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EC number: 202-598-0 | CAS number: 97-64-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
Test material
- Reference substance name:
- Ethyl lactate
- EC Number:
- 202-598-0
- EC Name:
- Ethyl lactate
- Cas Number:
- 97-64-3
- Molecular formula:
- C5H10O3
- IUPAC Name:
- ethyl 2-hydroxypropanoate
- Test material form:
- liquid
- Remarks:
- colorless transparent liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- The Test Guideline OECD 422 is designed for use with the rat. The
rats are the standard experimental rodent of choice and
recommended by OECD Guideline and in the international
validation program for the detection of endocrine disrupters the rat
was the only species used. - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were acclimated to the condition identical to the
condition during the experiment 5 days prior to the start of treatment.
The acclimation was according to standard operation procedures.
The animals were acclimated during 5 days to the animal room
conditions identical with the conditions defined for the experimental
part of the study. On the arrival, they were placed into the cages, 3
rats per cage and were weighted after 48-hours.
The animals were housed in TECNIPLAST cages 1500U from the
Tecniplast Company, Italy. The cages have high density
polypropylene body, measuring 480 x 375 x 210 mm - floor area
1500 cm2. The cages, cage racks and other equipment were sanitized
according to standard operation procedures.
On arrival, animals were placed into the cages, 5 rats per cage.
48-hours after arrival animals were weighted and kept in their cages
until the start of the study to allow for acclimation to the animal
room conditions, which are identical as defined for the experimental
part of the study. After randomisation were placed three and two rats
of the same sex.
The study was carried out in the experimental animal house of the
Test Site with the pressure air-condition system. The animals were
housed in one room under the defined laboratory conditions. The
temperature and relative humidity in the animal room were recorded
daily (dataloger No.: TH 464); mean values of temperature were
23.1±0.6°C at mean relative humidity 54.0±4.6% (mean±SD). The
artificial lighting was setting in a 12-hour light and 12-hour dark
photoperiod.
The sanitation was performed according to standard operation
procedures.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Dose volume was 5.0 mL/kg of body weight and was adjusted according to the weight development of the animals.
Once per day.
Females were treated during:
• 14-day pre-mating,
• 14-day mating (maximum)
• 22-day gestation (approximately)
• 13-day lactation
Females with no evidence of copulation and that failed to deliver
were dosed for a total of 51 doses (from 27.8.2018 to 17.10.2018).
Males were treated during:
• 14-day pre-mating,
• 14-day mating (maximum)
The animals designated for post-treatment observation (5
animals per sex in control and high dose groups, respectively)
were remain untreated for subsequent 14 days.
The animals in all dose groups were treated during declared
periods excluding 4.9.2018 because of change of test doses. The
control animals received doses of vehicle without interruption on
this day, it means 1 day more as it is stated for dose groups. - Vehicle:
- olive oil
- Details on oral exposure:
- Thirteen females were used per group for pre-treatment estrous
cycle examination, treatment and mating. Ten males per group were
treated and paired with females in ratio 1:1 (one male:one female).
In summary, 40 males and 52 females were treated within the
reproductive part of study. Five males and five females per group
were orally exposed to test item in the two satellite groups (Control
and High dose group). Totally, 50 male rats and 62 female rats were
used in the study. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The tested item was administered orally by gavage in a single dose daily. Test item Ethyl lactate was available as a suspension in olive oil. The dose volume was 0.5 ml/100 g body weight of rat.
The dose of thetest substance was given at similar times each day.
• Animals of Group 1 received 100 mg/kg b.w.
• Animals of Group 2 received 200 mg/kgb.w.
• Animals of Group 3 received 500 mg/kg b.w.
• Animals of Group 4 received 800 mg/ kg b.w.
• Animals of Group 4 received 1200 mg/ kg b.w. - Duration of treatment / exposure:
- The animals were dosed daily for 7 days a week.
- Frequency of treatment:
- daily
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- One day before the treatment, all animals were randomized. Within the frame of treatment groups, each rat was marked by code on the tail root to identify animal individually. Each cage was provided with a cage card.
Rats were inspected twice daily for evidence of reaction to treatment or ill-health. The observation focused on changes in skin, fur, eyes and mucous membranes, occurrence of secretions and excretions and autonomic activity as lacrimation, piloerection, pupil size, and unusual respiratory pattern. Moreover, possible changes in gait, posture and response to handling as well as the presence of clonic or tonic movements or bizarre behaviour (self-mutilation, walking backwards) were observed.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Rats were inspected twice daily for sings of toxicity. No deviations from normal findings in terms of: clinical signs, sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli), changes in skin, fur, eyes and mucous membranes, occurrence of secretions and excretions and autonomic activity as lacrimation, piloerection, pupil size, and unusual respiratory pattern were observed. No changes in gait, posture and response to handling as well as the presence of clonic or tonic movements or bizarre behaviour (self-mutilation, walking backwards) were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- Three mortality cases were recorded during the study. Animals No 15 (♂) and No 29 (♀) died one week after administration of the test substance. Animal No 8 (♂) died in second week of administration of test substance. All three animals died probably during the night hours, because cadavers were in state of autolysis.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- During the study, body weight of animals increased in time in all group of rats. The test substance was an unpleasant taste and smell for the animals which resulted in lack of appetite of animals. Body weight of male rats in groups G4 800mg/kg and G5 1200mg/kg was little lower.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- At the end of the study, the animals were subjected to gross necropsy. During gross pathology examination, organs were examined macroscopically and any abnormal tissue were collected and stored for possible future analysis. Tissues were added into fixative solution (10 % buffered formalin).
During the necropsy there were observed diffuse discolorations (red) on thymus in male rats No (♂5), (♂6) from Group 2 –200mg/ kg, (♂7), (♂9) from Group 3 – 500mg/kg and No (♂11) from Group 4 – 800mg/kg.
These findings are not considered to be caused by the test substance.
No macroscopic findings were observed during the necropsy in female rats.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 600 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Clinical observations throughout the first two weeks of test item application indicated presence of
signs of systemic toxicity in the high dose group of female rats (800 mg/kg b.w.). There were three
test item-related deaths of animals (High dose) during the study. Parental female mortality at this
dose overreached 10%.
After reduction of test item doses tested, since Day 10 of exposure, no test item-related mortality,
no significant behavioural changes (except the female rat No.: 81), no clinical signs or any deviation
from normal findings were recorded during the study neither in adult exposed animals nor in
offspring.
No statistically significant differences in body weight amongst the treated groups of adult male and
female rats including the animals in the both satellite groups were observed.
Unlike adult animals, the test item induced alteration of physical development being demonstrated
as increase of pup body weight on Day 13 of lactation exposure, in significant extent in High dose
group male pups.
Food consumption was not significantly different amongst the experimental groups. Influence of
treatment associated stress and/or decreased appetite was observed at the start of treatment and
increased physiological demands in pregnant and lactating female rats was evident. The decrease in
food consumption in the adult male rats exposed to high dose of test item observed on a week 3 was
not statistically significant and not accompanied with statistically significant changes in the body
weight; it is not considered to be of toxicological relevance.
Within the scope of all observed reproductive parameters (except of body weight), anogenital
distance/anogenital index (AGD/AGI) were only parameters that showed significant differences
amongst experimental groups in male as well as in female pups. Dose dependent statistically
significant reduction of AGI in male offspring (from the Low- and Mid dose group) and in female
offspring (from the Low dose, the Mid dose at the limit of significance and the High dose group)
unexplainable by significant change of animal size at birth was observed.
Records of pre-implantation and early post-implantation loss might suggest potential effect of Low-
and Medium-dose of the test item during a very short critical developmental window.
Changes of number live pups per dam on postnatal day 0 and 4 and changes in litter weight at birth
described in Mid dose offspring and analysed as statistically nonsignificant should not be omitted
due to high differences in litter characteristics.
Nonsignificant post-natal loss (higher incidence of records of clinical observations, cases of
morbidity and mortality) described in the Mid dose group could point out on potential to induce
non-monotonous dose response effects by the action of the test item.
The clinical chemistry parameters measured in serum of male and female rats showed some
statistically significant differences. These differences were minimal in nature and had no biological
or toxicological significance.
No significant differences in haematological parameters among groups exposed to the test item and
controls were found in all evaluated parameter with exception of PT and APTT values. The
differences were minor had no biological or toxicological significance.
The observed significant changes in T4 levels in the male and female offspring rats (significant
decrease) not accompanied with significant alterations in changes in the mean relative weight of
thyroids (after fixation) as well as with the histological examinations revealed no serious
morphological alterations were considered to be findings without biological/toxicological
significance.
In the urine no significant changes against normal physiological conditions were detected.
Functional battery observation tests (tail flick test and grip strength test) conducted at the end of the
dosing period and at the end of recovery period revealed no abnormalities.
During the gross necropsy, there were found some abnormal tissues in the treated male and female
rats. Described macroscopic findings (being sporadic incidence and without test item dose
dependence) were supplemented/elucidated with histopathological evaluations and considered not
to be test item related alterations in the sense of the prevalence, severity and character.
Significant changes of relative organ weights, being sensitive indicator of the adverse effect of the
test item, were observed in the Cowper´s glands, kidneys (males), spleen (males) and Levartor ani
& bulbocavernosus muscles. Yet, the histological examinations revealed no serious morphological
alterations and mentioned statistically significant differences (when compared to the control
animals) were considered to be without biological significance.
Histopathological lesions found in the treated animals were either of spontaneous character or not
in direct relation with the test item administered. Macroscopically described lesions in the stomach
or jejunum as change of colour (diffuse or focal), were histologically detected as hyperaemia of
capillaries in the mucosa and submucosa. Sporadic findings as defect in renal pelvis histologically
evaluated as dilatation of the renal pelvis, mucification found in the cervix uteri, dilatation of acinus
in prostate, gold brown pigment particles in ovary, cystic dilatation in the vagina wall and uterus
lumen dilatation were classified as lesions not related with application of test item.
Applicant's summary and conclusion
- Conclusions:
- After consideration of the study results following conclusions were made regarding the test item.
• The High dose of Ethyl lactate 800 mg/kg b.w. induced systemic parental toxicity which
overreached 10% mortality, therefore test doses were reduced since 10th day of application.
• Test item did not induce significant clinical findings or behavioural deviations in the
experimental animals exposed to doses of Low dose - 75 mg/kg b.w., Mid dose -300 mg/kg
b.w. and High dose - 600 mg/kg b.w. No test item-related mortality in significant extent
was recorded during the study. No moribund animals were isolated due to exposure to three
abovementioned doses of test item.
• No statistically significant differences in body weight amongst the treated groups of adult
male and female rats were revealed. The animals grew over time in all experimental groups,
no significant reduction or stagnation of body weight was recorded.
• The test item caused statistically significant increase of body weight in offspring males at
the high dose (600 mg/kg) at Day 13 post-partum.
• Test item did not affect the food consumption. Food consumption was not significantly
different amongst the experimental groups.
• The clinical chemistry parameters measured in serum of male and female rats showed some
statistically significant differences. These differences were minimal in nature and had no
biological or toxicological significance.
• No significant differences in haematological parameters among groups exposed to the test
item and controls were found in all evaluated parameters with exception of PT and APTT
values. The differences were minor, had no biological or toxicological significance.
• In the urine no significant changes against normal physiological conditions were detected.
• The observed significant reduction in T4 levels in the male and female offspring not
accompanied with significant alterations in the mean relative weight of thyroids (after
fixation) as well as with no serious morphological alterations were considered to be findings
without biological/toxicological significance.
• Functional battery observation tests (tail flick test and grip strength test) conducted at the
end of the dosing period and at the end of recovery period revealed no abnormalities.
• Macroscopic findings described during the gross necropsy, were observed in the all treated
groups but incidence was sporadic without clear dose dependency. From microscopic point
of view no significant item related alterations in the sense of the prevalence, severity and
character were described.
• Test item did not cause histopathological changes on examined reproduction organs
Significant changes of mean relative organ weights in male rats, being sensitive indicator of
the adverse effect of the test substance, were observed in Cowper`s glands, musculus
bulbocavernosus, kidneys and spleen. The histological examinations revealed no serious
morphological alterations and statistically significant differences (when compared to the
control animals) were considered to be findings without biological significance.
• Dose-dependent statistically significant reduction of AGI with adverse potential in male
pups (feminization in Low and Mid dose group male pups) and probably realized via non-
traditional mechanisms resulting in inverted-U-shape dose-response curve (because of
mechanism deletion in High dose group) might be regarded as specific developmental effect
of prenatal exposure to test item and should be considered for setting of NOAEL.
• Records of pre-implantation and early post-implantation loss might suggest potential effect
of Low- and Medium-dose of the test item during a very short critical developmental
window.
• Changes of number live pups per dam on postnatal day 0 and 4 and changes in litter weight
at birth described in Mid dose offspring and analysed as statistically nonsignificant should
not be omitted due to high differences in litter characteristics
• Nonsignificant post-natal loss (higher incidence of records of clinical observations, cases of
morbidity and mortality) described in the Mid dose group could point out on potential to
induce non-monotonous dose response effects by the action of the test item.
Based on these results,
- the no-observed-adverse-effect-level (NOAEL) was 600 mg/kg/day for parental systemic
toxicity.
- the NOAEL for reproductive toxicity was considered to be less than 75 mg/kg/day.
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