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EC number: 212-133-3
CAS number: 764-99-8
A NOAEL for subacute toxicity of 1000 mg/kg bw/day was derived from a 28 day toxicity in rats after oral (gavage) administration.For evaluation of the subchronic toxicity read across to 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. A NOAEL of 300 mg/kg bw/day was derived from a 2 generation reproduction toxicity study with rats after oral (gavage) administration.
For repeated dose toxicity, only a 28-day
subacute toxicity study with the test substance
1,1'-[oxybis(ethyleneoxy)]diethylene is available indicating a NOEL in
rats of 1000 mg/kg bw/day. To address longer subchronic exposure time,
read across to the structural analogue 3,6,9,12 -Tetraoxatetradeca-1,13
-diene (CAS 765 -12 -8) was made. The NOEL of 300 mg/kg bw/day was
derived from a 2 -generation reproduction toxicity study. Both
substances behave very similar in acute toxicity tests (oral and dermal
LC50 > 2000 mg/kg bw) and also in skin and sensitisation tests. Both
substances are not irritating to skin and eye and do not show any signs
of skin sensitisation. In addition mutagenicity tests show negative
results in both substances. In conclusion, read across is supported by
the structural similarity and the available toxicological information.
The use of the 2 -generation study instead of a 90d repeated dose
toxicity study is scientifically justified, as the animals were treated
for a comparable time period (F0: 20 weeks, F1: 19 weeks).
The test item was administered to rats by
intragastric intubation, daily, for twenty-eight consecutive days at
dosage levels of 30, 100, 300 and 1000 mg/kg bw/day (Charles River
Laboratories, 2007). Microscopic observations attributed to the test
article were limited to minimal to mild epithelial hyperplasia and
hyperkeratosis in the non glandular region of the stomach of both males
and females treated with 1000 mg/kg/day and one female treated with 300
mg/kg/day. There was no other toxicity observed in the male and female
rats as high as 1000 mg/kg/day. The stomach findings were considered of
minimal toxicological significance and possibly an indication of local
irritation rather than systemic toxicity. Therefore the
no-observable-adverse-effect-level (NOAEL) was considered to be 1000
mg/kg/day in both the male and female rats (highest dose tested).
subchronic toxicity (read across)
The structural analogue
3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) of the test item
was orally administered in a 2-generation reproduction toxicity study to
groups of 25 male and 25 female Wistar rats at dosages of 0, 100, 300
and 1000 mg/kg bw/d for up to 20 weeks (OECD 416; BASF 73R0162/03041).
There were no indications for reproductive or developmental toxicity.
The clinical examinations of the F0 and F1 parental rats for general
signs of toxicity revealed some substance-related effects at the high
dose (1000 mg/kg bw/d). These were substantiated by unsteady gait and/or
abdominal position, which occurred intermittently in several, but not
all top dose rats shortly after gavage dosing and persisted only for
some minutes. Moreover, all male and nearly all female F0 and F1
parental animals of the high dose group (1000 mg/kg bw/d) showed
transient salivation during major parts of the treatment period.
Salivation persisted in the respective animals only for some minutes
after daily gavage dosing. There occurred no mortalities that could be
causally related to the test substance. Food consumption and body weight
data of the F0 and F1 parents, collected during premating, gestation,
and/or lactation phases, were not influenced by the test substance
administration. Regarding pathology, kidneys and liver proved to be the
target organs in both genders of the two parental generations at the top
dose (1,000 mg/kg body weight/day). The absolute and relative kidney
weights were statistically significant increased in high dose F0 and F1
males and showed corroborative histopathological findings (i.e.
increased incidence of chronic progressive nephropathy). The mean liver
weights were statistically significantly increased in high dose F0 males
(relative) and in the top dose F1 males and F1 females (absolute and
relative). The increased liver weights correlated with a minimal
centrolobular hypertrophy of hepatocytes that was noted in seven high
dose F1 males (controls: one F1 male). Although there was no
histopathological correlate for the F0 males and F1 females at 1000
mg/kg, the increased liver weights of these rats are also considered as
substance related. Thus, the NOAEL for overall general toxicity on the
parental rats could be fixed at 300 mg/kg body weight/day.
No data are available on the dermal or
The criteria for classification according to
EU Directive 67/548/EEC and EU Classification, Labelling and Packaging
of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008 are not
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