Glycollic acid

Basic toxicokinetics

Administrative data

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.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1971

Materials and methods

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

Test material

Test material information

Constituent 1

Reference substance name:

Ethane-1,2-diol

EC Number:

203-473-3

EC Name:

Ethane-1,2-diol

Cas Number:

107-21-1

Molecular formula:

C2H6O2

IUPAC Name:

ethylene glycol

Details on test material:

- Name of test material (as cited in study report): Ethylene glycol
- Labelling: ~14C (specific activity 780/uc/m-mole)
- Source: Tracerlab, Waltham, Mass.
- Purity: Checked by thin-layer chromaotraphy and found to be homogeneous.

Radiolabelling:

yes

Remarks:

14C labelled

Test animals

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):

Administration / exposure

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.

Doses / concentrations

Remarks:

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

No. of animals per sex per dose / concentration:

1 - 6

Results and discussion

Toxicokinetic / pharmacokinetic studies

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

Toxicokinetic parameters:

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

Metabolite characterisation studies

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.

Applicant's summary and conclusion

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.