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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:
weight of evidence
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A non GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data.

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the Dermal Subchronic Toxicity of Phenoxyethyl Isobutyrate in the Rat
Author:
Api AM
Year:
2004
Bibliographic source:
Food and Chemical Toxicology 42 (2004) 307-311

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption, distribution and elimination of the test material was investigated by dosing rats topically with radiolabelled test material formulated in diethyl phthalate at three nominal concentrations; 1000, 100 and 10 mg/kg bw. Doses were applied to the skin on gauze squares which were held in place by semi-occlusive dressing. The gauze squares and dressings were removed at 6 hours post dose and the dose area washed with diethyl phthalate. Urine, faeces and expired air were collected for 72 hours after dosing and at 72 hours post dose blood, selected tissues and the remaining carcasses were analysed for radioactivity.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid (undefined)
Details on test material:
- Name of test material (as cited in study report): 2-[ring U 14C]-phenoxyethyl isobutyrate (PEIB).
- Physical state: colourless liquid.
- Specific activity: 4.5 µCi/mg
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: Crl: CD(SD)
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent
- Age at study initiation: Approximately 9 weeks old.
- Housing: Animals were housing individually after exposure.
- Individual metabolism cages: Yes.

Administration / exposure

Route of administration:
dermal
Vehicle:
other: Diethyl phthalate
Details on exposure:
TEST SITE
- Preparation of test site: The application site was shaved with animal clippers 24 hours prior to application of the test material.
- Area of exposure: The test material was applied to the backs of the animals. The test material was applied to foil backed gauze squares approximately 4 x 4 cm in size.
- Type of cover / wrap if used: The test material was applied to the skin using gauze squares backed with aluminium foil, the gauze was held in place with a semi occlusive dressing (50 mm Micropore 3M and Blenderm tape 3M).

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: Test sites were washed with diethyl phthalate.
- Time after start of exposure: 6 hours.

TEST MATERIAL
- Concentration: 0.5, 5 and 50 %

VEHICLE
- Amount(s) applied (volume or weight with unit): Dose volume 2 mL/kg bw.
Duration and frequency of treatment / exposure:
6 hours.
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 100 and 1000 mg/kg bw.
No. of animals per sex per dose:
Four per dose.
Control animals:
no
Details on study design:
- Dose selection rationale: Dose selections were conservatively based on the estimated human skin exposure from use of multiple cosmetic products (0.07 mg/kg/day) and the average maximum concentration applied to the skin in fragrance products (1.4%).
Details on dosing and sampling:
SAMPLE COLLECTION
- Analysis of organs: Tissue samples were collected from the liver, kidneys, gastrointestinal tract, treated skin and non-treated skin. The remaining carcass was retained for total radioactivity analysis.

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled urine, faeces, cage wash, blood, expired air, liver, kidneys, gastrointestinal tract, treated skin and non-treated skin. The remaining carcass was retained for total radioactivity analysis.
- Time and frequency of sampling:
Collection of blood: 72 hour after dosing, blood was collected from the vena cava.
Collection of urine: Sampling intervals as follows; 0-6, 6-24, 24-48 and 48-72 hours.
Collected of faeces: Sampling intervals as follows; 0-24, 24-48 and 48-72 hours.
Collection of expired air: Sampling intervals as follows; 0-24, 24-48 and 48-72 hours.
Animals were sacrificed as 72 hours and necropsied.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Approximately 30% of the test material was absorbed
Type:
distribution
Results:
Approximately 04-0.7% of the absorbed test material was retained in the animal body 72 h after dosing.
Type:
distribution
Results:
Low levels of radioactivity also measured in the liver, kidney and gastrointestinal tract (approximately 0.01–0.03 %).
Type:
distribution
Results:
Plasma levels increased in a dose-related manner, with concentrations from 0.02, 0.2, and 2.0 µg equiv/mL from low to high dose, respectively.
Type:
excretion
Results:
The majority of the absorbed test material was elminated via the urine (approximately 18-19 %)
Type:
excretion
Results:
Small amounts of the test material (approximately 0.3-0.8 %) was eliminated via the faeces
Type:
excretion
Results:
0.01 to 0.61 % of the administered dose was recovered from the cage air, indicating that the 14C-label was either exhaled or volatilised from the skin.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Around 30% of the test material applied was absorbed. The test material had a steady rate of dermal penetration over 72 hours, approximately 23-27% (calculated from the amount of radioactivity found in urine, faeces, tissues, carcass and washed, treated skin).
Details on distribution in tissues:
The absorbed test material in the body after 72 hours was 0.4-0.7% with low levels in the liver, kidneys and gastrointestinal tract. (approximately 0.01-0.03%). Around 2-7% of the radioactivity was present in the skin where the test material had been applied. 18-37% of this remained even after washing indicating that the residual label was bound to the skin.
Details on excretion:
Most of the absorbed test material was eliminated in the urine (approximately 18-19%) with a small amount in the faeces. Faecal excretion was postulated to result from biliary excretion (after dermal absorption) into the gastrointestinal tract.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1. Recovery of Total Radioactivity Following Topical Administration of the Test Material

Area of Recovery

Interval (hours)

10 mg/kg

Total Recovery

100 mg/kg

Total Recovery

1000 mg/kg

Total Recovery

Urine

0-6

1.21

 

2.09

 

2.8

 

0-24

8.17

 

9.16

 

10.66

 

0-48

14.45

 

15.35

 

16.65

 

72 total

 

18.09

 

19.34

 

19.49

Faeces

0-24

0.14

 

0.22

 

0.16

 

0-48

0.28

 

0.28

 

0.25

 

72 total

 

0.34

 

0.41

 

0.84

Cage Wash

72 total

 

1.97

 

1.35

 

0.91

Cage Air

72 total

 

0.61

 

0.30

 

0.01

Treated Skin

72 total

 

4.66

 

7.05

 

1.72

Untreated Skin

72 total

 

0.62

 

0.64

 

0.28

Tissue:

 

 

 

 

 

 

 

Kidney

 

0.01

 

0.00

 

0.00

 

Liver

 

0.01

 

0.01

 

0.01

 

GI Tract

 

0.03

 

0.03

 

0.03

 

 Tissues total

72 total

 

0.05

 

0.04

 

0.04

Carcass

72 total

 

0.44

 

0.35

 

0.72

Dressing

6

 

54.98

 

56.60

 

59.34

Skin Wash

6

 

6.32

 

5.63

 

10.11

Gloves

72 total

 

4.18

 

3.93

 

2.76

Total

72 total

 

92.23

 

95.62

 

96.22

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The results from the dermal ADME study clearly indicate that the 14C-label from the test material was about 30% absorbed. Additionally the study indicated that the 14C-label had steady dermal penetration over 72 h that totalled 23–27% of the administered dose. This range was calculated from the amount of radioactivity found in urine, faeces, tissues, carcass and washed, treated skin. Most of the absorbed radiolabel was eliminated in the urine (approximately18–19% of administered dose) with a small amount being excreted in faeces (approximately 0.3–0.8%). The faecal excretion may be due to dermal absorption followed by biliary excretion into the gastrointestinal tract.

The absorbed test material that was retained in the animal body 72 h after dosing was approximately 0.4–0.7%, with low levels of radioactivity also measured in the liver, kidney and gastrointestinal tract (approximately 0.01–0.03%). Larger amounts of radioactivity (approximately 2–7%) were still present on the dosed area of the skin at study termination. Even after the dosed area was washed to remove any ‘free’ 14C-labeled material, 18–37% of the 14C-label remained. This residual label appeared to be bound to the skin.
Executive summary:

The absorption, distribution and elimination of the test material was investigated by dosing rats topically with radio labelled test material formulated in diethyl phthalate at 3 concentrations; 50, 5 and 0.5%. These concentrations were equivalent to dose levels of approximately 1000, 100 and 10 mg/kg bw. Doses were applied to the skin on gauze squares which were held in place by semi-occlusive dressing. The gauze squares and dressings were removed at 6 hours post dose and the dose area washed with diethyl phthalate. Urine, faeces and expired air were collected for 72 hours after dosing and at 72 hours post dose blood, selected tissues and the remaining carcasses were analysed.

Under the conditions of the test, the results clearly indicate that the 14C-label from the test material was approximately 30% absorbed. Additionally the study indicated that the 14C-label had steady dermal penetration over 72 h that totalled 23–27% of the administered dose. This range was calculated from the amount of radioactivity found in urine, faeces, tissues, carcass and washed, treated skin. Most of the absorbed radiolabel was eliminated in the urine (approximately18–19% of administered dose) with a small amount being excreted in faeces (approximately 0.3–0.8%). The faecal excretion may be due to dermal absorption followed by biliary excretion into the gastrointestinal tract.

The absorbed test material that was retained in the animal body 72 h after dosing was approximately 0.4–0.7%, with low levels of radioactivity also measured in the liver, kidney and gastrointestinal tract (approximately 0.01–0.03%). Larger amounts of radioactivity (approximately 2–7% dose) were still present on the dosed area of the skin at study termination. Even after the dosed area was washed to remove any ‘free’ 14C-labeled material, 18–37% of the 14C-label remained. This residual label appeared to be bound to the skin.