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Toxicological information

Basic toxicokinetics

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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: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
metabolism
toxicokinetics
Principles of method if other than guideline:
Evaluation of the systemic exposure and to determine the main pharmacokinetic parameters of free Hexylene glycol, and its potential metabolites, 4 Hydroxy-4-Methyl-2-Pentanone (HMP), methylisobutylketone (MIBK) and methylisobutylcarbinol (MIBC) after single oral administration to male Sprague Dawley rats
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name: Hexylene glycol
- Batch number: A1TX6K010101
- Expiry date: 22 July 2010
- Description: colorless solution
- Purity: 99.95%
- Storage conditions: at room temperature, protected from humidity and heat in a dry, cool and well-ventilated place.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, l’Arbresle, France
- Age at study initiation: 9 to 10 weeks old
- Weight at study initiation: 292 g (range: 284 g to 297 g)
- Fasting period before study: at least 14 hours before dose administration
- Housing: in threes, in suspended wire-mesh cages
- Individual metabolism cages: no
- Diet (ad libitum): pellets SSNIFF R/M-H (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water (ad libitum): filtered tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 50 ± 20
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was administered as a suspension in corn oil. Specifically, 2.9497 g of test item was mixed with 9.1998 g of vehicle. The dosage form was prepared by slowly adding the test item to the vehicle, at room temperature, under continuous stirring. The quantity of test item used for dosage form preparation was calculated, taking into consideration the molecular weight.

The dosage form suspension was continually stirred until use.
The test item dosage form was prepared on the day of treatment and was stored at room temperature and protected from light prior to use.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 295 mg/ml
- Amount of vehicle (if gavage): 2 ml/kg
Duration and frequency of treatment / exposure:
Single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
590 mg/kg (5 mmol/kg)
No. of animals per sex per dose:
9
Control animals:
no
Details on study design:
- Dose selection rationale: The dose-level selected was consistent with a previous pharmacokinetics probe study (CIT/Study No. 20991 PAR) using methylisobutylketone and methylisobutylcarbinol, and a NOAEL of 450 mg/kg bw/day for hexylene glycol, identified in a 90-day oral subchronic toxicity study (CIT/ Study No. 15837 TCR).
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling:. 0.5, 1, 1.5, 3, 4.5, 6, 9, 12 and 24 hours post gavage
- From how many animals: 3 per time point
- Method type for identification: GC-FID
- Limits of quantification: < 0.500 mg/mL

TREATMENT FOR CLEAVAGE OF CONJUGATES : no

Results and discussion

Main ADME resultsopen allclose all
Type:
other: Toxicokinetics
Results:
free-HG was quantifiable from 0.5 to 6 hours after gavage. The mean plasma conc. increased to a maximum of 0.833 mg/mL at 1.5 hours after administration and then decreased in an essentially monophasic manner. AUC0-t (from 0 to 6 hours) was 3.86 mg.h/mL
Type:
metabolism
Results:
The plasma concentrations of the potential metabolites HMP, MIBK and MIBC were below the limit of quantification of: 0.5 mg/mL.

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
Cmax: 0.833 mg/ml
Toxicokinetic parameters:
other: Clast: 0.641 mg/ml
Toxicokinetic parameters:
Tmax: 1.5 h
Toxicokinetic parameters:
half-life 1st: 21.2 h
Toxicokinetic parameters:
AUC: 3.86 mg.h/mL

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Mortality, morbidity and clinical signs

No deaths, morbidity or clinical signs occurred during the study.

       

Body weight

On the day of treatment the mean body weight ± standard deviation was 292 g ± 4.4 g (range between 284 g and 297 g).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Hexylene glycol was well tolerated following a single oral administration at 590 mg/kg to male Sprague-Dawley rats. Plasma concentrations of free Hexylene glycol were quantifiable from 0.5 to 6 hours after dose administration. The AUC0-t value was 3.86 mg.h/mL, and the Cmax value of 0.833 mg/mL was reached at 1.5 hours after gavage. No plasma metabolite (HMP, MIBK and MIBC) concentrations were identified with a limit of quantification of 0.5 mg/mL.
Executive summary:

The objective of this study was to evaluate the systemic exposure and to determine the main pharmacokinetic parameters of free hexylene glycol (HG), and its potential metabolites, 4-hydroxy-4-Methyl-2-Pentanone (HMP), methylisobutylketone (MIBK) and methylisobutylcarbinol (MIBC) after single oral administration to male Sprague-Dawley rats.

Nine Sprague-Dawley rats received 590 mg/kg bw of HG as a suspension in corn oil by the oral route (gavage) on a single occasion.

Blood samples for the determination of plasma levels of free HG, HMP, MIBK and MIBC were taken at 0.5, 1, 1.5, 3, 4.5, 6, 9, 12 and 24-hour post-gavage. For the blood sampling, the animals were divided into three sampling sets (each containing three animals) and each animal was sampled three times in total and sacrificed after its last blood sampling occasion. During the study period, the animals were observed at least twice daily for morbidity, mortality and clinical signs.

No death or morbidity occurred during the study and no clinical signs were observed. The main pharmacokinetic (PK) parameters of free HG after a single oral (gavage) administration of HG at the dose-level of 590 mg/kg to male Sprague-Dawley rats are :

PK parameters

t1/2

tmax

Cmax

Clast

tlast

AUC0-t

AUCextrapolated

Units

h

h

mg/mL

mg/mL

h

mg.h/mL

%

Results

21.2

1.5

0.833

0.641

6

3.86

84

The mean plasma concentrations increased to a maximum of 0.833 mg/mL at 1.5 hours after administration and then decreased until 6 hours after administration in an essentially monophasic manner. The terminal half-life calculated was long (higher than 6 hours), but this value should be interpreted with caution due to the high percentage of extrapolation in the AUC calculation(> 80%) and no conclusion can be drawn on the elimination behavior of the test item. The plasma concentrations of the potential metabolites, HMP, MIBK and MIBC were below the limits of quantification of 0.5 mg/mL.