2-methylpentane-2,4-diol

Basic toxicokinetics

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. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

2-methylpentane-2,4-diol

EC Number:

203-489-0

EC Name:

2-methylpentane-2,4-diol

Cas Number:

107-41-5

Molecular formula:

C6H14O2

IUPAC Name:

2-methylpentane-2,4-diol

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 or test system 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 / concentration:

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 results

Main ADME results 1

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

Main ADME results 2

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 parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Cmax: 0.833 mg/ml

Toxicokinetic parameters 2

Toxicokinetic parameters:

other: Clast: 0.641 mg/ml

Toxicokinetic parameters 3

Toxicokinetic parameters:

Tmax: 1.5 h

Toxicokinetic parameters 4

Toxicokinetic parameters:

half-life 1st: 21.2 h

Toxicokinetic parameters 5

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).

Table 1: DETERMINATION OF HEXYLENE GLYCOL IN PLASMA (mg/mL) ON DAYS 1 FOLLOWING ORAL ADMINISTRATION (590 mg/kg) OF THE TEST ITEM TO SPRAGUE DAWLEY RATS

Period	Sex	Animal	Sampling time (h)
		number	0,5	1	1,5	3	4,5	6	9	12	24
		U20501	BLQ			0,642			BLQ
		U20502	0,643			0,760			BLQ
		U20503	0,763			0,717			BLQ
		U20504		0,722			0,728			BLQ
Day 1	Male	U20505		0,628			0,690			BLQ
		U20506		BLQ			0,655			BLQ
		U20507			0,824			0,670			BLQ
		U20508			0,854			0,674			BLQ
		U20509			0,821			0,580			BLQ

BLQ: Below limit of quantification (< 0.500 mg/mL)

Applicant's summary and conclusion

Conclusions:

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.