Propanoic acid, 2-hydroxy-, propyl ester, (2S)-

Endpoint summary

Description of key information

In an acute oral and dermal toxicity study conducted according to OECD guideline 401 and 402, groups of Wistar rats (5/sex) were given Propyl (S)-lactate (99.5 % purity) as a single dose of 2000 mg/kg bw. No mortality occurred and an oral and dermal LD50 value of greater than 2000 mg/kg bw, both in male and female rats, was determined in these studies.

In acute inhalation toxicity studies conducted according to OECD guideline 403, groups of Wistar rats (5/sex) were exposed to the source substances Ethyl lactate, Ethylhexyl (S)-lactate and L(-) lactic acid for 4 hours. No mortality occurred in any study.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-06-16 to 1994-06-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted on February 24, 1987

Deviations:

yes

Remarks:

, a slight deviation on the humidity levels, which sometimes exceeded the upper limit of 70% given in the guideline

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): n-propyl lactate
- Analytical purity: 99.5%
- Lot/batch No.: 3
- Appearance: clear, colourless liquid
- Storage conditions: ambient

TREATMENT OF TEST MATERIAL PRIOR TO TESTING:
undiluted

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan/CPB, Austerlitz, The Netherlands
- Age at study initiation: 5-6 weeks
- Housing: 5 animals/cage (stainless steel cages, fitted with wire-screen floor and front)
- Diet: standard laboratory diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 45 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 59-92.5
- Air changes (per hr):10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no vehicle used

MAXIMUM DOSE VOLUME APPLIED: 2 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical symptoms were recorded once daily; body weights were measured on day 3, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: gross pathology, the abdomen and the thorax were examined

Statistics:

No data

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: The only clinical symptom observed was sluggishness 1 and 4 h post-treatment, in all rats.

Body weight:

other body weight observations

Remarks:

All animals gained weight during the 14-day observation period

Gross pathology:

No treatment-related gross alterations were observed.

Other findings:

No other findings were observed.

Interpretation of results:

other: CLP criteria not met

Conclusions:

Propyl (S)-lactate is not acutely toxic when administered to rats by gavage, at a single dose of 2000 mg/kg bw. The LD50 is greater than 2000 mg/kg bw for both sexes.

Executive summary:

In an acute oral toxicity study conducted according to OECD guideline 401, groups of Wistar rats (5/sex) were given propyl (S)-lactate (purity 99.5%) as a single oral dose of 2000 mg/kg bw. The animals were observed for 14 days after the single exposure. No mortalities and no further signs of toxicity occurred. Therefore, the oral LD50 is greater than 2000 mg/kg bw, both in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

GLP guideline study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

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

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.4 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

None of the rats died during or after exposure.

Clinical signs:

other: See remarks

Remarks:

During the entire exposure dreased breathing frequency. Wet noses were seen after 30 minutes of exposure and piloerection after 60 minutes. Half-closed eyes and lachrymation were all observed only at 15 minutes after the start of the study

Body weight:

Body weight gain was not visibly affected by the exposure. All animals gained weight in a normal way.

Gross pathology:

Gross-examination at autopsy revealed pale lungs in one male and three females. In three females the lungs showed a few petechiae.

The decrease in breathing frequency together with the wet nares and lachrymation are indicative of irritational properties of the test material.

Interpretation of results:

other: CLP criteria not met

Conclusions:

In an acute inhalation toxicity study in rats conducted according to OECD Test Guideline 403, no mortality occurred at the concentration of 5.4 mg/L air. Based on the results and in accordance with OECD Guideline 403, the LC50 was determined to be greater than 5.4 mg/L air in both male and female rats.

Executive summary:

In an acute inhalation toxicity study conducted according to OECD Guideline 403, groups of SPF-reared, Wistar derived rats (n= 5/sex) were exposed to a concentration of approximately 5.4 mg ethyl lactate/L for 4 hours and were observed afterwards for 15 days. All animals survived until the end of the study. A decreased breathing rate was observed during exposure. Wet noses were seen after 30 minutes of exposure and piloerection after 60 minutes. Half-closed eyes and lachrymation were all observed only at 15 minutes after the start of the exposure. These signs had all disappeared the next day. All animals appeared normal for the remainder of the 15 day observation period and gained weight in a normal way. At necropsy, gross-examination revealed pale lungs in one male and three females. In three females the lungs showed a few petechiae. The level of 5.4 mg/L was the maximum attainable concentration due to the physical properties of the test material. Based on these results, the LC50 of ethyl lactate is determined to be greater than 5.4 mg/L. Therefore, classification for acute inhalation toxicity according to CLP Regulation 1272/2008 is not warranted.

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 attached read-across report (see IUCLID section 13).

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting 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

Mass median aerodynamic diameter (MMAD):

µm

Duration of exposure:

min

Control animals:

no

Sex:

male

Dose descriptor:

other: RD50, rat

Effect level:

791 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

30 min

Sex:

male

Dose descriptor:

other: RD50, mouse

Effect level:

772 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

30 min

Mortality:

None of the animals died.

Clinical signs:

other: No abnormalities were observed before, during and after exposure. During the 7-day observation period, no abnormalities were observed except for alopecia in the neck region of one rat.

Body weight:

The day after exposure, slight body weight gain or slight body weight loss was observed in all animals, which was explained by stress induced by the exposure conditions. Seven days after exposure all rats had gained weight whereas most mice had gained weight too.

Gross pathology:

In both species there was no increace in relative lung weight with increasing concentration. Macroscopic changes at necropsy were limited to grey discoloured or irregular surfaced lungs, with grey stains and/or grey/black, white or red. somewhat swollen spots or specks. A concentration-response relationship was not observed.

Other findings:

Respiratory irritation:
The RD50 was calculated using the maximum decreases, in this case the mean of the tree last measurements during exposure (viz. at 23, 26 and 29 min). The regression line through the mean response of the four exposure groups at 23, 26 and 28 min was R = 1.5663 - 0.3693 logC, with a correlation coefficient of -0.9047. From this regression equation for mice a RD50 of 772 mg/m³ was calculated. In view of the monotonic, asymptotic decrease during almost the entire exposure period, the RD50 value was also calculated using the mean of the reactions through the exposure period, after the first 5 minutes. An RD50 value of 886 mg/m³ was obtained which was slightly higher (as could be expected) than that obtained using the three last measurments, showing the maximum responses. According to a method described by Bos et al. (1992), it was checked whether a concentration-response-relationship was present which could point at other (toxic) actions but sensory irritation. In this study in mice with ethyl lactate there was no concentration-response relationship. After exposure to the three lowest levels, relative breathing frequencies increased and almost reached pre-exposure values (up to 95%); the recovery ion relative breathing rate after the first exposure to 3000 mg/m³ reached a highest level of 70% only.
For rats, maximal responses were observed at about 7, 8 and 9 minutes after the start of the exposure; thereafter increases in breathing rate were noted. The RD50 value was therefore calculated using the mean of the trhee measurements at 7, 8 and 9 minutes. The regression line was: R = 1.8160 - 0.4541 logC (C in mg/m³) with a correlation coefficient of 0.8981. From this regression equation an RD50 value of 791 mg/m³ was estimated which turned out to be in good agreement with that observed in mice. The Bos method again did not show any concentration-response relationship. After exposure, relative breathing frequencies increased and reached highest values of up to 80-87%.

Interpretation of results:

study cannot be used for classification

Conclusions:

The RD50 values of Ethyl (S)-lactate were 772 mg/m³ in mice and 791 mg/m³ in rats. In the same study an RD50 of 760 mg/m³ in mice and 701 mg/m³ in rats was found for n-butyl-L-lactate. The similarity in the results supports the conclusion, that the effects on breathing rate can be attributed to irritating effects from the lactic acid formed at hydrolysis of the substances, which is a rapid process during and after uptake in the organism. The sensory irritating effect is thus a pH effect and not a toxic effect.

Executive summary:

The airway irritating properties of Ethyl (S)-lactate were studied by exposing four groups of male rats and mice for a single period of 30 minutes. All groups consisted of four animals. Concentrations of ethyl lactate were between 0.333 and 4.020 g/m³. Animals were necropsied seven days after exposure. No abnormalities were observed before, during and after exposure, and during the 7-day observation period, no treatment-related abnormalities were observed. None of the animals died. The day after exposure, slight body weight gain or slight body weight loss was observed in all animals. Seven days after exposure all rats had gained weight whereas most mice had gained weight too.

In both species after exposure there was no increase in relative lung weight with increasing concentration. Macroscopic changes at necropsy were limited to grey discoloured or irregular surfaced lungs, with grey stains and/or grey/black, white or red, somewhat swollen spots or specks. A concentration-response relationship was not observed.

From the results of the present study, it was concluded that RD50 values of Ethyl (S)-lactate were 772 mg/m³ in mice and 791 mg/m³ in rats. In the same study an RD50 of 760 mg/m³ in mice and 701 mg/m³ in rats were found for n-butyl-L-lactate. The similarity in the results supports the conclusion, that the effects on breathing rate can be attributed to irritating effects from the lactic acid formed at hydrolysis of the substances, which is a rapid process during and after uptake in the organism. The irritating effect on breathing is thus a pH effect and not a toxic effect.

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.

Reference 3

Endpoint:

acute toxicity: inhalation

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 read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7.94 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

1 female died.

Clinical signs:

other: Please refer to box "Any other information on results incl. tables".

Body weight:

At the beginning of the study, mean body weicihts for individual groups were within 20% of the overall mean for each sex. All groups of male rats gained weight within the first week after exposure in comparison to pre-exposure weights (3% for sham-exposed, 2< for L(+)-lactic acid,respectively). Female rats in the sham group gained weight during the first week after exposure (less than 1%). Female rats in the treated group lost weight during the first week after exposure (7%). After 14 days, all surviving animals had gained weight in comparison to pre-exposure weights (14% for males, 7% for females). No significant differences were observed in body weight between treated and control groups.

Gross pathology:

All surviving animals were necropsied at the termination of the study. The animal that died during the study was necropsied immediately. No gross lesions were observed at necropsy.

Clinical signs:

Rapid breathing and eye tearing were observed during exposure. At one and three hours after exposure, all animals (including the sham controls) had a hunched posture, ruffled and ungroomed fur, brown stained fur and red-stained fur surrounding the eyes (tearing). By 24 hours, female treated rats had ruffled and stained coats. All other animals appeared normal at 24 hours and for the remainder of the 14 day observation period. Several treated female rats continued to have ruffled fur up to 4 days after exposure.

Mass Median Diameter:

The Mass Median Diameters ranged from 2.03 to 2.14 microns and averaged 2.09.

Interpretation of results:

other: CLP criteria not met

Conclusions:

Based on these results, the LC50 of L(+)-lactic acid is greater than 7.94 mg/L.

Executive summary:

In an acute inhalation toxicity study according to OECD 403, groups of young adult F344 rats (5/sex/dose) were exposed by inhalation route to L(+)-lactic acid in a concentration of approximately 7.94 mg/L for 4 hours.

Rapid breathing and eye tearing were observed during exposure. At one and three hours after exposure, all animnals (including the sham controls) had a hunched posture, ruffled and ungroomed fur, brown stained fur and red-stained fur surrounding the eyes (tearing). After 24 hours, female treated rats had ruffled and stained coats. All other animals appeared normal at 24 hours and for the remainder of the 14 day observation period. Several treated female rats continued to have ruffled fur up to 4 days after exposure. One female rat from the treated group died on day 9. All other animals survived until the end of the study. At gross pathology no adverse lesions were observed.

Based on these results, the LC50 of L(+)-lactic acid is greater than 7.94 mg/L.

This acute inhalation study is classified as acceptable. It does satisfy the guideline requirement for an acute inhaltion study (OECD TG 403) in rats.

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.

Reference 4

Endpoint:

acute toxicity: inhalation

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

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.6 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Two females were found dead or sacrificed for ethical reasons on day 2 after exposure. No further mortality occurred (see Table 3 in attached background material).

Clinical signs:

other: No clinical signs were noted during exposure. Lethargy, hunched posture, rales and/or piloerection were shown by the surviving animals between days 1 and 4 after exposure. Rales were also noted among two animals at later time points during the observation

Body weight:

Reduced body weight gain and body weight loss was noted among the surviving animals during the first week post-exposure. All surviving animals regained weight during the second week (see Table 5 in attached background material).

Gross pathology:

No abnormalities were found at macroscopic post mortem examinantion of the surviving animals and the animal found dead. Macroscopic examination of the animal sacrificed for ethical reasons during the study revealed pale discolouration of the liver (see Table 6 in attached background material).
Incidental finding included pelvic dilation of the right kidney of one male. This finding is occasionally seen among rats ot this age and strain and was therefore considered not related to treatment.

Interpretation of results:

other: CLP criteria not met

Conclusions:

Based on these results, the LC50 of ethylhexyl (S)-lactate is greater than 5.6 mg/L.

Executive summary:

In an acute inhalation toxicity study conducted according to OECD TG 403 groups of young adult Wistar rats (5/sex) were exposed by inhalation route nose-only to ethylhexyl (S)-lactate (purity 99%) for 4 hours at a concentrations of approximately 5.6 mg/L (limit test). Animals then were observed for 14 days.

Two females were found dead or sacrificed for ethical reasons on day 2 after exposure. No further mortality occurred. No clinical signs were noted during exposure, excpet lethargy, hunched posture, rales and/or piloerection by the surviving animals between days 1 and 4 after exposure. Rales were also noted among two animals at later time points during the observation period. The two females found dead or sacrificed showed lethargy, ventro-lateral recumbency, hunched posture, slow breathing, laboured respiration and/or piloerections prior to death.

Reduced body weight gain and body weight loss was noted among the surviving animals during the first week post-exposure. All surviving animals regained weight during the second week. No abnormalities were found at macroscopic post mortem examination of the surviving animals and the animal found dead. Macroscopic examination of the animal sacrificed for ethical reasons during the study revealed pale discolouration of the liver.

Based on these results, the LC50 of ethylhexyl (S)-lactate is greater than 5.6 mg/L and in accordance with CLP Regulation 1272/2008 no classification for acute inhalation toxicity is warranted.

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 (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 400 mg/m³ air

Physical form:

inhalation: aerosol

Quality of whole database:

GLP guideline studies

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-06-16 to 2000-02-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 24th February 1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): n-propyl lactate
- Analytical purity: 99.5%
- Lot/batch No.: 3
- Appearance: clear, colourless liquid
- Storage conditions: ambient

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
Test material was used undiluted.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 6-7 weeks
- Housing: 5 animals/cage (stainless steel cages, fitted with wire-screen floor and front); during treatment animals were housed individually
- Diet: standard laboratory diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 65 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 52.5 - 92.5
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: at least 20 cm²
- % coverage: at least 10% of the total body surface
- Type of wrap if used: plastic foil

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with lukewarm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: observations were made within 1 hour and within 4 hours after the start of dosing, and subsequently at least once daily throughout an observation period of 14 days
- Frequency of weighing: on day 0, day 3, 7 and 14
- Necropsy of survivors performed: yes, at the end of the observation period (day 14) all animals were killed with carbon dioxide and examined for external changes. Next, the abdomen and thorax of each animal was opened and examined for gross pathological changes.
- Skin reactions were scored according to Draize et al., 1944 (see Table 1 in box "Any other information on materials and methods incl. tables") and were made on day 1, 3, 7 and 14 after patch removal

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured during the 14-day observation period.

Clinical signs:

other: Encrustation of the nose, on day 1 or at 72 h or day 3 recorded in some of the animals. In the skin site treated with the test substance, only slight encrustation was observed in 2 males and 1 female on day 1 of the study. No other clinical symptoms obser

Body weight:

other body weight observations

Remarks:

no adverse effects on bodyweight gain were noted

Gross pathology:

No treatment-associated changes were detected in the animals.

Interpretation of results:

other: CLP criteria not met

Conclusions:

Propyl (S)-lactate is not dermally toxic and the LD50 is >2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study conducted according to OECD TG 402 groups of young adult Wistar rats (5/sex) were dermally exposed to n-propyl-lactate (purity 99.5%) for 24 hours to at least 10% of the total body surface area at a dose of 2000 mg/kg bw. Animals were observed for 14 days. No mortality was observed among the animals. The only clinical symptom detected was encrustation of the nose on days 1 or 3 of the study. All animals gained weight day during the 14-day observation period, except for a slight dip in the body weight of all males and 4 females, recorded on day 3. No treatment-associated changes were detected in the animals during the gross pathology examination.

Based on the results, the dermal LD50 of the substance for both male and female rats can be considered to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

GLP guideline study

Additional information

In an acute oral and dermal toxicity study conducted according to OECD guideline 401 and 402, groups of Wistar rats (5/sex) were given Propyl (S)-lactate (99.5 % purity) as a single dose of 2000 mg/kg bw. No mortality occurred and an oral and dermal LD50 value of greater than 2000 mg/kg bw, both in male and female rats, was determined in these studies.

In acute inhalation toxicity studies conducted according to OECD guideline 403, groups of Wistar rats (5/sex) were exposed to the source substances Ethyl lactate, Ethylhexyl (S)-lactate and L(-) lactic acid for 4 hours. No mortality occurred in any study. Based on the results from these studies, the LC50 is considered to be greater than 5.4 mg/L (Ethyl lactate), 5.6 mg/L (Ethylhexyl (S)-lactate and >7.94 mg/L (L(-) lactic acid..

In addition, in a sensory irritation study, the RD50 values of Ethyl (S)-lactate were 772 mg/m³ in mice and 791 mg/m³ in rats. In the same study an RD50 of 760 mg/m³ in mice and 701 mg/m³ in rats was found for Butyl (S)-lactate. The similarity in the results for of lactate esters support the conclusion that the effects on breathing rate can be attributed to irritating effects from the lactic acid formed at hydrolysis of the substances, which is a rapid enzymatically process during and after uptake in the organism. The sensory irritating effect is thus a pH effect and not a toxic effect. As Propyl (S)-lactate is hydrolysed to lactic acid as well, it is expected to have a sensory irritating effect.

Justification for classification or non-classification

Based on the available data, the target substance Propyl (S)-lactate does not warrant classification for acute toxicity in accordance with CLP Regulation 1272/2008. The LD50 value for the oral and dermal route is above the limit value of the relevant OECD guidelines and in acute inhalation toxicity studies (OECD 403) conducted with suitable read-across substance no mortality occurred at the maximal achievable concentrations.