Glycollic acid

Endpoint summary

Description of key information

Acute oral LD50 in rats of a 70% glycolic acid solution was >2000 mg/kg bw. The LD50 was based on 100% glycolic acid dosed (adjusted for 70% purity of the test substance).
The acute inhalation median lethal concentration for a 4-hour nose-only exposure was 3.6 mg/L for male rats and 5.2 mg/L for female rats.
In view of the extensive human exposure without adverse effect as a consequence of cosmetic uses, no dermal toxicity study was conducted.  No dermal toxicity is anticipated.

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:

IN-LIFE DATES: From: August 13, 1998 To: September 9, 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline and GLP-compliant regulatory study. Study report revised in 2010 to re-calculate the LD50 value following re-evaluation of mortality data.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD (SD) IGS BR rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source of rats was Charles River Laboratories, Raleigh, North Carolina, USA. Male rats were 57 or 58 days old in a body weight range of 239.5 – 267.0 g. Female rats were 78 or 79 days old in a body weight range of 203.8 – 242.9 g prior to fasting overnight from day -1 to day of dosing.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Individual doses were adjusted to take account of animal’s fasted bodyweight and the specific gravity of the test material (1.25 g/mL) to achieve the dose levels. Additionally, the doses were adjusted for purity. The rats were fasted overnight (approximately 18 hours) prior to dosing. Post exposure period was 14 days.

Doses:

1000, 2000 and 3000 mg/kg as a 70% aqueous solution
- maximum administered dose volume was 3.40 ml/kg bw

No. of animals per sex per dose:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina.
- Age at study initiation: Male rats were 57 or 58 days old and female rats were 78 or 79 days old on day of dosing.
- Weight at study initiation: Average fasting body weights were between 224 g and 234.5 g for males and between 207.1 g
and 213.5 g for females.
- Fasting period before study: Approximately 18 hours prior to dosing. Food was returned within approximately 3 hours
after dosing.
- Housing: Rats were housed singly in suspended, stainless steel, wire-mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum.
- Water (e.g. ad libitum): Ad libitum.
- Acclimation period: Rats were quarantined, weighed and observed for general health for 6 days.
- 10 (5 male and 5 female) per dose group
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 1°C.
- Humidity (%): 50+/- 10%.
- Photoperiod (hrs dark / hrs light): Timer controlled (12-hour light/12-hour dark cycle) lighting.

Control animals:

no

Details on study design:

Daily observations (weekends and holidays excluded unless warranted by the condition of the rats) of mortality, clinical observations of toxicity or behavioural change and body weights. All rats found dead or sacrificed were necropsied.

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Observations for mortality, signs of illness, injury or abnormal behavior were made daily. Rats were weighed and observed for clinical signs of toxicity daily (weekends and holday excluded unless warranted by the condition of the rats).
- Necropsy of survivors performed: Yes.
- Other examinations performed: Clinical signs, body weight, mortality, gross observations
 
Statistics
Average fasting body weight, LD50 95% confidence interval, mortality ratio (deaths/exposed).

Statistics:

Method of determination of LD50 was calculated by probit analysis (Finney, D. J., Probit Analysis, 1971).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 040 mg/kg bw

95% CL:

1 443 - 2 469

Remarks on result:

other: LD50 recalculated in revised report to address death of one intermediate dose female that died following apparent dosing trauma. The LD50 was based on 100% glycolic acid dosed (adjusted for 70% purity of the test substance).

Mortality:

Mortalities at the 1000, 2000 and 3000 mg/kg dose levels were 0, 50 and 90%, respectively. Mortalities occurred up to four days after dosing. One female dosed at 2000 mg/kg bw died following apparent dosing trauma. Since the death was not directly attributable to an effect of glycolic acid this data was excluded from the calculation of the median lethal dose when the study report was revised in 2010.

Clinical signs:

other: other: Clinical signs observed included lethargy, lung noise, ocular discharge, prostrate posture, hunched posture, stained face or chin, clear oral discharge, bloating, pallor, inappetance and moribundity.

Gross pathology:

Black stomach discolouration was observed in 5 male rats at 3000 mg/kg and 1 and 4 female rats at 2000 and 3000 mg/kg, respectively. Most rats exhibiting stomach discolouration also had stomachs distended with black fluid. Brown lung discolouration, possibly due to a gavage accident, was observed in one female rat at 2000 mg/kg - the death of this rat was attributed to mal-administration rather than a result of systemic toxicity. The gross observations for the other male and female rats were non-specific and not indicative of target organ toxicity.

Other findings:

No further information.

Table               Study summary
Group	Dose level (mg/kg)	Average dose volume (mL)	Mean bodyweight (g)			% mortality
			Day 1^1	Day 7	Day 15
Male	1000	0.26	224	277.6	338.5	0
Female		0.24	208.7	240.3	258.2	0
Male	2000	0.53	234.5	239.7	321.8	40
Female		0.47	207.1	224.6^2	262^2	80
Male	3000	0.78	229.8	na	na	100
Female		0.72	213.5	243.9^2	271.1^2	80
LD50value	2040 mg/kg bw
^1= fasted body weight na – not applicable, all rats dead ^2= single surviving female

Interpretation of results:

GHS criteria not met

Conclusions:

Fasted male and female rats were dosed at 1000, 2000 and 3000 mg/kg by oral gavage administration of the test material, glycolic acid 70% solution. Clinical signs and body weights were observed over 14 days post-dose and all animals were subjected to a necropsy. Mortalities in the treatment groups were 0, 50 and 90% for the 1000, 2000 and 3000 mg/kg doses, respectively. Clinical signs observed included lethargy, lung noise, ocular discharge, prostrate posture, hunched posture, stained face or chin, clear oral discharge, bloating, pallor and moribundity. There were few signs among rats dosed at 1000 mg/kg and the primary effects at 3000 mg/kg were prostration and lethargy. The majority of decedents were found dead on day 2, with isolated deaths occurring on days 1, 3 or 4.  LD50(male and female rates combined) – 2040 mg/kg (95% confidence limits of 1443 to 2469 mg/kg).

Executive summary:

Fasted male and female rats were dosed at 1000, 2000 and 3000 mg/kg by oral gavage administration of the test material, glycolic acid 70% solution. Clinical signs and body weights were observed over 14 days post-dose and all animals were subjected to a necropsy.

Mortalities in the treatment groups were 0, 50 and 90% for the 1000, 2000 and 3000 mg/kg doses, respectively. Clinical signs observed included lethargy, lung noise, ocular discharge, prostrate posture, hunched posture, stained face or chin, clear oral discharge, bloating, pallor and moribundity. There were few signs among rats dosed at 1000 mg/kg and the primary effects at 3000 mg/kg were prostration and lethargy. The majority of decedents were found dead on day 2, with isolated deaths occurring on days 1, 3 or 4.  LD50 (male and female rates combined) – 2040 mg/kg (95% confidence limits of 1443 to 2469 mg/kg).

 

Under the conditions of this test, the oral LD50 of Glycolic Acid for male and female rats combined was 2040 mg/kg with 95% confidence limits of 1443 - 2469 mg/kg. No classification of Glycolic acid is necessary on basis of the oral acute median lethal dose in rats.

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 040 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

; 3 minor deviations, insignificant. 4 of the rats, 3.8 mg/L, without gross evaluation at necropsy. No tissues from 2 male rats in the 5.2 mg/L available for microscopy. 0.60 mg/L animals in recovery for 15 days rather 14 days

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

yes

Remarks:

; 3 minor deviations, insignificant. 4 of the rats, 3.8 mg/L, without gross evaluation at necropsy. No tissues from 2 male rats in the 5.2 mg/L available for microscopy. 0.60 mg/L animals in recovery for 15 days rather 14 days

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

Charles River Breeding Laboratories, Raleigh, North Carolina, USA

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Rats were individually restrained in perforated stainless steel cylinders with conical nose pieces. The restrainers were inserted into the faceplate of the exposure chamber so that only the nose of each rat extended into the chamber. The chamber was a glass cylinder with a nominal internal volume of 34 L. The chamber airflow was set at approximately 12 air changes per hour. Airflow was monitored continually and recorded at 30 minute intervals. Chamber environmental conditions were monitored regularly through exposure.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric analysis at 30-45 min intervals during exposure

Duration of exposure:

4 h

Remarks on duration:

single exposure period

Concentrations:

0, 0.6, 2.1, 3.8 and 5.2 mg glycolic acid/L air.

Characterization of the chamber atmosphere during each exposure showed the mean total aerosol concentration to be 5.2, 3.8, 2.1 and 0.60 mg/L Glycolic Acid.

No. of animals per sex per dose:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, North Carolina.
- Age at study initiation: Approximately 8 weeks old.
- Weight at study initiation: Males ranged from 237 g to 295 g, females ranged from 198 g to 202 g.
- Housing:Singly or in pairs (sexes separate) in suspended, stainless steel, wire mesh cages.
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: Quarantined for 6 days prior to testing.
- Dosing: One group of 5 male and 5 female rats and three groups of 10 male rats. Additional satellite groups of 5 rats were tested for the four test concentrations. A control group of 10 rats was used. Additionally, four groups of 5 male rats per dose were used for a satellite experiment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-1°C.
- Humidity (%): 50 +/- 10%.
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark on a timer-controlled cycle

Control animals:

yes

Details on study design:

One group of 5 male and 5 female rats and 3 groups of 10 male rats each were exposed to an atmosphere of Glycolic Acid in air and allowed to recover for 14 or 15 days. These rats were designated for LC50 determination. The 0.60 mg/L group of rats was inadvertently kept for a 15-day recovery period. This deviation did not affect the results of the study. After the recovery period, all surviving rats were sacrificed for gross pathology evaluations. Male and female rats also underwent microscopic examination of the nose, larynx, pharynx, and lungs. Four groups of 5 male rats each were exposed along with the groups designated for LC50 determination. These rats were designated as satellite animals. All surviving satellite animals were sacrificed approximately 24 hours after exposure for microscopic examination of the nose, larynx, pharynx, and lungs. One group of 10 male rats was exposed to air only. These rats were designated as controls. Five control rats were sacrificed approximately 24 hours after exposure for microscopic examination of the nose, larynx, pharynx, and lungs. The remaining 5 rats were allowed to recover for 14 days, then received the same treatment as the control rats from the initial sacrifice. All rats were exposed nose-only for a single 4-hour period.

Statistics:

Finney, D.S. (1971). Probit analysis, Third Edition, Cambridge University Press, Cambridge.

Sex:

female

Dose descriptor:

LC50

Effect level:

> 5.2 mg/L air

Exp. duration:

4 h

Remarks on result:

other: nose-only

Sex:

male

Dose descriptor:

LC50

Effect level:

3.6 mg/L air

95% CL:

2.4 - 8.9

Exp. duration:

4 h

Remarks on result:

other: nose-only

Mortality:

Exposure to 5.2 mg/L glycolic acid produced 60% mortality in male rats and no mortality in female rats. Subsequent exposures were made on male rats only. Mortality in male rats exposed to 0.6, 2.1 and 3.8 mg/L glycolic acid was 0, 20 and 60% respectively. Rats died either during exposure, or within 1 to 10 days following exposure to the test substance. Mortality was associated with ulcerative lesions founds in the larynges.

Clinical signs:

other: Observations for clinical signs commenced after removal of the rats from the restrainers. Signs of toxicity included gasping, lung noise, hunched posture, nasal and ocular discharge. Additional clinical signs noted later during the recovery period includ

Body weight:

All exposed rats showed body weight losses the day after exposure. One rat in the 5.2 mg/L treatment and all rats in the 3.8, 2.1 and 0.6 mg/L treatments experienced an overall weight gain during the recovery period, although some transient weight losses did occur.

Gross pathology:

No test substance associated target organ gross changes were observed in exposed male or female rats.

Microscopic changes, attributed to treatment induced tissue irritation, were observed in the noses, larynges and lungs of male rats and nose and larynges of female rats. Mild to severe laryngeal ulceration was present in all treated male groups and mild effects were present in the female group. There was not a clear dose response in regard to lesion severity at lower exposure levels, but exposure to 3.8 mg/L and above was associated with severe ulceration. Minimal to mild subacute/chronic inflammation was present in lungs of rats exposed to 2.1, 3.8 and 5.2 mg/L glycolic acid.

Other findings:

No further information.

Mortality

-No mortality was observed in male rats designated as satellite animals or in control rats.

-5.2 mg/L produced 60% mortality in male rats (3/5) and no mortality in females (0/5).

-Only male rats were used for subsequent exposures at concentrations less than 5.2 mg/L.

-Male rat mortality at the other exposure concentrations were 60% for 3.8 mg/L (6/10), 20% for 2.1 mg/L (2/10), and 0% for 0.60 mg/L (0/10).

 

Clinical signs

-Clinical signs were collected for LC50 rats, but not for satellite or control rats.

-Immediately following exposure, gasping, lung noise, hunched posture, nasal and ocular discharge were observed. Stained fur, wet fur and perinea were also observed, but attributed to the method of restraint.

-During recovery, gasping, lung noise, hunched posture, lethargy, ocular and nasal discharge, sore eyes, sore nose, sore chin, vocalization, alopecia and stained and/or wet fur and/or perinea were observed

 

Bodyweight

-Body weights were collected for LC50 rats, but not for satellite or control rats.

-All male rats and 4 of 5 female rats which survived the exposure to 5.2 mg L Glycolic Acid experienced slight to severe body-weight losses the day after exposure. Males lost 12-15% of pre-exposure body weight and females lost 0.1 to 5.1%. All male rats that survived the 3.8 mg/L exposure had losses that ranged from 6.5 to 16% of pre-exposure body weight. Rats from the 2.1 mg/L group showed losses that ranged from 2.4 to 14 % of pre-exposure body weight and rats from the 0.60 mg/L group exhibited losses that ranged from 0.3 to 14% of pre-exposure body weight. One rat in the 5.2 mg/L group and all rats in the 3.8, 2.1 or 0.60 mg/L groups experienced overall weight gain during the recovery period, though some transient weight losses did occur.

 

Pathology

No test substance-associated target organ gross changes were observed in exposed male or female rats designated for LC50 determination. Four male rats exposed to 3.8 mg/L did not receive gross evaluations due to inadvertent errors at necropsy.

 

Other findings

Microscopic Observations

- Test substance-associated microscopic changes, attributable to tissue irritation, were observed in noses, larynges and lungs of male rats and nose and larynges of female rats. Minimal to mild nasal lesions, seen in all treated groups, consisted of degeneration of respiratory and/or olfactory epithelium. In the respiratory region, changes were in the mucosa lining the dorsal, middle and ventral meatuses, and on the septum and turbinates of the anterior nose. The changes consisted of loss of columnar and/or transitional cells and denudation of mucosal epithelium or presence of degenerate acidophilic cells or basophilic regenerative cells, occasionally flattened to cover maximal surface area. In the olfactory region, changes were on the septum and ethmoid turbinates and ranged from segmental loss of neuroepithelial cells, the usual, to occasional loss of neuroepithelial and sustentacular cells, resulting in mucosal denudation. Regeneration was noted as basophilic, slightly disorganized hypercellular segments of olfactory mucosa.

-Mild to severe laryngeal ulceration was present in all treated male groups and mild effects were present in the female group. In most instances, sections of larynges were examined microscopically at the base of the epiglottis and ventral pouch region. There was not a clear dose response in regard to lesion severity at lower exposure levels, but exposure to 3.8 mg/L and above was associated with severe ulceration.

- Minimal to mild subacute/chronic inflammation was present in lungs of rats exposed to 2.1, 3.8, and 5.2 mg/L Glycolic Ac

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

For nose only exposure:
female 4 hour LC50 = >5.2 mg/L
male 4 hour LC50 = 3.6 mg/L (95% confidence limits of 2.4 – 8.9 mg/L).
Based on the microscopic pathology observations, the no-observed-effect level (NOEL) for a single 4-hour exposure to aerosols of glycolic acid in male and female rats was not established.

The purpose of this study was two-fold. The primary purpose was to determine a 4-hour inhalation LC50 for Glycolic Acid in male and female rats. The secondary purpose was to evaluate the potential of the test substance to induce lesions in the nose, pharynx, larynx and lungs following a single 4-hour inhalation exposure.

Under the conditions of this study, the 4-hour inhalation median lethal concentration (LC50) for Glycolic Acid in female rats was greater than 5.2 mg/L. The 4-hour LC50 for Glycolic Acid in male rats was 3.6 mg/L (95% confidence limits 2.4-8.9 mg/L). Based upon the microscopic pathology observations, the no-observed-effect level for a single 4-hour exposure to aerosols of Glycolic Acid in male and female rats was not established.

Executive summary:

For nose only exposure: female 4 hour LC50= >5.2 mg/L, male 4 hour LC50= 3.6 mg/L (95% confidence limits of 2.4 – 8.9 mg/L). Based on the microscopic pathology observations, the no-observed level (NOEL) for a single 4 -hour exposure to aerosols of glycolic acid in male and female rats was not established. Under the conditions of this study, Glycolic acid is considered harmful by inhalation.

Endpoint conclusion

Dose descriptor:

LC50

Value:

3 600 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral toxicity

Fasted male and female rats were dosed at 1000, 2000 and 3000 mg/kg by oral gavage administration of the test material, glycolic acid 70% solution. Clinical signs and body weights were observed over 14 days post-dose and all animals were subjected to a necropsy. Test substance related mortalities in the treatment groups were 0, 50 and 90% for the 1000, 2000 and 3000 mg/kg doses, respectively. One female dosed at 2000 mg/kg died after an apparent mal-administration dosing error - this animal has been excluded for the mortality data used to determine the LD50 value. Clinical signs observed included lethargy, lung noise, ocular discharge, prostrate posture, hunched posture, stained face or chin, clear oral discharge, bloating, pallor and moribundity. There were few signs among rats dosed at 1000 mg/kg and the primary effects at 3000 mg/kg were prostration and lethargy. The majority of decedents were found dead on day 2, with isolated deaths occurring on days 1, 3 or 4.  The oral LD50 of Glycolic Acid for male and female rats combined was 2040 mg/kg with 95% confidence limits of 1433 - 2469 mg/kg. The LD50 was based on 100% glycolic acid dosed (adjusted for 70% purity of the test substance).

 

Inhalation

For nose only exposure:

Female 4-hour LC50 >5.2 mg/L

Male 4-hour LC50 = 3.6 mg/L (95% confidence limits of 2.4 – 8.9 mg/L)

Based on the microscopic pathology observations, the no-observed-effect level (NOEL) for a single 4-hour exposure to aerosols of glycolic acid in male and female rats was not established.

Justification for classification or non-classification

Based on the LC50 value of 3.6 mg/L, Glycolic acid is considered harmful by inhalation. According to Regulation (EC) No 1272/2008, it is considered as acute tox 4 category for inhalation and is assigned the hazard statement H332 "Harmful if inhaled" and the pictogram GHS07.

 

According to Regulation (EC) No 1272/2008, no classification of glycolic acid is required for oral exposure based on an LD50 value of greater than 2000 mg/kg bw.

 

According to Regulation (EC) No 1272/2008, no classification is necessary for dermal exposure, based on extensive human exposure without adverse effects.