Reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publication, meets generally accepted scientifically principles

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Data source

Reference

Reference Type:

publication

Title:

Inhibition of Metabolism of Diethylene Glycol Prevents Target Organ Toxicity in Rats

Author:

Lauren M. Besenhofer, Patrick A. Adegboyega, Michael Bartels, Mark J. Filary, Adam W. Perala, Marie C. McLaren and
Kenneth E. McMartin

Year:

2010

Bibliographic source:

TOXICOLOGICAL SCIENCES 117(1), 25–35 (2010)

Materials and methods

Objective of study:

other: metabolism and toxicity

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were treated by oral gavage with water, 2 g/kg bw DEG (low dose), 10 g/kg bw DEG (high dose), or 10 g/kg bw DEG + fomepizole, and blood and urine were collected over 48 h to investigate the mechanism for the acute toxicity of DEG, and the effect of the alcohol dehydrogenase inhibitor 4-methylpyrazole (fomepizole), by determining the relationship between accumulation of DEG or its metabolites and the resulting kidney and liver toxicity.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-oxydiethanol

EC Number:

203-872-2

EC Name:

2,2'-oxydiethanol

Cas Number:

111-46-6

Molecular formula:

C4H10O3

IUPAC Name:

2,2'-oxydiethanol

Test material form:

not specified

Details on test material:

- Supplier: Shell Chemicals
- Analytical purity: 99.78 %
- Impurities (identity and concentrations): EG (0.05 %), and triethylene glycol (0.08 %)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan, indianapolis, IN
- Age at study initiation: adult animals were used
- Weight at study initiation: 425–475 g
- Housing: in metabolic cages for 48 h for urine collection
- Individual metabolism cages: yes
- Diet: ad libitum: yes
- Water: ad libitum: yes


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

no data

Duration and frequency of treatment / exposure:

- DEG was administered once by oral gavage at time 0
- Fomepizole (15 mg/kg bw) was administered ip as a 10 mg/ml solution in saline at 15 min and then at 12, 24, and 36 h (10 mg/kg bw) for a total of four ip doses

Doses / concentrations

Remarks:

Doses / Concentrations:
- 2 g/kg bw or 10 g/kg bw DEG
- 10 g/kg bw DEG + Fomepizole (15 mg/kg bw)

No. of animals per sex per dose / concentration:

Six male rats per group

Control animals:

yes

Positive control reference chemical:

no

Details on study design:

The purpose of this study was to investigate the mechanism for the acute toxicity of DEG, and the effect of the alcohol dehydrogenase inhibitor 4-methylpyrazole (fomepizole), by determining the relationship between accumulation of DEG or its metabolites and the resulting kidney and liver toxicity.

Details on dosing and sampling:

- Urine was collected at 4, 8, 12, 24, 36, and 48 h over ice to minimize degradation of urinary metabolites
- Approximately 1 mL of blood was collected via the indwelling jugular catheter at 4, 8, 12, 24, 36, and 48 h into heparinized syringes

Statistics:

Differences between treatment groups and time points were assessed with two-way ANOVA with Bonferroni post-hoc test. To compare differences between treatment groups only, one-way ANOVA with Tukey post-hoc test was used. All analyses were performed using GraphPad Prism 5 for Windows. Tests were considered significant if p < 0.05.

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

After low and high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Small amounts of ethylene glycol (EG), but not oxalate or glycolate, were observed in the urine.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Not applicable

Any other information on results incl. tables

Rats treated with highdose DEG had metabolic acidosis, increased blood urea nitrogen and creatinine, and marked kidney necrosis, noted by histopathology. A minor degree of liver damage was noted at the high dose.

Treatment with fomepizole blocked the formation of HEAA and DGA and the development of metabolic acidosis and the kidney and liver toxicity.