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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 Nov 2012 to 11 Feb 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Objective of study:
other: hydrolysis in digestive fluid simulants
Test guideline
Qualifier:
according to
Guideline:
other: EFSA Note for Guidance for Food Contact Materials Annex 1 to Chapter III MEASUREMENT OF HYDROLYSIS OF PLASTICS MONOMERS AND ADDITIVES IN DIGESTIVE FLUID SIMULANTS (30 Jul 2008)
Deviations:
no
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
other: The source of the digestive fluid was not specified in the study report.
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Not applicable.

Administration / exposure

Route of administration:
other: mixing
Vehicle:
other: acetonitrile
Details on exposure:
For the hydrolysis investigation the ester was dissolved in acetonitrile. This solution was added to the intestinal-fluid simulant tempered to 37°C. The concentration of acetonitrile in the reaction mixture was about 0.1%. Samples were taken after 0, 1, 2 and 4 hours. A naphthalene solution in acetone was added as an internal standard to the samples and the enzyme was precipitated by the addition of ice-cold acetone. After filtration the acetone was evaporated. The aqueous solution was acidified with 0.1 M hydrochloric acid (pH 1.2) and extracted three times with dichloromethane. After addition of an alkane standard (tridecane) and derivatization with N-Methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) at 60°C for one hour the concentrated dichloromethane solution was analysed by gas chromatography coupled with a mass spectrometer (GC/MS). Quantification of the ester and the hydrolysis product was performed specifically by external calibration curves.
Duration and frequency of treatment / exposure:
0, 1, 2 and 4 hours
Doses / concentrations
Dose / conc.:
28.43 ppm
No. of animals per sex per dose:
Not applicable.
The analysis was performed in triplicate.
Control animals:
no
Details on dosing and sampling:
A duplicate of three different concentrations of the alcohol was performed. For the recovery investigations the alcohol was dissolved in acetonitrile. This solution was added to the intestinal-fluid simulant tempered to 37°C. After 4 hours a naphthalene solution in acetone was added as an internal standard to the samples and the enzyme was precipitated by the addition of ice-cold acetone. Work-up and quantification was performed as already described. For the ester Bis-(2-(2-butoxyethoxy)-ethyl)-adipate the recovery was performed also from water as of the quick decrease of the ester in the enzyme solution. Therefore the stock solution of the ester in acetonitrile was added to water, work-up and quantification was done as already described.

Results and discussion

Main ADME resultsopen allclose all
Type:
other: Hydrolysis of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate with intestinal-fluid simulant
Results:
sampling time 0 h: 28.43 ppm (100%) Ester, 0 ppm Alcohol
Type:
other: Hydrolysis of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate with intestinal-fluid simulant
Results:
sampling time 1 h: 0.77 ppm (2.72%) Ester, 14.74 ppm Alcohol
Type:
other: Hydrolysis of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate with intestinal-fluid simulant
Results:
sampling time 2 h: 0.75 ppm (2.63%) Ester, 16.11 ppm Alcohol
Type:
other: Hydrolysis of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate with intestinal-fluid simulant
Results:
sampling time 4 h: 0.72 ppm (2.55%) Ester, 15.01 ppm Alcohol

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:
The alcohol being released during the hydrolysis reaction is Diethylene glycol mono-n-butyl ether, CAS 112-34-5, MW=162.23 g/mol. Per 1 equivalent ester 2 equivalents alcohol are released.

Any other information on results incl. tables

Table. 1: Quantitative results of the hydrolysis reaction analysis

Contact time

Ester

Alcohol

[h]

[ppm]

[%]

[ppm]

0

28.43

100.00

0.00

1

0.77

2.72

14.74

2

0.75

2.63

16.11

4

0.72

2.55

15.01

Table. 2: Mass balance of the ester hydrolysis reaction

Contact time

Ester

Alcohol

[h]

[µmol]

[µmol] calc.

[µmol] exp.

0

0.327

0.000

0.000

1

0.009

0.636

0.545

2

0.009

0.637

0.596

4

0.008

0.638

0.555

* One ester reacts to two alcohols

Table. 3: Results of the recovery experiment

Ester (from pancreatic medium)

Ester (from water)*

Alcohol (from pancreatic medium)

[ppm]

calc.

[ppm]

exp.

Recovery

[%]

[ppm]

calc.

[ppm]

exp.

Recovery

[%]

[ppm]

calc.

[ppm]

exp.

Recovery

[%]

28.43

0.80

2.81

12.88

13.64

105.9

8.71

7.23

83.0

-

-

-

27.60

30.26

109.6

19.36

17.24

89.0

-

-

-

46.00

48.02

104.4

33.88

31.28

92.3

* As of the quick decrease of the ester in the enzyme solution recovery was performed also from pure water

Conclusion:

The result of the pancreatic digestion of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate shows a decrease of about 97% within 1 hour (recovery experiments indicate a far quicker hydrolysis). No further decrease was measured. The mass balance of this reaction is shown in the Table 2; it displays good congruence of expected and measured values.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: ≥ 97% of Bis-(2-(2-butoxyethoxy)-ethyl)-adipate is hydrolysed in digestive fluid simulants within 1 hour.