Glycollic acid

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No information available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Peer reviewed appraisal of metabolic pathway for glycolic acid pre-cursor and breakdown products of ethylene glycol. Publication accepted after critical evaluation.

Objective of study:

metabolism

toxicokinetics

Qualifier:

no guideline available

Principles of method if other than guideline:

The appraisal of ethylene glycol metabolism complied with the broad principle of establishing evidence of a metabolic pathway using methods available at the time. The investigations provide a sound basis for further investigation of glycolic acid metabolism and are in broad agreement with the testing principles subsequently established by statute within the EU.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[1-14C]glycolic acid

Species:

monkey

Strain:

other: Rhesus

Sex:

female

Details on test animals or test system and environmental conditions:

The two female monkeys were weighing about 3 kg.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

The solution was administered by stomach tube in a volume of 4 ml/kg approximately 20 hr after the last feed, and was followed immediately by an equal volume of water.

Duration and frequency of treatment / exposure:

Single acute administration of glycollate or glyoxalate. Second group had two acute administrations separated by a period of circa six months.

TEST ANIMALS
- Weight at study initiation: 3-3.5 kg approximately
- Fasting period before study: 20 hours

Female rhesus monkeys (A and B) received 500 mg/kg oral doses of [1-14C]glycolic acid, in aqueous solution. The solution was administered by stomach tube in a volume of 4 ml/kg and was followed immediately by an equal volume of water.

Remarks:

Doses / Concentrations:
500 mg/kg bw glycollate and 60 or 500 mg kg bw glyoxalate
A solution of 5 grams unlabelled glycolic acid in about 30 ml water, dissolved by the addition of 10 N-NaOH, was adjusted
to pH 6 and made up to 40 ml. This solution was used to dissolve the contents of one vial (50 uc) of the [1-14C]glycolic
acid. The solution gave a count of 2,675,000 disintegrations/ml/min, indicating a specific activity of 0.73/uc/mmole.

No. of animals per sex per dose / concentration:

2 females per group

Control animals:

no

Positive control reference chemical:

no

Details on study design:

Two female rhesus monkeys (A and B), each weighing about 3 kg, received 500 mg/kg oral doses of 14C glycolic acid, in aqueous solution.

Details on dosing and sampling:

The solution was administered by stomach tube in a volume of 4 ml/kg approximately 20 hr after the last feed, and was followed immediately by an equal volume of water. Urine was collected in polyethylene bottles containing 10 ml 6 N-HCI as preservative; the samples were stored in a frozen condition, and were thawed only for the purpose of removing samples for analysis. The collection periods were 0-8, 8-24, 24-48 and 48-72 hr. In one case, a 72-96 hr sample was also obtained.

Preliminary studies:

None described.

Details on absorption:

Not determined in this assay.

Details on distribution in tissues:

Not determined in this assay.

Details on excretion:

The faecal output of 14C following the 500 mg/kg dose of glycolic was generally of minor importance.

Analysis of the individual acids showed that 34-44% of the glycolate was excreted unchanged, 0.3 – 2.2% excreted as the glyoxylate, 0.3% as hippurate and 0.3 – 1.3% as oxalate. (6% of urinary 14C was unaccounted for in terms of the various acids). Urinary radioactivity showed that the 96 hour excretion of 14C-glycolic acid was 51% of administered dose. Faecal radioactivity resulting from oral administration of 500 mg/kg doses of glycolic acid was low indicating poor absorption.

Faecal excretion of 14C following administration of 500 mg glyoxylate/kg collate was approximately 1% and 3% for 500 mg glycollate/kg. Urinary excretion after 96 hours was 37-52% of the glycollate dose and 34-69% of the glyoxylate dose. Analysis of the individual acids showed that 34-44% of the glycollate was excreted unchanged, 0.3 – 2.2% excreted as the glyoxylate, 0.3% as hippurate and 0.3 – 1.3% as oxalate. (6% of urinary 14C was unaccounted for in terms of the various acids). For the 500 mg glyoxylate dose 24-59% was excreted unchanged, , 0.1% was hippurate, 3% as oxalate and approximately 2% as glycollate. . (6.5 to 16% of urinary 14C was unaccounted for in terms of the various acids). Some of the unaccounted radioactivity was present as labelled unconjugated glycine. At the lower concentration, 60 mg glyoxylate/kg, the metabolism and distribution was dramatically altered. Only 20% of 14C appeared in urine within 96 hours and only 1-1.5% of the dose was unchanged parent. 70% of the total 14C was oxalic acid with labelled hippurate forming a very minor metabolite.

Metabolites identified:

yes

Details on metabolites:

glyoxylate, hippurate, oxalate, glyoxylic acid, hippuric acid, and oxalic acid

The most important excretory product in the urine of both rat and monkey (after the unchanged parent ethylene glycol) was glycolic acid – recovered at approximately 12% of a 1 mL/kg dose. The proposed metabolic pathway for ethylene glycol contains both glycolic acid and the minor metabolites oxalate and hippurate. It can be presumed that glycolic acid metabolism would proceed along the same pathway and at a rate consistent with this scheme. The observed rapid conversion of EG to CO2 implies the existence of a series of labile intermediary products. Specific enzymes, such as alcohol dehydrogenase and glycolic acid dehydrogenase catalyse these reactions, which are involved in the disposition not only of EG and ethanol but of such normal body constituents as ethanolamine. Glyoxylic acid, once formed, may undergo a variety of reactions, involving its reversible transamination to glycine, conversion to CO2 and formate (possibly through intermediate condensation with α-ketoglutarate , oxidation to oxalate and incorporation into the general body carbon pool in such forms as malate.

Faecal excretion of ¹⁴C following administration of 500 mg/kg glyoxylate collate was approximately 1% and 3% for 500 mg/kg glycollate.  Urinary excretion after 96 hours was 37-52% of the glycollate dose and 34-69% of the glyoxylate dose.  Analysis of the individual acids showed that 34-44% of the glycollate was excreted unchanged, 0.3 – 2.2% excreted as the glyoxylate, 0.3% as hippurate and 0.3 – 1.3% as oxalate. (6% of urinary ¹⁴C was unaccounted for in terms of the various acids). For the 500 mg glyoxylate dose 24-59% was excreted unchanged, 0.1% was hippurate, 3% as oxalate and approximately 2% as glycollate. (6.5 to 16% of urinary ¹⁴C was unaccounted for in terms of the various acids). Some of the unaccounted radioactivity was present as labelled unconjugated glycine. At the lower concentration, 60 mg/kg glyoxylate, the metabolism and distribution was dramatically altered. Only 20% of ¹⁴C appeared in urine within 96 hours and only 1-1.5% of the dose was unchanged parent. 70% of the total ¹⁴C was oxalic acid with labelled hippurate forming a very minor metabolite.

The plasma half-life for ethylene glycol after oral administration of a 1 mL/kg dose was about 3 hours. Following intravenous administration of 0.125 mL/kg of radio-labelled ethylene glycol, excretion of ¹⁴CO₂ began almost immediately and within 4 hours circa 5% of administered dose had been excreted by this route. At four hours, 90% of the administered dose was present in the soft tissues. Liver and kidney contained larger amounts of ¹⁴C than blood, heart, lungs, spleen, brain or adrenals. The 24 hour urinary excretion of unchanged ethylene glycol was 22% but the total ¹⁴C excreted in this period was 45%, indicating approximately half the urinary radioisotope was present in forms other than the parent.  At 4 hours the total soft tissue concentrations accounted for circa 80% of administered dose. The distribution suggested that ethylene glycol was uniformly occupying all of the available water space.

The most important excretory product in the urine of both rat and monkey (after the unchanged parent ethylene glycol) was glycolic acid – recovered at approximately 12% of a 1 mL/kg dose.

Conclusions:

The 96 hour excretion of 14C-glycolic acid was 51% of administered dose. Low faecal radioactivity indicated poor absorption.
Faecal excretion of 14C following administration of glycollate averaged 3 %. Within 96 hours of administration, urinary excretion of 14C accounted for 37-52% of the 500 mg/kg dose of glycollate. Analysis for individual labelled acids revealed that 34- 44 % of the dose was excreted unchanged,
while 0.3-2.2 % was excreted as glyoxylate, 0.3 % as hippurate and 0-3-1.3 % as oxalate. Only about 6% of the urinary 14C was not accounted for in terms of these acids. The 96 hour excretion of 14C-glycolic acid was 51% of administered dose. Low faecal radioactivity indicated poor absorption. The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).

Executive summary:

The method used for determining glycolic acid did not distinguish between radio-labelled and non-labelled forms. Following oral administration of radio-labelled glycolic acid, the amounts appearing in the urine were so great that practically all glycolate in urine must have carried the ¹⁴C label. The situation was less clear cut following administration of the glyoxylic acid since mammalian enzymatic action catalyses the reduction of glyoxylate to glycolate. Therefore some of the radioactivity found in urine but not accounted for as glyoxylic, hippuric or oxalic acid in the 0-24 hour period may have derived from glycolate but it appears unlikely that there was any in later intervals. An estimate of 2.5% of administered dose was postulated for the amount of glyoxylate excreted as glycolic acid. Urinary radioactivity showed that the 96 hour excretion of ¹⁴C-glycolic acid was 51% of administered dose and for ¹⁴C-glyoxylic acid the value was 44%. Faecal radioactivity resulting from oral administration of 500 mg/kg doses of glycolic or glyoxylic acids was low indicating poor absorption. Fecal excretion of ¹⁴C following administration of glycollate averaged 3 %. Within 96 hours of administration, urinary excretion of ¹⁴C accounted for 37-52 of the 500 mg/kg dose of glycollate. Analysis for individual labelled acids revealed that 34- 44 % of the dose was excreted unchanged, while 0.3-2.2 % was excreted as glyoxylate, 0.3 % as hippurate and 0-3-1.3 % as oxalate. Only about 6% of the urinary ¹⁴C was not accounted for in terms of these acids.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Peer reviewed appraisal of metabolic pathway for glycolic acid pre-cursor and breakdown products of ethylene glycol. The first step in the metabolic pathway of Ethylene Glycol (EG) in mammals involves the conversion of EG to Glycolic acid (GA) via alcohol dehydrogenase. The metabolism of EG to GA has been observed in all species studied, including rats, mice, dogs, rabbits, monkeys, and man. Publication accepted after critical evaluation. This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Objective of study:

distribution

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

The appraisal of ethylene glycol (precursor in metabolic pathway for glycolic acid) metabolism complied with the broad principle of establishing evidence of a metabolic pathway using methods available at the time. The investigations provide a sound basis for further investigation of glycolic acid metabolism and are in broad agreement with the testing principles subsequently established by statute within the EU.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

14C labelled

Species:

other: chimpanzees, rats, and rhesus monkeys

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: male rats 200-290 g; rhesus monkeys 2.2 - 7 kg
- Individual metabolism cages: yes
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):

Route of administration:

other: intravenenously and gavage

Vehicle:

not specified

Remarks:

i.v. doses diluted with saline.

Duration and frequency of treatment / exposure:

Once or once followed by a second dose one week later.

Remarks:

Doses / Concentrations:
139 mg/kg (intravenously) or 1 mg/kg (gavage)

No. of animals per sex per dose / concentration:

1 - 6

Details on distribution in tissues:

Four hours after an oral dose of 1 mL/kg, tissue and serum concentrations of ethylene glycol in monkeys were approximately 100 mg/100 g, while at 48 hr no measurable ethylene glycol was present. The peak blood level was about 125 mg/100 ml at 1-2 hours.

Details on excretion:

Rats and monkeys began excreting 14CO2 in expired air and 14C-labelled compounds in the urine immediately after intravenous administration. Within 24 hours rats had excreted over 60% of the dose by these two routes. In monkeys receiving an equivalent ethylene glycol dose (139 mg/kg), 15% was excreted in urine and expired air within 4 hours. The mean 24-hr urinary excretion in monkeys was 44% of the dose, and 1% was excreted in the next 24 hours. Rats dosed orally excreted a mean of 56% of the 14C in the urine within 24 hr (32% as ethylene glycol). After unchanged ethylene glycol, the next most important urinary excretion product was glycolic acid. In the monkey this accounted for at least 12% of the dose. The output of oxalic acid was quite small in both species, being about 0.3% of the dose in the monkey and about 2.5% in the rat. Between 24 and 48 hours after an oral dose of ethylene glycol, monkeys excreted 0.1% of the dose as hippuric acid.

Toxicokinetic parameters:

other: Plasma half-life was 2.7-3.7 hours, depending on the age of the monkeys.

Metabolites identified:

yes

Details on metabolites:

After CO2, glycolic acid is the most important metabolite in both the monkey and the rat. Small amounts of oxalic acid and hippuric acid were also excreted.

Conclusions:

Low bioaccumulation potential based on study results
Both rat and monkey began excreting 14CO2 in expired air and 14C-labelled compounds in the urine immediately after intravenous administration. Within 24 hours rats had excreted over 60% of the dose by these two routes; the remainder of the label was distributed widely and uniformly in the tissues. In monkeys receiving an equivalent ethylene glycol dose (139 mg/kg), 15% was excreted in urine and expired air within 4 hours, while the remainder was widely, and generally uniformly, distributed in the tissues. Monkeys readily tolerated oral doses of 1 ml ethylene glycol/kg, the peak blood level being about 125 mg/100 ml at 1-2 hr. The plasma half-life was 2.7-3.7 hr, depending on the age of the monkeys, and the 24-hour excretion as unchanged ethylene glycol amounted to about 22% of the dose; no additional ethylene glycol was excreted in the 24-48 hour period. With 14C-ethylene glycol, the mean 24-hr urinary excretion in monkeys was 44% of the dose, and 1% was excreted in the next 24 hours. Four hours after an oral dose of 1 mL/kg, tissue and serum concentrations of ethylene glycol in monkeys were approximately 100 mg/100 g, while at 48 hours no measurable ethylene glycol was present. Rats receiving the same oral dose in labelled form excreted a mean of 56% of the 14C in the urine within 24 hours (32% as ethylene glycol). After unchanged ethylene glycol, the next most important urinary excretion product was glycolic acid. In the monkey this accounted for at least 12% of the dose. The output of oxalic acid was quite small in both species, being about 0.3% of the dose in the monkey and about 2.5% in the rat. Between 24 and 48 hours after an oral dose of ethylene glycol, monkeys excreted 0.1% of the dose as hippuric acid.

Executive summary:

The metabolism of ethylene glycol was studied rat and rhesus monkey, and in a preliminary study in the chimpanzee, using both unlabelled and 14C-labelled compound. Both rat and monkey began excreting 14CO2 in expired air and 14C-labelled compounds in the urine immediately after intravenous administration. Within 24 hours rats had excreted over 60% of the dose by these two routes; the remainder of the label was distributed widely and uniformly in the tissues. In monkeys receiving an equivalent ethylene glycol dose (139 mg/kg), 15% was excreted in urine and expired air within 4 hours, while the remainder was widely, and generally uniformly, distributed in the tissues. Monkeys readily tolerated oral doses of 1 ml ethylene glycol/kg, the peak blood level being about 125 mg/100 ml at 1-2 hr. The plasma half-life was 2.7-3.7 hr, depending on the age of the monkeys, and the 24-hour excretion as unchanged ethylene glycol amounted to about 22% of the dose; no additional ethylene glycol was excreted in the 24-48 hour period. With 14C-ethylene glycol, the mean 24-hr urinary excretion in monkeys was 44% of the dose, and 1% was excreted in the next 24 hours. Four hours after an oral dose of 1 mL/kg, tissue and serum concentrations of ethylene glycol in monkeys were approximately 100 mg/100 g, while at 48 hours no measurable ethylene glycol was present. Rats receiving the same oral dose in labelled form excreted a mean of 56% of the 14C in the urine within 24 hours (32% as ethylene glycol). After unchanged ethylene glycol, the next most important urinary excretion product was glycolic acid. In the monkey this accounted for at least 12% of the dose. The output of oxalic acid was quite small in both species, being about 0.3% of the dose in the monkey and about 2.5% in the rat. Between 24 and 48 hours after an oral dose of ethylene glycol, monkeys excreted 0.1% of the dose as hippuric acid.

Reference 3

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Experiments were conducted using methods similar to OECD guideline 428 "Skin Absorption: in-vitro method" and were repeated multiple times. The integrity of skin was not checked and the total recovery of radioactivity was not calculated. Not GLP.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Deviations:

yes

Remarks:

The integrity of the skin was not tested. Total recovery not calculated

Principles of method if other than guideline:

Percutaneous absorption studies using a flow-through diffusion cell system with skin specimens from 24 healthy women to assess the penetration of glycolic acid (GA). Followed background on the use of an in vitro method reported in "In vitro Percutaneous Absorption: Principles, Fundamentals and Applications" by Bronaugh RL and Maibach HI. (1991)

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[1,2-14C] glycolic acid

Species:

other: human skin samples obtained from24 volunteers - Age at study initiation: 19-48 years (35 ± 10 years) - Other: The participants were judged to be healthy based on medical history and physical evaluation

Strain:

other: human volunteers

Sex:

female

Details on test animals or test system and environmental conditions:

Not applicable.

Type of coverage:

open

Duration of exposure:

6-24 hr.

Doses:

100 μL of 4% GA solution

No. of animals per group:

N represents the numbers of human volunteers, and n represents the numbers of experimental repeats.
N = 3-4
n= 10-31

Control animals:

no

Details on study design:

Twenty-four healthy women participated in the study by providing the skin tissue. The skin specimens were collected from the hospital after plastic surgery. The skin tissue was transferred in the sterilized culture media to maintain the tissue's viability. The skin sample was prepared and used within 4 hours after surgery. Experiments were also conducted using frozen skin sections (frozen at -20°C in HHBSS and the storage duration was no longer than 2 months). The percutaneous absorption experiments were conducted using a Diffusion Cell System (Crown Glass, PA, USA).

Details on in vitro test system (if applicable):

One hundred micro litres of glycolic acid solution spiked with (14C) glycolic acid (0.25 µCi/µl) was applied on the SC side of the skin section. Experiments were conducted for 6-24hours. A single fraction of effluent from each individual cell was collected for the 6-hour duration. For a 24-hour experiment, a total of four fractions of the 6-hour duration were obtained. At the end of the incubation time, skin surface was washed with 1% soap solution and water using a Q-tip cotton swab to remove unabsorbed material. The Q-tips from the individual cell were combined in a vial and 10ml of scintillation liquid was added to enable measuring the radioactivity. The results obtained were analysed using SAS software.

Dose:

100µl of a 4% GA solution

Parameter:

percentage

Absorption:

>= 1.5 - <= 2.6 %

Remarks on result:

other: 24 hours

Remarks:

pH 3.8

Dose:

100µl of a 10% GA solution

Parameter:

percentage

Absorption:

>= 0.6 - <= 1.2 %

Remarks on result:

other: 24 hours

Remarks:

pH 3.8

Dose:

100µl of a 20% GA solution

Parameter:

percentage

Absorption:

>= 0.2 - <= 0.9 %

Remarks on result:

other: 24 hours

Remarks:

pH 3.8

Conversion factor human vs. animal skin:

Not applicable.

After 24 hr exposure, the percentage of radio-labelled GA found in the skin after application of 4% GA at pH 2.0 or pH 3.8 were as follows (p less than 0.05 in each case):

 - stratum corneum (SC) = 2.65 ±1.80 and 1.13 ± 1.14

 - viable skin (VS) = 13.46 ± 7.44 and 2.23 ±1.15 and

 - effluent fraction (EF) = 12.22 ± 9.03 and 1.42 ± 0.77

 

An increased penetration of GA through the skin was observed after application of 4-60% GA at their native pH. The percent of GA in the skin after application of 20% GA for 24 hrs at pH 1.9 were as follows: SC = 2.69 ± 2.26; VS = 4.07 ±1.78 and EF=6.12 ±4.95.

 

Exposure duration after affected the extent of penetration. Application of 20% GA at pH 1.9 for 6 hr resulted in the following levels: SC = 1.16 ± 0.80 (p0.05); VS = 4.07 ± 1.78; and EF = 6.12 ±4.95. The results of this study indicated that under the conditions of low concentration and partially neutral pH (3.0-4.2), most of the GA appeared to stay in SC and VS layers with very limited penetration through the skin. Due to the similarity of absorption through the viable and the dead tissue, the absorption of GA might be a passive process rather than an active one.

Conclusions:

As there are no differences in absorption between fresh (live) and frozen (dead) skin specimens, it is considered that dermal absorption of glycolic acid is a passive diffusion process. The absorption process is influenced by time, pH, concentration, type and composition of the formulation, and by the degree of occlusion of the site of application. The estimated permeability coefficient ranges from 3 x 10-5 to 2 x 10-4 cm/h, which is in reasonable agreement with the experimentally determined permeability coefficient of 3 x 10-4 cm/h.

Executive summary:

Penetration of dermis by glycolic acid (GA) was investigated using a flow-through cell system with skin specimens from 24 healthy women. Radio-labelled 14C-glycolic acid was applied to the skin for 24 hours as a 4% glycolic acid preparation at pH 2.0 or pH 3.8 or as 4 to 60% glycolic acid preparations at native pH values. The percent radio-labelled GA appearing in the stratum corneum was 2.65 at pH 2.0 and 1.13 at pH 3.8; in viable skin the values were 13.46 at pH 2.0 and 2.23 at pH 3.8 and in the effluent fraction 12.22 at pH 2.0 and 1.42 at pH 3.8. At higher concentrations, the penetration was greater, e.g. for 20% GA (pH 1.9) the percentages were 2.69%, 4.88% and 30.69% for stratum corneum, viable skin and effluent fraction respectively. The duration of exposure also affected skin penetration – application of the 20% GA (pH 1.9) for only 6 hours resulted in stratum corneum radioactivity of 1.16%, viable skin levels of 4.07% and effluent fraction levels of 6.12%. Absorption of glycolic acid through human skin was found to be pH, concentration and time-dependent. The in vitro human skin model is considered a suitable model for estimation of in vivo human absorption.The pH factor is most critical to dermal penetration. Absorption across a range of glycolic acid concentrations is enhanced with decreased pH. Glycolic acid is a weak acid, with a pKa value of 3.83, at pH values of less than 3 most of the GA is in the uncharged acid form which facilitates penetration through the lipid layer in the stratum corneum enhancing dermal absorption. This is important, particularly in human cosmetic usages, since high absorption of GA at low pH causes severe skin irritation. As there are no differences in absorption between fresh (live) and frozen (dead) skin specimens, it is considered that dermal absorption of glycolic acid is a passive diffusion process. The absorption process is influenced by time, pH, concentration, type and composition of the formulation, and by the degree of occlusion of the site of application.

 

Absorption of GA in human skin is pH-, concentration-, and time-dependent. The in vitro method appeared to provide an appropriate model to reflect in vivo absorption of GA through human skin.

Description of key information

Short description of key information on bioaccumulation potential result: 
A key study report published in 1972 with experimental results is supported by several other  reviews and supplementary publications.
Oral absorption is estimated to be 100%.
Urinary excretion of glycolic acid  was circa 50% of administered dose.
The primary metabolites of ethylene glycol identified were glyoxylate, hippurate and oxalate.  Glyoxylic acid, hippuric acid, and oxalic acid all appear in the proposed metabolic pathway for ethylene glycol
The plasma half life for ethylene glycol is circa 3 hours and expected to be of similar duration for glycolic acid
The Vmax/Km ratio for the conversion of glycolic acid to glyoxylic acid for rat, rabbit, and human liver tissues were 0.28, 0.03, and 0.43 h-1g-1, respectively. These ratios indicated that liver tissue from human was the most effective of the three species for the transformation of glycolic acid to glyoxylic acid. Hepatic clearance of glycolic acid in vivo would therefore be expected to be greater for human compared with that for rat or rabbit
Short description of key information on absorption rate: 
A key study report was published in 1998 with experimental results. In vitro penetration of human skin membranes was considered indicative of human in vivo absorption although absorption of glycolic acid is pH dependent, with low pH increasing dermal penetration

Key value for chemical safety assessment

Absorption rate - dermal (%):

2.6

Additional information

Toxicokinetics

 

Absorption

Oral Absorption

In rats: a) 2% recovered in faeces, b) 50% in expired air and c) 7% in urine = 59%. At high doses, a) 22% recovered from faeces , b) 51% in respiratory carbon dioxide and c) 3% in urine. Urinary excretion of radioactivity is 51% for glycolic and 44% for glyoxalic acid. From the urinary and respired air excretion values, oral absorption was considered to approximately 100%. Inhalation absorption not measured but estimated to be high since glycolic acid is readily absorbed in upper airways.

 

Dermal absorption
It is affected by exposure time, pH conditions and formulation composition and concentration. Rate of penetration is calculated to be 3 x 10E-4 cm/h. For a 4% solution of glycolic acid at pH 2, absorption was circa 28%; absorption increased with higher concentrations and at 60 or 70%; penetration was circa 100%.

Distribution

Widespread distribution = 0.56 L/kg, indicating almost ubiquitous presence in body water. Monocarboxylate transport mechanism is also widely found in mammalian organs.

 

Excretion- see absorption figures given above.

Discussion on bioaccumulation potential result:

The toxicokinetics of glycolic acid have been well investigated in laboratory animals and humans. This is primarily because glycolic acid is both a precursor of oxalic acid, which is a common component of kidney stones, and the major metabolite of ethylene glycol, which is an ingredient in antifreeze products and a frequent cause of poisoning by ingestion.

Absorption of glycolic acid
Oral absorption has been determined for rats and Rhesus monkeys following oral administration of aqueous solutions of radio-labelled material. For the rat, only 2% of the radioactivity was recovered in faeces. At the lowest dose level, 50% of the administered dose was recovered as respiratory carbon dioxide and approximately 7% as glycolic, glyoxylic and oxalic acids in the urine. At the highest dose level, 22% of the administered dose was recovered as respiratory carbon dioxide, 51% as glycolic acid in the urine and 3% as glyoxylic and oxalic acids in the urine. In monkeys only 3% of excreted glycolic acid was found in faeces. 

Urinary radioactivity showed that the 96 hour excretion of¹⁴C-glycolic acid was 51% of administered dose and for¹⁴C-glyoxylic acid the value was 44%.  Faecal radioactivity resulting from oral administration of 500 mg/kg doses of glycolic or glyoxylic acids was low.  Based on the excretion of radiolabel in expired air and urine, oral absorption was considered to be approximately 100%. The most important excretory product in the urine of both rat and monkey (after the unchanged parent ethylene glycol) was glycolic acid, recovered at approximately 12% of a 1 mL/kg dose. The proposed metabolic pathway for ethylene glycol contains both glycolic acid and the minor metabolites oxalate and hippurate. It can be presumed that glycolic acid metabolism would proceed along the same pathway and at a rate consistent with this scheme. The observed rapid conversion of EG to CO2 implies the existence of a series of labile intermediary products. Specific enzymes, such as alcohol dehydrogenase and glycolic acid dehydrogenase, catalyse these reactions, which are involved in the disposition not only of EG and ethanol but of such normal body constituents as ethanolamine. Glyoxylic acid, once formed, may undergo a variety of reactions, involving its reversible transamination to glycine, conversion to CO2 and formate (possibly through intermediate condensation with α-ketoglutarate, oxidation to oxalate) and incorporation into the general body carbon pool in such forms as malate.

The method used for determining glycolic acid did not distinguish between radio-labelled and non-labelled forms. Following oral administration of radio-labelled glycolic acid, the amounts appearing in the urine were so great that practically all glycolate in urine must have carried the¹⁴C label. The situation was less clear cut following administration of the glyoxylic acid since mammalian enzymatic action catalyses the reduction of glyoxylate to glycolate and, therefore, some of the radioactivity found in urine but not accounted for as glyoxylic, hippuric or oxalic acid in the 0-24 hour period may have derived from glycolate. But it appears unlikely that there was any in later intervals. An estimate of 2.5% of administered dose was postulated for the amount of glyoxylate excreted as glycolic acid.

 

Urinary radioactivity showed that the 96 hour excretion of ¹⁴C-glycolic acid was 51% of administered dose and for ¹⁴C-glyoxylic acid the value was 44%.  Faecal radioactivity resulting from oral administration of 500 mg/kg doses of glycolic or glyoxylic acids was low indicating poor absorption. Faecal excretion of ¹⁴C following administration of glycolate averaged 3 %. Within 96 hours of administration, urinary excretion of ¹⁴C accounted for 37-52 of the 500 mg/kg dose of glycolate. Analysis for individual labelled acids revealed that 34-44 % of the dose was excreted unchanged, while 0.3-2.2 % was excreted as glyoxylate, 0.3 % as hippurate and 0-3-1.3 % as oxalate. Only about 6% of the urinary ¹⁴C was not accounted for in terms of these acids.

 

In vitro comparisons of rat, rabbit and human liver metabolism of ethylene glycol indicated that there were some qualitative differences in the metabolite profiles but there were greater quantitative differences in the rate of production of glyoxylic acid among the different mammalian systems. The Vmax/Km ratio for the conversion of glycolic acid to glyoxylic acid for rat, rabbit, and human liver tissues were 0.28, 0.03, and 0.43 h-1g-1, respectively. These ratios indicated that liver tissue from human was the most effective of the three species for the transformation of glycolic acid to glyoxylic acid. Hepatic clearance of glycolic acid in vivo would therefore be expected to be greater for human compared with that for rat or rabbit.

 

Discussion on absorption rate:

Penetration of human dermis by glycolic acid (GA) was investigated in vitro using a flow-through cell system with skin specimens from 24 healthy women. Radio-labelled 14C-glycolic acid was applied to the skin for 24 hours as a 4% glycolic acid preparation at pH 2.0 or pH 3.8 or as 4 to 60% glycolic acid preparations at native pH values.

 

The percent radio-labelled GA appearing in the stratum corneum was 2.65 at pH 2.0 and 1.13 at pH 3.8; in viable skin the values were 13.46 at pH 2.0 and 2.23 at pH 3.8 and in the effluent fraction 12.22 at pH 2.0 and 1.42 at pH 3.8. At higher concentrations, the penetration was greater, e.g. for 20% GA (pH 1.9) the percentages were 2.69%, 4.88% and 30.69% for stratum corneum, viable skin and effluent fraction respectively. The duration of exposure also affected skin penetration – application of the 20% GA (pH 1.9) for only 6 hours resulted in stratum corneum radioactivity of 1.16%, viable skin levels of 4.07% and effluent fraction levels of 6.12%.

Absorption of glycolic acid through human skin was found to be pH, concentration and time-dependent. The in vitro human skin model is considered a suitable model for estimation of in vivo human absorption.

 

The pH factor is most critical to dermal penetration. Absorption across a range of glycolic acid concentrations is enhanced with decreased pH. Glycolic acid is a weak acid, with a pKa value of 3.83, at pH values of less than 3 most of the GA is in the uncharged acid form which facilitates penetration through the lipid layer in the stratum corneum enhancing dermal absorption. This is important, particularly in human cosmetic usages, since high absorption of GA at low pH causes severe skin irritation. 

 

1.5 -2.6% of 4% GA was absorbed at pH 3.8

0.6 -1.2% of 10% GA was absorbed at pH 3.8

0.2 - 0.9% of 20% GA was absorbed at pH 3.8