Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
29 Aug - 30 Nov 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (no data on GLP and analytical purity, no hydrolysis test in saliva and gastric juice simulants performed, limited details in reporting).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
other: hydrolysis in intestinal fluid simulant
Test guideline
Qualifier:
equivalent or similar 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
Deviations:
yes
Remarks:
no hydrolysis test in saliva and gastric juice simulants; limited details in reporting
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2,2-dimethyl-1,3-propandiolheptanoate
- Analytical purity: no data
Radiolabelling:
no

Test animals

Species:
other: not specified; presumably pig in accordance with the test method used
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST DIGESTIVE SIMULANTS
INTESTINAL FLUID SIMULANT
- Description: intestinal fluid simulant according to “Note of Guidance for Food Contact Materials”, no further details given.

Administration / exposure

Route of administration:
other: mixing
Vehicle:
other: acetonitrile
Details on exposure:
HYDROLYSIS WITH INTESTINAL-FLUID SIMULANT:
For the hydrolysis investigation, the esters were dissolved in acetonitrile. These solutions were 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 h.
Duration and frequency of treatment / exposure:
0, 1, 2 and 4 h
Doses / concentrations
Remarks:
Doses / Concentrations:
22.77 ppm
No. of animals per sex per dose:
not applicable, the test was performed in triplicates
Control animals:
other: not applicable
Details on dosing and sampling:
DETERMINATION OF HYDROLYSIS PRODUCTS
- Principle: following incubation, a naphthalene solution (solved in acetone) was added as an internal standard to the samples. Afterwards, the enzymes were precipitated by the addition of ice-cold acetone. After filtration the acetone was evaporated. The aqueous solutions were acidified with 0.1 M hydrochloric acid (pH 1.2) and were extracted 3 times with dichloromethane. After addition of an alkane standard (tridecane) and derivatisation with N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) at 60°C for 1 h the concentrated dichloromethane solutions were analysed by gas chromatography coupled with a mass spectrometer (GC/MS). Quantification of the esters and the hydrolysis products was performed specifically by external calibration curves.
- Recovery assays: a duplicate of 3 different concentrations of the acid (hydrolysis product) were performed. For the recovery investigations the acid was dissolved in acetonitrile. These solutions were added to the intestinal-fluid simulant tempered to 37°C. After 4 h 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 described above.
Recovery of the ester was determined using a hydrolysis sample analogue to the "0 hour" assay.
Statistics:
Mean values of triplicates were calculated.

Results and discussion

Main ADME results
Type:
other: ester hydrolysis in intestinal fluid simulant
Results:
85.7, 86.1 and 89.4% after 1, 2 and 4 h, respectively

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:
Quantification of the parent substance 2,2-dimethyl-1,3-propandiolheptanoate after hydrolysis in intestinal-fluid simulant after 0, 1, 2 and 4 h hydrolysis, respectively:
22.77, 3.26, 3.17 and 2.41 ppm corresponding to 100, 14.3, 13.9 and 10.6% of the initial test concentration. Thus, 2,2-dimethyl-1,3-propandiolheptanoate was hydrolysed to nearly 90% after pancreatic digestion for 4 h.

Quantification of the free fatty acid after hydrolysis in intestinal-fluid simulant after 0, 1, 2 and 4 h hydrolysis, respectively:
0, 15.72, 15.86 and 17.06 ppm

Any other information on results incl. tables

Table 1. Hydrolysis of 2,2 -dimethyl-1,3-propandiolheptanoate with intestinal-fluid simulant

Contact time (h)

Results

Ester (ppm)

Ester (%)

Acid (ppm)

0

22.77

100.0

0.000

1

3.26

14.3

15.72

2

3.17

13.9

15.86

4

2.41

10.6

17.06

Table 2. Mass balance of the ester hydrolysis

Contact time (h)

Results

Ester (µmol)

Acid (µmol) (calc.)

Acid (µmol) (exp.)

0

0.347

0.000

0.000

1

0.050

0.594

0.604

2

0.048

0.597

0.609

4

0.037

0.620

0.655

Table 3. Recoveries of ester and acid

Analyte

Results

ppm (calc.)

ppm (exp.)

Recovery (%)

Ester

(from pancreatic medium)

22.77

5.43

23.9

Ester

(from water)

13.90

13.12

94.4

30.88

31.29

101.3

46.32

51.52

111.2

Acid

(from pancreatic medium)

12.82

9.28

72.4

28.48

23.18

81.4

49.84

36.19

72.6

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results