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EC number: 248-363-6
CAS number: 27247-96-7
In an OECD 421 Reproduction / Developmental Toxicity Screening Test, the
test item, 2-EHN (CAS No. 27247-96-7), was administered daily by oral
gavage to male and female Sprague-Dawley rats, from before mating,
during mating, gestation and until day 5 post-partum, at dose-levels of
20, 100 or 500 mg/kg/day.
Systemic toxicity was observed at all dose-levels, as evidenced by
reduced body weight gain during, at least, the premating period (at
least 13% less weight gained than the controls during the first 2 weeks
of treatment) (statistically significant at 500 mg/kg/day). As body
weight gains which are reduced by more than 10% are considered
biologically significant, all groups had biologically significantly
reduced body weight gains. Clinical signs of hypoactivity and
half-closed eyes were also observed at 100 and 500 mg/kg/day and food
consumption was lower than controls’ for females given 500 mg/kg/day.
There were no effects of treatment on pairing but a relationship between
development of the fetuses and pups and treatment cannot be excluded
because there was one female with only implantation scars and a dead
fetus in the uterine horns and another female which delivered a litter
of small pups which consequently died on day 3 post-partum.
Mean pup body weight at 500 mg/kg/day was less than that of the controls
on day 1 post-partum and pup body weight gain was reduced at 100 and 500
There were no treatment-related findings observed at macroscopic or
microscopic examination of F0 animals and no effects on organ weights.
Based on the experimental conditions of this study, the No Observed
Adverse Effect Level (NOAEL) for parental toxicity was considered to be
20 mg/kg/day, and the NOAEL for toxic effect on reproductive performance
and on progeny was 100 mg/kg/day.
Three groups of ten male and ten female Sprague-Dawley rats received the
test item, 2-EHN (CAS No. 27247-96-7), daily, by oral (gavage)
administration, before mating and through mating and, for the females,
through gestation until day 5 post-partum, at dose-levels of 20, 100 or
500 mg/kg/day. Another group of ten males and ten females received the
vehicle, 0.5% tween 80 in purified water, alone, under the same
experimental conditions and acted as a control group. The dosing volume
was 10 mL/kg.
Clinical signs and mortality were checked daily. Body weight and food
consumption were recorded weekly until mating and then at designated
intervals. The dams were allowed to litter and rear their progeny until
day 6 post-partum. The total litter sizes and numbers of pups of each
sex were recorded after birth, pup clinical signs were recorded daily
and pup body weights were recorded on days 1 and 5 post-partum.
The males were sacrificed after completion of the mating period. The
body weight, testes and epididymides weights were recorded and a
macroscopic post-mortem examination of the principal thoracic and
abdominal organs was performed. A microscopic examination was performed,
for the control and high-dose group, on the testes and epididymides with
special emphasis on the stages of spermatogenesis and histopathology of
interstitial testicular structure.
The dams were sacrificed day 6 post-partum (or from day 25 post-coitum
for females which did not deliver) and a macroscopic examination of the
principal thoracic and abdominal organs was performed. In the females
which were apparently non-pregnant, the presence of implantation scars
on the uterus was checked using ammonium sulphide staining technique. A
examination was performed on the ovaries of the control and high-dose
The pups were sacrificed on day 6 post-partum and were carefully
examined for gross external abnormalities and a macroscopic post-mortem
examination was performed.
There were no animals prematurely sacrificed for reasons of poor
clinical condition during the study.
All animals given 500 mg/kg/day had ptyalism throughout the study which,
when measured, lasted 4-5 hours after dosing and may be related to the
taste of the test item formulations. Hypoactivity, half-closed eyes and
loud breathing were also observed sporadically in a few males and
females. One female also had emaciated appearance, round back and
piloerection for some days during the study. The majority of the females
given 100 mg/kg/day had ptyalism during the premating and gestation
periods and a few males had ptyalism during the premating period, which
may be related to the taste of the test item formulations. One female at
100 mg/kg/day had hypoactivity and half-closed eyes on day 12 of dosing.
There were no clinical signs at 20 mg/kg/day.
Male and female groups at all dose-levels gained less weight than the
controls during the premating period in a dose-related manner achieving
statistical significance at 500 mg/kg/day. Females given 500 mg/kg/day
continued to gain less weight during gestation, however all groups had
approximately comparable weight gains to the controls during lactation.
Females given 500 mg/kg/day consumed less food than the controls
throughout the study. This was not also observed in the males and there
were no effects of treatment at the other dose-levels.
All pairs mated and the mean number of days taken to mate was comparable
with the controls for all groups.
There were no effects on the numbers of corpora lutea or implantations.
The mean numbers of pups born per litter were comparable with the
controls at all dose-levels.
At 500 mg/kg/day, there was one female with one dead fetus and nine
implantation scars in the uterine horns and one female which delivered a
litter of small pups, all of which were dead by day 3 post-partum. As
pup survival was higher in the control group, a relationship to
treatment cannot be excluded.
Mean pup body weight at 500 mg/kg/day on day 1 post-partum was
non-statistically significantly lower than that of the controls. Pup
weight gain from day 1 to day 5 post-partum was non-statistically
significantly lower than the controls’ at 100 and 500 mg/kg/day in a
dose-related manner, and mean pup body weights were non-statistically
significantly lower than the controls’ on day 5 post-partum at both
There were no treatment-related pup clinical signs or necropsy findings.
The test item, 2-EHN (CAS No. 27247-96-7), was administered daily by
oral gavage to male and female Sprague-Dawley rats, from before mating,
during mating, gestation and until day 5 post-partum, at dose-levels of
20, 100 or 500 mg/kg/day.
In addition to the OECD 421 study, a proposal was also submitted for
reading-across to 2-EHN from a two-generation reproductive toxicity
conducted using the source substance, Di-2 -Ethylhexyl Terephthalate
(DEHT). This study was previously used in the registration dossier for
2-ethylhexan-1 -ol, a metabolite of 2 -EHN. A similar strategy, of
reading across to 2 -ethylhexan-1 -ol was also used to meet the
information requirements for several other endpoints for 2 -EHN. This
read-across strategy has been rejected (Decision: TPE-D-0000002102 -92
-05/F). Therefore, the Toxicity to reproduction endpoint, and the data
needed to meet current information requirements, will be re-evaluated
following completion of the currently scheduled 90 -day and prenatal
studies and evaluation of the study results (see Sections on Repeated
Dose Toxicity and Developmental Toxicity).
Several developmental toxicity studies in rodents are available for
read-across substances 2-ethylhexan-1-ol, sodium nitrate and
Pentaerythritol tetranitrate (PETN). No significant developmental
effects were observed in these studies. No study is currently available
in rabbits, and the requirement for a developmental study in a second
species has been waived previously. However, this read-across strategy
has been rejected (Decision: TPE-D-0000002102 -92 -05/F). Pre-natal
developmental toxicity studies (according to OECD Test Guideline 414)
with exposure to 2-EHN via the inhalation route are currently scheduled
in rats and rabbits, according to Decision TPE-D-0000002102 -92 -05/F.
The dossier will be updated with the study results once these become
Table 1: Summary of data (Litter mean ± standard deviation)
Test item 2-EH
Mean maternal weight [g]
283 ± 18
243 ± 25
286 ± 17
262 ± 24
310 ± 17
291 ± 26
371 ± 20
354 ± 32
Mean feed consumption [g]
97 ± 17
108 ± 14
107 ± 12
124 ± 12
113 ± 11
118 ± 10
106 ± 15 (a)
117 ± 13
Mean water intake [g]
196 ± 32
204 ± 46
203 ± 24
276 t 93
248 ± 30
265 ± 123
216 ± 36
248 ± 96
Mean corpora lutea per litter
15 ± 2
14 ± 4
Mean resorptions per litter
Mean number females per litter
7 ± 2
8 ± 2
Mean number males per litter
Mean fetal weight [g]
3.02 ± 0.20
3.19 ± 0.20
3.18 ± 0.30
3.28 ± 0.27
(a) Significantly different from control
The prenatal developmental toxicity of the source substance and test
item 2-Ethylhexan-1-ol (CAS 104-76-7) via the inhalation route in the
rat was measured in a GLP-compliant study using a “Prenatal
Developmental Toxicity Study” compliant with OECD TG 414 (2001),
with the sole deviation that the number of test animals was reduced (15
female test animals instead of 25). The validity criteria were met and
the experiment can be considered relevant and adequate for the endpoint,
however a reduced number of test animals were included. Nonetheless it
is deemed conclusive and was rated „reliable with restrictions“,
i.e. “Klimisch 2” according to the scale of Klimisch et al.
(1997). In consideration of possible read-across from this study to
metabolic precursors, additional uncertainties have to be taken into
account. The rating of the study for use in such analogue or metabolite
approach is lower compared to equally rated studies providing direct
data from a target substance.
Fifteen sperm-positive female Sprague-Dawley rats were exposed to
vapours of the test item through whole body exposure during gestation
days 0 -19. Hinners type 0.5m³ exposure chambers to vapours of the test
item at a concentration of 850 mg/m³ air was confirmed independently 2
methods; hourly by infrared analyzer and twice weekly by gas
chromatography of charcoal tubes from the exposed chamber.
No maternal toxicity or developmental toxicity was noted in a rat
inhalation study. The overall feed consumption was approximatley 10 -15%
lower in treated animals compared to controls. Although the weight gain
appeared to be lower in the treated animals, these differences did not
reach statistical significance. The reproduction parameters were
unchanged. No malformations were induced after exposure of the pregnant
rats to the test substance. The incidences of resorptions, the number of
fetuses per litter, the sex ratio, fetal weight, were not different to
the control group and no external, skeletal or visceral malformations
have been recorded.
In conclusion no substance-related adverse effects of the test item were
observed at the highest vapour concentration achievable. Therefore the
NOAEL (discriminating dose) was assigned to the highest test
concentration. The NOAEL for maternal and developmental toxicity and
teratogenicity in the rat is thus ≥ 850 mg/m³ air or ≥ 6.5 mmol/m³ as a
basis for equimolar comparison in read-across approaches.
Reading-across to the target substance, 2-Ethylhexyl nitrate (2 -EHN,
CAS 27247-96-7) delivers on the same molar concentration an air level of
≥1148 mg/m³ air. Taking the significantly lower vapour pressure of the
target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account,
an equimolar exposure exceeding saturated vapour concentrations of the
target chemical can be concluded to be non-toxic during developmental
Male and female sprague-dawley rats were exposed daily via oral gavage
to varying concentrations (0, 100, 500, 1000 mg/kg bw/day) of PETN. Male
rats were dosed 2 weeks prior to mating and throughout the mating period
until a total of 28 doses had been administered. Female rats were dosed
2 weeks prior to mating, through the mating and gestation period and up
to and including day 3 post-partum. Throughout the testing period
general clinical observations were made at least once a day. No rats
died following PETN exposure, however, four rats dies prior to scheduled
euthanasia due to esophageal perforations caused by oral gavage. No
differences were observed for gestation duration, number of pups
produced and pup sex ratio. Two pups in the 100 mg/kg bw.day group and 1
runt from a control animals were found dead on day 2. No gross lesions
were found for any of these pups. The only differences in body weight
and feed consumption were observed relative to dose and not considered
to be a direct cause of PETN toxicity.No differences in ovaryw eight
(expressed as organ/ body weight ratios), number of implantation sites
and number of corpora lutea were observed among treatment groups. Based
on the absence of adverse effects from repeated daily exposure of up to
1000 mg/kg bw/day, PETN is not expected to be a reproductive or
PETN has four nitrate groups that may be metabolized compared to one
nitrate group on 2 -EHN. Therefore, this study represents a worst case
scenario for 2 -EHN. As no developmental effects were seen wtih PETN, no
developmental effects are expected with 2 -EHN.
Based on results from the currently available studies, there is
insufficient evidence to require classification of 2 -EHN for
reproductive or developmental toxicity according to Regulation (EC) No
1272/2008. Prenatal developmental toxicity studies with exposure to 2
-EHN via the inhalation route are currently scheduled in rats and
rabbits, according to Decision TPE-D-0000002101 -92 -05/F. Once the
study results are available, the dossier will be updated and this
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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