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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
To follow the in vivo hydrolysis of the parent compound to its constituent alcohol to establish a hydrolysis half life and to subsequently follow the disappearance of the metabolite (ethoxypropanol) to establish a half life for the latter.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
Batch number : 16AC0082-L3 - 01/09/2016
99.2% (sum of isomers)
Ethoxypropyl acetate (S): 97.5%
Ethoxypropyl acetate (P): 1.7%
Specific details on test material used for the study:
Storage conditions : ambient temperature (15-25 ºC, protected from light)
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Laboratory rats were selected as a standard for rodent species. The strain chosen was also used in earlier toxicological studies.
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany.
- Age at study initiation: 9 weeks
- Weight at study initiation: 338-368g
- Housing: Macrolon cages with wood shavings as bedding, maximum 5 rats per cage.
- Diet (ad libitum): commercial rodent diet (SDS, Special Diet Services, Witham, England)
- Water (ad libitum): tap-water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): >45%
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 10 May 2017 and 16 May 2017 (reserve animal) for 1 day.

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
Dosing solutions prepared in physiological saline solution the day prior to application. Dosing by injection in tail vein at 3mL/kgbw
Duration and frequency of treatment / exposure:
Single treatment
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
After dose administration, blood samples were collected in K2-EDTA-coated Microvettes (Sarstedt) vials at 2, 5, 10, 15, 20 and 30 minutes, and 1, 2, 4, 8 and 24 hours post-dose. Samples stored on dry ice prior to analysis.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 47 minutes
Remarks:
Results for rate of hydrolysis using pooled data from high dose group animals. Correlation coefficient R=0.99. Note that the authors of the study report cited a figure of 45mins which is slightly but not singificantly different.
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: 21 mins
Remarks:
Results for rate of hydrolysis using pooled data from high dose group animals. Correlation coefficient R=0.80. Note that the authors of the study report cited a figure of 18 mins which is slightly but not singificantly different.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
no further metabolites examined.

Any other information on results incl. tables

In most cases, blood levels did not fall below the limit of quantification until around 2 -4 hours after dosing.

One animal died between 2 and 4 hours post-dose, however the data before this time point was considered valid and used in the calculations of the half-life value and mean residence time. Due to issues with the data on PGEEA, one additional animal received low dose treatment so that a total of 5 animals were available for calculating the results.

The measured concentrations of the hydrolysis product ethoxypropanol were much higher than the parent and dosed compound ethoxypropyl acetate. The highest detected concentration in any animal was 3.9mg/L at 2 minutes compared to 95mg/L for ethoxypropanol (again at 2 minutes, although the peak was much flatter for this substance.)

Applicant's summary and conclusion

Executive summary:

An in vivo study was carried out to determine the toxicokinetic parameters of propylene glycol ethyl ether acetate following intravenous dosing to male Sprague-Dawley rats and its metabolite propylene glycol ethyl ether. In addition, the toxicokinetic parameters of propylene glycol ethyl ether were determined. The test substance was dosed iv at dose levels of 10 and 100 mg.kg-1 body weight with analysis of the blood samples by GC-MS analysis using a method developed and validated in terms of selectivity, calibration, accuracy/recovery, repeatability and limit of quantification. The PGEEA data in blood showed a rapid decline. The half-life of the resultant metabolite PGEE in blood for the low and high dose group was ~21 and 47 minutes, respectively in the low and high dose animals.