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EC number: 701-281-9
CAS number: -
The study was performed to assess and
evaluate the toxic characteristics of the test substance, resulting from
a subacute oral administration via gavage to rats and comprises a
reproduction and developmental toxicity screening test, according to
OECD Guideline 422. A Dose Range Finding Study preceded this study.
All details given here refer to the
Main Study; a survey of the methods of the Dose Range Finding Study is
included into the Results of the Dose Range Finding Study (see below).
Test substance preparation for
dissolved with the vehicle.
Route of test substance
Dosing regimen: 1/day
for 28 consecutive days in males. 1/day until Day 4 post partum or for
55 Days in females. No test substance administration in the offspring.
Dose volume: 10
mL test substance preparation or vehicle per kg body weight.
Test system (animals): Rats,
Crl:CD(SD). 10 males and 10 females per group.
K (negative control
group) vehicle only,
(low dose group) 100 mg per kg
B (mid dose
group) 316 mg per kg body weight,
C (high dose
group) 1000 mg per kg body weight,
The target doses are derived from and
based on the results of the dose range finding study.
For a survey thereof, see below.
2 weeks pre-mating period;
2 weeks mating period; then sacrifice
of the males;
maintenance of the successfully mated
females throughout their pregnancy, birth, until Day 4 post partum, then
sacrifice of the dams and their offspring;
maintenance of the non-successfully
mated females for 26 days after the end of the mating period.
"Day 1" (of
the entire experiment) was the day of the 1st administration
of the test substance.
"Day 0 of pregnancy" (of
the given individual) was the day of proven mating.
"Day 0 post-partum" (of
the given individual) was the day of birth.
Analyses of the test substance
preparations: In selected samples. For homogeneity and concentration.
Animal observations: All animals, once
a day, plus a daily check for viability.
Detailed clinical observations: All
parental animals, once a week.
Functional observations: All parental
animals, once, prior to sacrifice.
Body weights: All males and all
females prior to successful mating once a week. All successfully mated
females on Days 0, 7, 14, 20 of pregnancy and on Days 0 and 4 post
partum. Pups as total litter weight on Days 0 and 4 post partum
consumption: All animals, for weekly periods.
Haematology: The first 5 parental
animals of all groups, prior to first dosing (Day 0) and on Day 15.
Clinical biochemistry: The first 5
parental animals of all groups, prior to first dosing (Day 0) and on Day
Necropsy with gross pathological
examination:All males on Day 15, all successfully mated females on Day 4
post partum, and all non-successfully mated females on Day 55. No
necropsy in pups.
weight determination: Selected organs in all parental animals at
necropsy. Not determined in pups.
Selected organs or tissues in the first 5 parental animals of groups K
and C. Organs and tissues with suspected test substance related
alterations also in groups A and B.
No histopathology in pups.
Data on reproduction and developmental
performance: Results of vaginal smear examinations; duration of
pregnancy; number, sex and viability of offspring. Number of corpora
lutea and implantation sites in the dams. Several parameters were
additionally derived from the primary data above.
Dose Finding Study:
Doses of 100 mg or 316 mg or 1000 mg
per kg body weight were given to groups of 5 male and 5 female rats once
a day for 7 consecutive days. Investigations performed: Animal
observations, body weights, feed consumption, and gross examination at
terminal necropsy. Summarised results: All animals survived until their
scheduled termination and were found to be normal at the daily
observations. Body weights, body weight gain, feed consumption did not
differ significantly or notably between control and test substance
exposed animals. All animals were normal at gross examination during the
Analyses of the test substance
preparations: The test substance was found to be sufficiently stable in
the preparations.The concentrations of the test substance in the
preparations for groups A and B were within the chosen limits, while the
determined concentration for group C was found to be clearly too low (87
% of the target concentration). As a consequence of this, the actual
dose for the high dose group is defined at 870 mg per kg instead of 1000
mg per kg, the target dose.A
fraction of the test substance was missing in the final preparations,
possibly by being placed during the weighing procedure on positions of
the beaker without contact to the vehicle and thus not being dissolved.
This might have happened due to the high viscosity of the test substance
and low absolute amounts weighed in. As a consequence, the actually
administered doses were, at least on some terms of the administration
period, lower than the target doses. For the estimation of the actually
administered doses, the analytical data with the highest deviation from
the target were used.
Mortality 2 animals died in the course
of taking blood samples on day 0 and were replaced by spare animals.
in life, clinical and functional observations, grip strength
determination: Loss of hair was observed in several animals in all dosed
Body weights and feed consumption:
There were no significant differences in body weights between the groups.
Haematology: No significant group
differences were noted at both blood sampling terms.
Clinical biochemistry: Only, but all,
parameters with significant differences to the negative control group
(indicated by a black background) are given in this survey:
low dose100 mg/kg(% of the negative controls)
mid dose316 mg/kg(% of the negative controls)
high dose1000 mg/kg*(% of the negative controls)
*actual received dose: 870 mg/kg bw/day
The significant group differences are
not given a toxicological relevance.
The elevated ALT level in the mid
dosed group is not given a toxicological relevance due to the lack of a
Organ weight determination: There were
no significant group differences in organ weights.
Necropsy with gross pathological
examination and histopathology: Histopathologically, indications for a
slight gastric irritation (proliferation of the limiting ridge) without
signs of inflammation were noted in some high dosed males. A slight
basophilia of centrolobular hepatocytes is interpreted as a possible
indication of enzyme induction. This alteration is taken as an adaptive
response and was present statistically significantly only in high dosed
Reproduction data: No indications for
a test substance related effect was made with any of the reproduction
Discussion and Conclusion
The test substance caused minimal
irritation on the mucous membranes of the stomach noted by a
proliferation of the limiting ridge in male animals of the high dose
In the livers of the high dosed males
a centrolobular cytoplasmatic basophilia of the hepatocytes is
interpreted as indicator of an induction of metabolizing enzymes. As the
liver weight was not affected, the amount of enzyme induction is assumed
to be rather low. Enzyme induction is not taken as an adverse effect,
but as an adaptive response.
The few other alterations were not
given toxicological significance.
There was no indication noted for a
systemic toxic effect of the test substance.
There was no indication for an effect
of the test substance on the reproduction.
There was no pronounced sex difference
in the response to the test substance.
The effects noted histopathologically
were minimal to mild.
The determined concentration of the
test substance in group C was found to be approximately 870 mg/kg and
therefore less than the target concentration of 1000 mg/kg. Therefore
the NOEL for the female animals had to be corrected from 1000 mg/kg
(target concentration) to 870 mg/kg (actual determined concentration).
No-observed-adverse-effect-level (NOAEL) of the test substance was set
to 870 mg/kg bw/day (top dose) for females and males.
The No-observed-effect-level (NOEL)
was set to 316 mg/kg bw/day for males.
No severe toxic effects were noted at
doses of up to 870 mg/kg bw/day (top dose)
No toxic effects on reproduction were
noted at doses of up to 870 mg/kg bw/day.
According to Regulation (EC) No
1272/2008 (CLP), "3-hydroxy-2-(hydroxymethyl)-2-methylpropionaldehyde"
does not need to be classified for neither "Reproductive Toxicity" or
"Specific Target Organ Toxicity after Repeated Exposure".
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