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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988 to 1989-09-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Version / remarks:
1985
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Ethyl lactate
EC Number:
202-598-0
EC Name:
Ethyl lactate
Cas Number:
97-64-3
IUPAC Name:
ethyl 2-hydroxypropanoate
Specific details on test material used for the study:
- Name of the test material used in the report: Ethyl lactate

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test substance Ethyl lactate was supplied by the sponsor and applied "neat". All doage calculations were based on 100% purity and activity.

Test animals

Species:
rat
Strain:
other: Crl:CD®(SD)BR
Details on test animals or test system and environmental conditions:
not further specified

Administration / exposure

Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 7 x 5 cm
- Type of wrap if used: an aluminium foil patch (covering at least the shaved dorsal area of dosage application) that will be held in place by a medical-type adhesive bandage (e.g. Poroplast®).
- Time intervals for shavings or clipplings: Shaving will be repeated as necessary throughout the dosage period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After completion of the approximately six-hour exposure period/day the bandage and dressing were removed and the application site was wiped with clean water.
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): sham, 517, 1551 and 3619 mg/kg bw/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: Each rat was fitted with an Elizabethan collar.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
There were 25 presumed pregnant rats in each group.
Duration of treatment / exposure:
Between gestation day 6 and gestation day 15
Frequency of treatment:
Daily between gestation day 6 and 15
Duration of test:
On gestation day 20 all animals were sacrificed
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control group
Dose / conc.:
517 mg/kg bw/day (nominal)
Remarks:
Low dose group
Dose / conc.:
1 551 mg/kg bw/day (nominal)
Remarks:
Mid dose group
Dose / conc.:
3 619 mg/kg bw/day (nominal)
Remarks:
High dose group
No. of animals per sex per dose:
25 presumed pregnant female rats/group
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: The high dosage was selected because it was the maximum volume of Ethyl lactate that could be applied to a surface area of approximately 35 cm² on each rat's back.

Examinations

Maternal examinations:
Day 0 of presumed gestation was defined as the day spermatozoa were identified in a smear of the vaginal contents or a copulatory plug was found in situ. Each rat was observed daily during the dosage and postdosage periods for evidence of skin reactions and other clinical signs of test substance effects, including: death, abortion, premature delivery, body weight and feed consumption.
All dams were sacrificed and necropsied on day 20 of presumed gestation. Maternal tissues with gross lesions present were retained in neutral bufferd 10% formalin. The liver of each dam was weighed.
Ovaries and uterine content:
The uterine contents were examined for implantations, early and late resoprtions, and live and dead fetuses. Corpora lutea were counted for each ovary.
Blood sampling:
Not determined
Fetal examinations:
Fetuses were evaluated for viability, body weight, sex and gross external morphology. Approximately one-half of the fetuses in each litter were fixed in Bouin's solution prior to visceral evaluation (Wilson's sectioning). The remaining fetuses in each litter wer eviscerated, fixed in alcohol and processed for skeletal evlutation (alizarin red S staining).
Statistics:
A statistical analysis was conducted (averages, standard deviations and significance)
Indices:
Number of corpora lutea, implantation sites, early and late resorptions, number of live and dead foetuses, sex ratio,fetal body weights and percentage of dead or resorbed conceptuses.
Historical control data:
Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see box "Details on results"
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
see box "Details on results"
Mortality:
no mortality observed
Description (incidence):
see box "Details on results"
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see box "Details on results"
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
see box "Details on results"
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
see box "Details on results"
Gross pathological findings:
no effects observed
Description (incidence and severity):
see box "Details on results"
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
see box "Details on results"
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
see box "Details on results"
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
see box "Details on results"
Early or late resorptions:
no effects observed
Description (incidence and severity):
see box "Details on results"
Dead fetuses:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
see box "Details on results"
Other effects:
not examined
Details on maternal toxic effects:
No deaths occurred during this study. Of 25 animals assigned to each group, pregnancy occurred in 25, 24, 23 and 25 rats in the 0 (Sham), 517, 1551 and 3619 mg/kg bw/day dosage groups, respectively.
One low dosage group rat was inadvertently sacrificed on day 18 of gestation, reducing the number of low dosage group rats with day 20 of gestation litters from 24 to 23. The high dosage of Ethyl lactate resulted in a biologically important increase (not statistically significant) in the number of rats with slight (grade 1) erythema and slight (grade 1) desquamation, as compared with the sham control group number. These minimal signs of irritation or dehydration generally did not occur until the last one or two days of the dosage period and sometimes persisted until day 20 of gestation. Hyperactivity occurred on two days for one high dosage group rat; this clinical sign may have been interrelated with the minimal erythema and desquamation that also occurred for this rat.
No other skin reactions or clinical observations and no necropsy observations were considered effects of percutaneous administration of the test substance to the dams at dosages as high as 3619 mg/kg bw/day.
There were no dosage-dependent or statistically significant differences in average maternal body weight gains during the dosage period (calculated as days 6 to 16 of gestation). Similar average maternal body weight changes also occurred for the dams in the four dosage groups during the postdosage period.
Average maternal liver weights and liver weight/terminal body weight ratios (%) were unaffected by percutaneous administration of the test substance at dosages as high as 3619 mg/kg bw/day.
There were no biologically important or statistically significant differences in the absolute (g/day) or relative (g/kg/day) maternal feed consumption values during the dosage period (the entire dosage period is calculated as days 6 to 16 of gestation). Similarly, while slightly decreased for the high dosage group rats during the postdosage period (days 16 to 20 of gestation), there were no biologically important or statistically significant differences in absolute or relative maternal feed consumption average values for the four groups.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
1 551 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: see Remarks
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
3 619 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
see box "Details on results"
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in sex ratio:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in litter size and weights:
not examined
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Skeletal malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Visceral malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
No observation made at Caesarean-sectioning of the dams was attributed to the test substance. Average values for corpora lutea, implantations, litter sizes, live and dead fetuses, and early and late resorptions were comparable in the four dosage groups. Similarly, the averages for fetal sex ratios, body weights and percentage of dead or resorbed conceptuses per litter were biologically comparable among the four groups. There were no statistically significant differences.
Gross external, soft tissue and skeletal examinations of the fetuses did not reveal any malformations or variations that were considered effects of the test substance.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
3 619 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a developmental toxicity study, ethyl lactate was administered to 25 female Crl:CD®(SD)BR presumed pregnant rats /dose applied percutaneously at dose levels of 0, 517, 1551 and 3619 mg/kg bw/day from days 6 through 15 of gestation. Based on the results, the maternal NOAEL is 1551 mg/kg bw/day and the NOAEL for developmental toxicity is 3619 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted according to EPA OTS 798.4000, ethyl lactate was administered for six hours/day to 25 female Crl:CD®(SD)BR presumed pregnant rats/dose group percutaneously under occlusive conditions at levels of 0, 517, 1551 and 3619 mg/kg bw/day from day 6 through 15 of gestation. On day 20 of gestation the animals were sacrificed.

Dermal application of ethyl lactate to pregnant rats at the highest dose that could be given (3619 mg/kg bw/day) caused slight erythema and/or desquamation more frequently in comparison to the control group. Hyperactivity occurred on two days for one rat from the high dose group, which is probably related to the slight erythema and desquamation that also occurred for this rat. No other skin reactions or clinical observations and no adverse necropsy findings were observed in the animals. There were no treatment-related effects on mortality, body weight, food consumption and caesarean parameters. Gross external, soft tissue and skeletal examinations of fetuses did not reveal any malformations or variations that were considered adverse.

It is concluded that percutaneous application of ethyl lactate to pregnant rats was minimally toxic to the dams at the highest dosage that could be tested (3619 mg/kg bw/day), and that this maximum dosage did not result in developmental toxicity. Based on the results, the maternal NOAEL is considered to be 1551 mg/kg bw/day, and the developmental NOAEL is considered to be 3619 mg/kg bw/day.