Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study meets scientific standards with acceptable restrictions (22 glycols tested, partly limited documentation, e.g. no details about test substance & method; no data about other routes of excretion; only 24-h urine analysed).

Data source

Reference
Reference Type:
publication
Title:
Studies in detoxication. 80. The metabolism of glycols
Author:
Gessner PK, Parke DV, Williams RT
Year:
1960
Bibliographic source:
Biochem J 74: 1-5

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Excretion of the unlabelled test substance and their metabolites via the urine measured in rabbits after gavage.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test substance was presented by G.A.H. Buttle and E.E. Connolly of The Distillers Co. Ltd . (Chemical Division), Hull. Boiling points and melting points were
checked with the literature.
No further data available.
Radiolabelling:
no

Test animals

Species:
rabbit
Strain:
Chinchilla
Sex:
not specified
Details on test animals and environmental conditions:
Body weight: 2-3 kg; rabbits kept on a constant diet of 60 g of rat cubes (diet 41; Associated London Flour Millers) and 100 ml of water per day.
No further data available.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Totally 8 g test substance were given to 4 rabbits.
Duration and frequency of treatment / exposure:
single application
Doses / concentrations
Remarks:
Doses / Concentrations:
Each rabbit gavaged with 1-1.5 g/kg bw (no further data).
No data were given on application volume and concentration.
In the Table on page 3 the authors mentioned a dose of 2 mmole/kg bw which is in contrast to the text on page 2 (8 g test substance were given to 4 rabbits).
No. of animals per sex per dose:
4 rabbits (sex unknown) received the above mentioned dose.
Control animals:
no
Positive control:
no
Details on study design:
No further details
Details on dosing and sampling:
The 24-h urine of the four rabbits (pooled data) brought to pH 10.0 with NH3 solution and then continuously extracted with ether for 6 h; evaporation of the
extract and sublimation of the residue. The residual urine brought to pH 4.0 with HCl and again continuously extracted with ether for 6 hr; evaporation of the extract gave an acidic gum which partly crystallized on keeping at 0°C for a week. Repeated crystallization of this material from ethanol/ether mixtures.
Statistics:
No data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
62% (range 53-67%) of the applied dose was found in the 24-h urine as the conjugate of glucuronic acid indicating rapid absorption after oral application.
Details on distribution in tissues:
No data
Details on excretion:
Beside the glucuronic acid conjugate (62% of applied dose) also the unchanged test substance was found but only 56 mg or 0.7 % of the applied dose (8000 mg); 150 mg of the metabolite 3-hydroxy-2,2-dimethylpropionic acid were detected (1.9% of applied dose).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
- glucuronic acid conjugate of neopentyl glycol (62% in 24-h urine)
- 3-hydroxy-2,2-dimethylpropionic acid (1.9%)
- unchanged neopentyl glycol (0.7%)

Any other information on results incl. tables

No further data were presented in the result section.

Applicant's summary and conclusion

Conclusions:
Rapid absorption of the test substance followed by conjugation with glucuronic acid and excretion via urine.
Executive summary:

The study meets scientific standards with accepatable restrictions (22 glycols tested, partly limited documentation, e.g. no details about test substance & method; no data about other routes of excretion; only 24-h urine analysed).

Each of 4 rabbits were gavaged with 1000 -1500 mg/kg bw unlabelled neopentyl glycol and excretion of the test substance and their metabolites via urine was determined the following 24 h (pooled data). 62% (range 53-67%) of the applied dose was found in the 24-h urine as the conjugate of glucuronic acid indicating rapid absorption after oral application. 1.9% of the applied dose was excreted as 3-hydroxy-2,2-dimethylpropionic acid and 0.7% as unchanged neopentyl glycol.

Conclusion: Rapid absorption of the test substance followed by conjugation with glucuronic acid and excretion via urine.