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Diss Factsheets

Administrative data

Description of key information

Two sub-acute inhalation toxicity studies with ethyl (S)-lactate revealed clear respiratory local effects, described as histopathological changes in the olfactory and respiratory epitheliums. No clear systemic toxic effects were detected.

There are no reliable studies available for the assessment of the sub-chronic repeated dose toxicity with the target substance ethyl (S)-lactate. Therefore, available data from an oral sub-chronic repeated dose toxicity study conducted with a suitable read-across partner, calcium lactate, was used to assess the specific target organ toxicity of the target substance. High levels of exposure to calcium lactate in the diet (up to 30% in feed) did not lead to any lactate-associated effects after sub-chronic exposure. In addition, in an sub-chronic repeated dose toxicity, ethanol was administered to Fischer 344 rats/sex/dose via oral feed ad libitum at dose levels of 0, 1, 2, 3, 4, 5 and 10% for 13 weeks. Based on the results, the NOAEL can be considered to be 2%, which is calculated to be equivalent to 2400 mg/kg bw/day, This dose is much higher as the limit dose of 1000 mg/kg bw/day mentioned in the OECD TG 408. In summary, no classification for specific target organ toxicity is warranted for the target substance.

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Details on results:
All observed effects could be attributed to calcium overload/imbalance. No lactate toxicity was observed.
Dose descriptor:
NOAEL
Effect level:
50 000 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
no
Conclusions:
In conclusion, 5% calcium lactate in drinking water or diet does not result in adverse effects attributable to lactate.
Executive summary:

In a subchronic toxicity study (similar to OECD 408), Calcium lactate was administered to Fischer 344/DuCrj rats. In Experiment I, Calcium lactate was mixed at 5, 2.5, 1.25, 0.6, and 0.3 % in the drinking water and the rats were given this solution ad libitum for 13 weeks. As a result, the inhibition of body weight gain in the 5% group fell within 10% of that in the control group. Some examination values showed variations in the hematological and hematobiochemical studies, but no controversial findings were obtained in the pathohistological search. Since the highest solubility of Calcium lactate is 5%, experiments II and III were carried out by giving blended diet in order to study the toxicity at higher doses. In experiment II, Calcium lactate was mixed at concentrations of 30, 20, 10, and 5% in the B-blend powder diet and then the rats were given this diet ad libitum for 20 weeks. In experiment III, the rats were given the CRF-1 or the B-blend powder diet ad libitum for 8 weeks. As a result, in experiment II, nephrocalcinosis was observed in all the groups including the control group. The degree of the lesion was in reverse correlation with the administered concentrations of calcium and the lesion was seen more intensely in female rats. In experiment III, nephrocalcinosis resulting from the administration of the B-blend diet was already observed in the 4th week. Nephrocalcinosis as observed in experiments II and III was attributable to the small Ca/P value in the B-blend diet.

From the above results, the optimal dose for a long-term toxicity/carcinogenicity study has been determined to be 5 and 2.5% based on the values obtained from experiment I.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Frequency of treatment:
daily
Clinical signs:
no effects observed
Description (incidence and severity):
No adverse signs were detected.
Mortality:
no mortality observed
Description (incidence):
No mortality was observed in any dose group.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
All groups gained weight though final weights decreased with dose
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Consumption in the 10% group was reduced relative to controls (182 ml diet/kg-d versus 195 ml diet/kg-d).
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:
no effects observed
Description (incidence and severity):
Serum liver enzymes were not affected by treatment and kidney findings were minimal.
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
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Liver yellowing was observed in some of the 3 and 4% dose animals and most of the 5% dose animals. It was considered to be dosage-related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hepatic centrilobular steatosis increased in severity with dose as did the frequency and severity of Mallory bodies (hyaline) and acidophilic degeneration and necrosis. Most liver findings were absent or mild at 2% w/w ethanol but became more significant at 3% and higher dose. Reticulo-endothelial cell proliferation was slight at 1 and 2%. A few kidney casts were noted in animals from the 1-3% dose groups and there were a few calcifications in the 3-5% groups. Slight tubular fatty change occurred in all groups.
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
2 other: % w/w ethanol in liquid diet
Sex:
male/female
Basis for effect level:
other: no adverse signs of toxicity observed
Critical effects observed:
no
Conclusions:
In conclusion, in a sub-chronic repeated-dose toxicity study, ethanol was administered to rats for 13 weeks via the liquid diet. Based on the results, the NOAEL was established to be 2% (approximately 2400 mg/kg bw/day) for ethanol in oral feed ad libitum in rat. The LOAEL in this study was 3% (approximately 3600 mg/kg bw/day) due to dose related hepatic yellowing and centrilobular steatosis.


Executive summary:

In a repeated dose toxicity study, ethanol was administered to 10 Fischer 344 rats/sex/dose via oral feed ad libitum at dose levels of 0, 1, 2, 3, 4, 5 and 10% for 13 weeks.

No substance-related changes between the treatment groups and controls were found in mortality, clinical signs of toxicity, body weights or clinical chemistry. Histopathplogical findings were a Hepatic centrilobular steatosis, which increased in severity with dose as did the frequency and severity of Mallory bodies (hyaline) and acidophilic degeneration and necrosis. Most liver findings were absent or mild at 2% ethanol but became more significant at 3% and higher dose.

Based on the results and in accordance with the OECD SIDS, 2004 the NOAELcan be considered to be 2%, which is calculated to be equivalent to 2400 mg/kg bw/day, This dose is much higher as the limit dose of 1000 mg/kg bw/day mentioned in the OECD TG 408.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1991-02-15 to 1991-04-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Version / remarks:
not specified
Deviations:
yes
Remarks:
not measured: food consumption, haematological and clinical chemistry, organ weight determinations, and microscopical examination of tissues and organs other than the nose.
Principles of method if other than guideline:
A sub-acute (28-day) inhalation toxicity study followed by a (28-day) recovery period was conducted in rats to provide data on recovery from, persistence of, or delayed occurrence of toxic effects on the nose. In a previous study (TNO report
no. V 90.322, see IUCLID section 7.5.2), ethyl lactate was irritating and toxic to the lining epithelium of the nasal cavity at levels of 150, 600 and 2500 mg/m³. Since it is necessary for the health risk evaluation of ethyl lactate to obtain a no-toxic effect level, an additional study had to be performed.
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
- Name of the test substance: etyhl-(S)(-)-lactate
- Trade name: Purasolv Elect
- Batch number no: EK 3003
- Appearance: clear liquid
- Expiry date: 31-01-1992
- Purity: 99.7%
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Wistar rats (Hsd/Cpb:WU) were obtained from Charles River Wiga, Sulzfeld, FRG
- Age at study initiation: 5-6 weeks old at arrival in the Institute; 6-7 weeks old at the start of the treatment
- Weight at study initiation: 196.7 g (males) and 143.4 g (females)
- Fasting period before study: no, but during exposure both control and test animals had no access to food or water
- Housing: During the acclimatization period (days -7 until -1) and during the main part of the recovery period (days 31-56) the rats were housed in groups of five, separated by sex in suspended, stainless steel cages, fitted with wire mesh floor and front. During the exposure period the rats were housed individually in wire mesh stainless steel cages in a modified H 1000 multitiered inhalation chamber manufactured by Hazleton Systems Inc., USA.
- Diet (e.g. ad libitum): except during exposure, the rats were maintained on the Institute's cereal-based, powdered stock diet for rats, mice and hamsters.
- Water (e.g. ad libitum): except during exposure, community tap water was supplied in glass bottles which were cleaned once weekly
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): generally between 20-24 °C during exposure, and between 19 and 25 °C before and after exposure. Occasionelly, levels of up to 25.5 °C were reached.
- Humidity (%): The relative humidity generally fluctuated between 40-70%, and during several days in inhalation chamber C (75 mg/m³; values of up to 77%). In addition, due to wet cleaning activities the relative humidity exceeded the upper limit, the peaks eaching maxima up to 97% for about half an hour each time.
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12


Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: vapour
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Animals were exposed to the test atmosphere in modified H1000 multitiered inhalation chambers manufactured by Hazleton Systems Inc., USA. The chambers have a pyramidal top and bottom. The chambers have been constructed of stainless steel with glass doors on two sides which allow observation of the animals during exposure.
- Method of holding animals in test chamber: The rats were housed individually in wire mesh stainless steel cages.
- System of generating particulates/aerosols: To generate the test atmospheres, metered amounts of ethyl lactate were transported by roller pumps (Watson-Marlow 502S/R) to pressurized air driven nebulizers (Lee dispenser, type 110 K, Lee Co., USA). The generated mixture of air and test material was diluted with filtered air till the required concentration was achieved. To allow all particles to mix with air and to evaporate, the animals were located in the cage unit at the right bottom level of each inhalation chamber. Animals in the control group were exposed to freshly filtered air under similar conditions as the test groups.
- Temperature, humidity, pressure in air chamber: The temperature fluctuated between 20-24°C during exposure. The relative humidity generally fluctuated between 40-70%, but during several days in inhalation chamber C (75 mg/m³) values up to 77% were reached. In addition, due to wet cleaning activities the relative humidity exceeded the upper limit, the peeks reaching maxima up to 97% for about half an hour each time. Each chamber was fitted with a micromanometer which showed the negative pressure inside (1-4 mm water column).
- Air flow rate: Airflow was monitored by means of an anemometer (Thermo-Air type 442) and was recorded three times each exposure day. Total airflow through the chambers varied between 38 and 40 m³/hour.
- Air change rate: between 17 and 18 air changes per hour during exposure, otherwise 10 air changes per hour.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of the test material was determined by means of a total carbon analyser (Ratfisch RS 55, FRG). Test atmosphere samples were taken sequentially from each of the chambers at a location close to the cage unit in which the animals were housed. The samples were drawn through sampling lines and were passed via a controlled valves system (Kuax-Control, Kuhnke 61.000) to the total carbon analyser. The response of the total carbon analyser was recorded in scale units and converted into concentration values (mg/m³). To ensure that no test material would condensate during sampling transport the sampling lines and the valves system were heated. Each chamber was monitored approximately once each half an hour for about 7 minutes, resulting in about 12 measurements per concentration level per day.
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of the test material was determined by means of a total carbon analyser (Ratfisch RS 55, FRG). Before the start of the study the response of the flame ionization detector (FID) was calibrated by passing flows of 25, 75, and 200 mg/m³ over the FID. The calibration mixtures corresponding to these flows, were prepared by injecting known quantities of test material (0.7, 2.2, or 5.8 µL) in 40-L teflon bags, which were filled with 30 L of air. After evaporation of the test material and careful mixing with the air, samples were passed to the total carbon analyser. The response of the FID (in scale units) was recorded. The calibration procedure was repeated towards the end of the exposure period. Similar data were obtained. The nominal concentration was determined by dividing the total daily amount of test substance used per treatment group by the total volume of air passed through each exposure unit.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours a day, 5 days a week
Dose / conc.:
0 mg/m³ air (nominal)
Remarks:
Control
Dose / conc.:
25 mg/m³ air (nominal)
Remarks:
Low concentration;
Mean daily concentration (analytical): 24 (+/- 1) mg/m³
Dose / conc.:
75 mg/m³ air (nominal)
Remarks:
Mid concentration;
Mean daily concentration (analytical): 73 (+/- 5) mg/m³
Dose / conc.:
200 mg/m³ air (nominal)
Remarks:
High concentration;
Mean daily concentration (analytical): 202 (+/- 3) mg/m³
No. of animals per sex per dose:
5, for the control and 200 mg/m³ exposure group 5 additional rats/sex were exposed (recovory group).
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: In a previous study, ethyl lactate was irritating and toxic to the lining epithelium of the nasal cavity at levels of 150, 600 and 2500 mg/m³. Clinical observations, growth, gross examination at autopsy and microscopical examination of the nose were used as criteria for disclosing possible harmful effects at lower concentrations of 25, 75 and 200 mg/m³.
- Rationale for animal assignment (if not random): One day before the start of the study, the rats were divided over the various groups in such a way that the mean initial body weight was about the same in all groups (< ± 20% of the mean weight). A few rats were replaced by reserve animals in order to equalize the mean initial body weight. Computer randomization according to body weight was not possible because the number of animals in each group was not the same (groups B and C comprised of less animals than groups A and B). Computer randomization was, however, performed upon arrival.
- Rationale for selecting satellite groups: To provide data on recovery from, persistence of, or delayed occurrence of toxic effects on the nose.
- Post-exposure recovery period in satellite groups: Following the exposure period, rats of the recovery groups (Control and 200 mg/m³) were kept for a 28-day period without treatment.
- Section schedule rationale (if not random): On nominal day 28, all rats of the main groups, and on day 56, all rats of the recovery groups, were killed in such a sequence that the average time of killing was about the same for each group.
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The general condition and behaviour of all animals were checked at least once daily throughout the study. All signs of ill health, reaction to treatment or mortality were recorded.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each rat was individually handled and carefully examined for clinical signs, abnormal behaviour or abnormal appearance at the weekly weighing.

BODY WEIGHT: Yes
- Time schedule for examinations: The individual body weights of all rats were recorded during the acclimatization period (day -4), one day before the start of the exposure (allocation procedure), just prior to the first exposure to the test substance (day 0), and subsequent at weekly intervals (including the day of autopsy).

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
On nominal day 28, all rats of the main groups, and on nominal day 56, all rats of the recovery groups, were killed in such a sequence that the average time of killing was about the same for each group. The animals were anaesthetized by ether, bied to death by cannulating the abdominal aorta and then examined macroscopically for pathological changes.

GROSS PATHOLOGY: Yes, the animals were examined macroscopically for pathological changes.

HISTOPATHOLOGY: Yes, the nose of all animals was preserved in a neutral, aqueous, phosphate-buffered, 4% solution of formaldehyde, decalcified, embedded in paraffin wax, sectioned at 5 µm and stained with haematoxylin and eosin. Histopathological examination was performed on 4 sections of the nose of each animal.
Statistics:
Body weight data of the main groups were analysed by one-way analysis of covariance using preexposure (day 0) weights as the covariate. When group means were significantly different (p< 0.05) individual pairwise comparisons were made using Dunnett's multiple comparison method. Body weight data of the recovery groups were analysed by Student t-test. Incidence of histopathological changes were analysed by Fisher's exact probability test. All pairwise comparisons were two tailed. Group mean differences with an associated probability of less than 0.05 were considered to be statistically significant.
Clinical signs:
no effects observed
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):
not examined
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:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
see box "Details on results"
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
see box "Details on results"
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
CLINICAL SIGNS AND SURVIVAL
No clinical symptoms or signs of systemic toxicity were observed during the study. All study animals survived to the scheduled sacrifice.

BODY WEIGHTS
There were no statistically significant differences in mean body weights between the test groups and the controls.

GROSS PATHOLOGY
Gross examination of animals of the main groups at autopsy revealed a slightly oedematous and red discoloured thymus in one male of the control
group and in one male of the mid-concentration group. The kidneys of one male of the control group were slightly enlarged and soft. These gross changes are common findings in rats and they are not considered to have any toxicological relevance. One female rat of the mid-concentration group showed a subcutaneous haemorrhage between the eyes, which was most probably caused
by trauma and was not regarded to have any clinical significance. Gross examination of rats of the recovery groups did not reveal any abnormalities.

HISTOPATHOLOGY: NON-NEOPLASTIC
In a few rats of either sex of both the main and the recovery groups (controls included), the respiratory epithelium of the nasal cavity showed minimal changes, seen as nest-like infolds and slight hypertrophy/hyperplasia. The changes were about equally distributed amongst the various groups or occurred in a single animal only. Therefore, the changes were not ascribed to inhalation of ethyl lactate.
Key result
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remarks'
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse systemic effects observed at the high concentration of 200 mg/m³
Critical effects observed:
not specified

Analytical results:

The mean daily concentrations of ethyl lactate in the test atmospheres during exposure were 24 (+/- 1) mg/m³, 73 (+/- 5) mg/m³ and 202 (+/- 3) mg/m³. The actual concentrations were generally close to the intended concentrations.

Conclusions:
In a sub-acute inhalation toxicity study in rats, Ethyl (S)-lactate showed no effects adverse effects. There were no compound related effects in mortality, clinical signs, body weight or gross and histological pathology. Microscopic examination revealed minimal changes (nest-like infolds, slight hypertrophy, and slight hyperplasia) in the nasal respiratory epithelium of animals in all groups, the control group included. Type and incidence of the changes were similar in the various groups, or the changes occurred in a single animal only. These changes were not ascribed to treatment. Based on the results, the NOEC is considered to be 200 mg/m³.
Executive summary:

In a sub-acute inhalation toxicity study, Ethyl (S)-lactate was administered to 5 male and 5 female Wistar rats/concentration by whole body exposure at concentrations of 0, 0.025, 0.075 and 0.2 mg/L (0, 25, 75 and 200 mg/m³) for 6 hours per day, 5 days/week for a total of 28 days. Two additional (recovery) groups of 5 male and 5 female Wistar rats exposed to 0 or 0.2 mg/ were kept untreated for 28 post-exposure days. Clinical observations, growth, macroscopical observations at autopsy and microscopical examinations of the nose were used as criteria for disclosing possible harmful effects. There were no compound related effects in mortality, clinical signs, body weight or gross and histological pathology. Microscopic examination revealed minimal changes (nest-like infolds, slight hypertrophy, and slight hyperplasia) in the nasal respiratory epithelium of animals in all groups, the control group included. Type and incidence of the changes were similar in the various groups, or the changes occurred in a single animal only. These changes were not ascribed to treatment. Based on the results, the NOAEC is considered to be 200 mg/m³.

In contrast to a previously conducted study (TNO report V 90.322, 1995), in which rats were exposed to 150, 600 or 2500 mg ethyl lactate per m³ for 28 days, the results of the present study show that rats exposed to 25, 75 or 200 mg ethyl lactate per m³ for the same period did not develop compound-related histopathological changes in the nose. The histopathological changes observed at an exposure concentration of 150 mg/m³ (TNO report V 90.322), viz. replacement of olfactory epithelium by respiratory epithelium, goblet cell hypertrophy and moderate goblet cell hyperplasia, were considered to be in line with the changes observed at concentration-response relationship including the response seen at the 150 mg/m³ exposure concentration. The minimal changes observed in the present study consisting of nest-like infolds and slight hypertrophy and hyperplasia are fully comparable to the minimal changes observed at the 150 mg/m³ level of the previous study. However, since in the present study these minimal changes were observed in all groups, controls included, and their incidences in treatment groups were not different from those in the control group, or the changes occurred in a single animal only, these minimal alterations were not ascribed to treatment. Therefore, it is concluded that the no-adverse-effect concentration, as regards to local effects, in the present study is 200 mg/m³, indicating that the level of 150 mg/m³ used in the previous study (TNO report V 90.322, 1995), should be considered a no-adverse-effect concentration as well.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
150 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP guideline study

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Vehicle:
other: cosmetic cream
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test animals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic examination. The investigators concluded this formulation is "safe in terms of cumulative toxicity" and that "based upon the exaggerated dose level used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use."
Dose descriptor:
LOAEL
Effect level:
886 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
haematology
organ weights and organ / body weight ratios
Critical effects observed:
no

No significant gross observations, with the exception of minimal skin irritation. Absolute brain weight and kidney-to-body weight ratios were increased for test animals.No lesions were observed at necropsy or at microscopic examination.

Conclusions:
Formulation (face cream containing 0.25% lactic acid) is safe in terms of cumulative toxicity. Based upon the exaggerated dose levels used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use.
Executive summary:

A sub-chronic dermal toxicity study with a face cream containing 0.25% lactic acid (equals 886 mg/kg bw/day) was conducted on female rats. All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test ammals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic exammation. The investigators concluded this formulation is "safe in terms of cumulative toxicity" and that "based upon the exaggerated dose level used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use."

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a sub-acute inhalation toxicity study ethyl (S)-lactate was administered to 5 male and 5 female Wistar rats/concentration by whole body exposure at concentrations of 0, 0.025, 0.075 and 0.2 mg/L (0, 25, 75 and 200 mg/m³) for 6 hours per day, 5 days/week for a total of 28 days. Two additional (recovery) groups of 5 male and 5 female Wistar rats exposed to 0 or 0.2 mg/L were kept untreated for 28 post-exposure days. Clinical observations, growth, macroscopical observations at autopsy and microscopical examinations of the nose were used as criteria for disclosing possible harmful effects.

There were no compound related effects in mortality, clinical signs, body weight or gross and histological pathology. Microscopic examination revealed minimal changes (nest-like infolds, slight hypertrophy, and slight hyperplasia) in the nasal respiratory epithelium of animals in all groups, the control group included. Type and incidence of the changes were similar in the various groups, or the changes occurred in a single animal only. These changes were not ascribed to treatment. The NOAEL was considered to be 200 mg/m³.

In contrast to a previous study (TNO report V 90.322), in which rats were exposed to 150, 600 or 2500 mg ethyl (S)-lactate per m³ for 28 days, the results of the last study show that rats exposed to 25, 75 or 200 mg ethyl lactate per m³ for the same period did not develop compound-related histopathological changes in the nose. The minimal changes observed in the present study consisting of nest-like infolds and slight hypertrophy and hyperplasia are fully comparable to the minimal changes observed at the 150 mg/m³ level of the previous study. However, since in the present study these minimal changes were observed in all groups, controls included, and their incidences in treatment groups were not different from those in the control group, or the changes occurred in a single animal only, these minimal alterations were not ascribed to treatment. Therefore, it is concluded that the no-adverse-effect level of ethyl lactate in the present study is 200 mg/m³, indicating that the level of 150 mg/m³ used in the previous study (TNO report V 90.322), should be considered a no-adverse-effect level as well.

The exposure to ethyl (S)-lactate at levels up to 2500 mg/m³ resulted in concentration-related adverse effects in the nose of all test groups and in growth retardation and decreased food consumption in rats exposed to 2500 mg ethyl lactate/m³ air. Growth retardation might be explained by the impaired ability to smell and taste as a result of severe damage to the olfactory epithelium. The increased blood glucose value in males exposed to 2500 mg/m³ is considered an isolated finding unrelated to treatment. Further all observed effects can be explained from the reduced food intake and subsequent growth retardation.

There are no reliable studies available for the assessment of the sub-chronic repeated dose toxicity with the target substance ethyl (S)-lactate. Therefore, available data from an oral sub-chronic repeated dose toxicity study conducted with a suitable read-across partner, calcium lactate, was used to assess the specific target organ toxicity of the target substance. High levels of exposure to calcium lactate in the diet (up to 30% in feed) did not lead to any lactate-associated effects after sub-chronic exposure. In addition, in a sub-chronic repeated dose toxicity, ethanol was administered to Fischer 344 rats/sex/dose via oral feed ad libitum at dose levels of 0, 1, 2, 3, 4, 5 and 10% for 13 weeks. Based on the results, the NOAEL can be considered to be 2%, which is calculated to be equivalent to 2400 mg/kg bw/day. This dose is much higher as the limit dose of 1000 mg/kg bw/day mentioned in the OECD TG 408. In summary, no classification for specific target organ toxicity is warranted for the target substance. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

 

Altogether, given the existing data and taking a weight-of-evidence approach, there is no systemic toxicity concern of ethyl (S)-lactate and no classification is warranted.

Justification for classification or non-classification

Based on the available data, the target substance ethyl (S)-lactate does not warrant classification for specific target organ toxicity in accordance with CLP Regulation 1272/2008.