal malformations and
In rats, maternal toxicity was observed at
40 and 85 ppm, including transient reductions in maternal body weight
and weight gain during the exposure period and clinical signs of
toxicity at 85 ppm, and reduced weight gain during the exposure period
at 40 ppm. Maternal food consumption was reduced at 85 ppm during the
exposure period (and increased in the postexposure period). Water
consumption was increased at 85 ppm during and after the exposure
period. There were no treatment-related clinical signs, gross necropsy
observations or hematologic changes. Gestational parameters, including
corpora lutea, total, nonviable or live implantations per litter, pre-
or postimplantation loss, sex ratio or fetal body weights (males,
females or total) per litter, were unaffected by exposures. There were
no effects of treatment on the incidence of malformations or variations
when examined by individual finding, findings by category or total
Exposure to the test substance vapor during
organogenesis in Fischer 344 rats resulted in transient maternal
toxicity at 85 and 40 ppm, and no embryofetal toxicity (including
teratogenicity) at any exposure concentrations employed. The "no
observable effect level" (NOEL) for maternal toxicity was 20 ppm for
rats and the NOEL for developmental toxicity was 85 ppm.
Substance intakes are shown in the section
on doses. Skeletal findings are regarded as spontaneous as all are
reported to occur historically in control rats (Kameyama, Cong Anom, 20,
25, 1980; Palmer AK, Methods in Perinatal Toxicology, ed Merker, 52,
Satellite group: There was no significant
effect on any of the parameters measured. It should however be borne in
mind that the statistical power of this part of the study is low with
only 5 or 6 animals per dose group. There was slight evidence for a fall
off in survival rate, number of implantation remnants per litter and
live newborns per litter but this was far from clear and levels in the
low dose group were higher than controls. The only sound conclusion that
can be drawn is those of the study author's that there is no evidence
for any adverse effects.
In a study that conformed to the basic requirements of the relevant OECD
guideline, 2 -(2 -butoxyethoxy)ethanol produced no significant evidence
of developmental toxicity when fed to rats in their diet at doses up to
633mg/kg bw/day during the whole gestation period (GD0 -20). A small
satellite group which looked at residual effects in pups after birth for
up to 10 weeks also failed to show any effects on the parameters
There are no data available for DEGHE. To cover this endpoint, a
read-across was conducted to the related analogues ethylene glycol hexyl
ether (EGHE) and diethylene glycol butyl ether (DEGBE). A read across
justification document has been attached to the corresponding enpoints
and to chapter 13.
Data generated with EGHE
In a teratogenicity study comparable to OECD guideline 414, 25
rats per group inhaled EGHE vapours from gestation day 6 to 15 for 6h
each day(DOW, 1987). The concentrations used in the whole body exposures
were 20, 40, and 85ppm. The top dose was the highest vapour
concentration, which could be achieved.
Body weight, food consumption, and clinical signs were regularly
monitored in maternal animals. After sacrifice, all organs and
haematological parameters were examined in addition to the number of
corpora lutea, number of implantations, resorptions, and live versus
dead foetuses. Gross examinations were performed for all foetuses per
litter, while half of the foetuses were used for either soft tissue and
head or skeletal examinations.
Treatment related clinical signs (urine stains on fur,
lacrimation, ocular wetness and encrustation) were observed during the
exposure period to 85ppm. There were significant decreases in maternal
body weight and weight gain at both the 40 and 85 ppm dose groups and
food consumption at 85 ppm dose group. Water consumption was increased
at the 85 ppm. At scheduled necropsy, there were no treatment related
findings at maternal gross examination. There were no changes in the
haematological parameters, on maternal organ weights, gravid uterine
weight, and gestational body weight. There were no effects of exposure
on gestational parameters including number of corpora lutea per dam,
number of total, non-viable or live implantations per litter, pre- and
post-implantation loss, sex ratio and fetal body weight. The incidence
of fetal malformations and variations were comparable between the
treatment groups. The NOEL for maternal toxicity was 20ppm, the NOAEL
for teratogenicity was 85ppm (app. 0.5mg/l).
Data generated with DEGBE
In a well-documented study performed similar to OECD guideline
414, 20 rats per group were exposed via feed from gestation day 0 to
20(Ema, 1988). 25% of the animals from each dose were allowed to deliver
naturally. Concentrations of 0.04, 0.2, and 1% correspond to daily doses
of about 25, 115, and 633mg/kg b.w. The maximum dose was selected based
on a pre-study with dietary doses of 0.2, 1, 5, and 10% in diet. 5 and
10% produced marked body weight and food consumption reduction therefore
1% selected as test dose maximum for the main study.
Animals were monitored daily for clinical signs, body weight
changes, and food intake. Post-mortem examinations included assessment
of the number of corpora lutea, number of implantations, number of
resorptions, number, sex, and weight of live and dead foetuses, and
calculation of pre- and post-implantation loss. External examinations
were performed on all foetuses. Half of the foetuses each were assessed
either for soft tissue or skeletal alterations.
The only effect on the maternal animals was a lower body weight
gain (-12 - -18%) in all doses, but without dose response relationship.
There were no effects on any implantation parameters, corpora lutea,
live fetus numbers, sex ratios, and fetal or placental body weight. No
external or internal anomalies were found. One fetus each showed
skeletal defects (fused sternebrae) in the mid and high dose
groups. Skeletal variations occurred in all dose groups. The rate was
slightly higher in the high dose group compared to control animals, but
the difference was not statistically significant. The degree of
ossification of the low dose group was significantly lower than controls
but this effect was not seen in any of the other dose groups.
Consequently, the NOAEL for maternal, developmental, and feto-toxicity
was 633 mg/kg.
Teratogenicity studies according to OECD 414 have been performed
also in rabbits with DEGBE and EGHE. No developmental or embryotoxic
effects were observed.
In all studies either with DEGHE or the read across substances, no
effect on fertility or developmental toxicity was observed.
Consequently, classification is not warranted according to CLP
Regulation (EC) No. 1272/2008.
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