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Toxicological information

Exposure related observations in humans: other data

Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
14 March 1995 to 25 May 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Experimental information for endocrine activity discussion.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Type of study / information:
Thyroid function after dermal absorption
Endpoint addressed:
basic toxicokinetics
dermal absorption
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
- Principle of test: The test item was topically applied on humans in a multiple dose study to determine the effects of the test item on the thyroid.
- Short description of test conditions: Topical applications of a 6% test item or placebo water in oil emulsion was applied twice daily to human for 14 days in parallel groups. Blood samples were taken for analysis of thyroid function.
- Parameters analysed / observed: Serum samples were assayed for TBG, TSH, FT4, FT3, T4 and T3.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Method

Ethical approval:
confirmed, but no further information available
Details on study design:
- Dose rationale: Approximate whole body dose of approximately 600 mg/day and the maximum allowable concentration within the EU for the test item, according to the EEC Cosmetics Directive.
- Test subjects: Healthy male and female volunteers between 18 and 40 years old (mean age: 27.8 for males, 27.7 for females). Smokers were encouraged to maintain their normal smoking habit. Subjects taking contraceptives were noted and the contraceptive method was recorded. The protocol limited the amount of paracetamol administration. All meals were standardised and controlled and alcohol was restricted completely 48 hours before the start of the test throughout the entire study period.
- Sampling: Blood samples were taken prior to the morning dose or at the corresponding time on Days 1, 4, 7, 12, 14, 16 and 21.
- Analysis: Serum samples were assayed for TSH, FT4, FT3, T4 and T3 using commercially available diagnostic kits. Thyroid volumes were calculated using Brunn's formula from ultrasound data. Blood samples were also analysed for haemotology, serum biochemistry and pregnancy (females only), and urine was analysed for drugs of abuse (alcohol, cannabinoids, amphetamines and benzodiazepines).
- Statistical methods: Repeated measures ANOVA using pre-dose day 1 values as a covariate, significance assessed at 5%.
Exposure assessment:
measured
Remarks:
91.91% of the weighed dose was applied
Details on exposure:
TYPE OF EXPOSURE: Dermal (600 cm2 on the dorsal surface and 600 cm2 on the ventral surface of the body). Treated skin areas were left uncovered for 4 hours after each application. Residues were wiped off with a paper towel 4 hours after the first daily dose. All participants showered for at least 5 minutes after the second daily dose.

TYPE OF EXPOSURE MEASUREMENT: Biomonitoring blood

EXPOSURE LEVELS: 6% water in oil emulsion, corresponding to 5 g test item.

EXPOSURE PERIOD: Test item was applied twice daily for 14 days. T4 has the longest serum half-life (7 days) of all the thyroid hormones assessed in this study, therefore any test item effects should be observed by Day 10 of the study at the latest.

POSTEXPOSURE PERIOD: 7 to 8 days after the last dose of the study

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: Parallel groups of humans (n = 24) were given the test item or control

Results and discussion

Results:
The test item was well-tolerated in the dose and application regime. The water in oil emulsion was well and rapidly absorbed and the skin was not greasy to the touch within 1 hour of application.

There were no statistically significant differences between the test item and placebo for any of the thyroid function measurements (TSH, FT4, FT3, T4, T3 and TBG). Gender, smoking and the use of hormonal contraceptives had no effect on any of the thyroid function measurements. The total thyroid volume for the test item treatment was statistically lower compared to the placebo, however post-study volumes were not statistically significant from pre-test volumes for both treatments. Thyroid volume is likely of little clinical relevance when considered together with the thyroid hormone determinations and the limitations of the accuracy of the method used.

Any other information on results incl. tables

Table 1. Summary of results

 Treatment  Test item  Placebo
 Number of subjects with adverse events  14  13
 Total adverse events (a)  18  18
 Possibly related to study medication  5  4
 - Rash  2  0
 - Burning sensation on abdomen  1  0
 - Pins and needles and itching on back  1  0
 - Headache  1  2
 - Vomiting  0  1
 - Itchy macular rash  0  1
 Non-assessable  4  3
 - Dysmenorrhoea  2  0
 - Backache  1  0
 - Constipation  1  0
 - Sore throat  0  2
 - Headache  0  1
 Not related  2  5
 - Maculo-papular rash  1  0
 - Headache  1  2
 - Toothache  0  1
 - Laceration to left thigh  0  1
 - Left shoulder pain  0  1
 Remote  7  6
 - Headache  4  4
 - Itchy papular rash - left shin  1  0
 - Back pain and chest pain  1  0
 - Diarrhoea  1  0
 - Stomach ache  0  1
 - Tickle in throat  0  1

(a) Multiple statements per subject were possible.

Applicant's summary and conclusion

Conclusions:
The test item was well-tolerated in the dose and application regime. There were no statistically significant differences between the test item and placebo for any of the thyroid function measurements (TSH, FT4, FT3, T4, T3 and TBG). Gender, smoking and the use of hormonal contraceptives had no effect on any of the thyroid function measurements. The total thyroid volume for the test item treatment was statistically lower compared to the placebo, however post-study volumes were not statistically significant from pre-test volumes for both treatments. Thyroid volume is likely of little clinical relevance when considered together with the thyroid hormone determinations and the limitations of the accuracy of the method used.
Executive summary:

The test item was topically applied on humans in a multiple dose study to determine the effects of the test item on the thyroid. A 6% test item (maximum allowable concentration in the EU) or placebo water in oil emulsion was applied twice daily to healthy male and female volunteers for 14 days in parallel groups. Treatments were applied on 600 cm2 area on the dorsal surface and 600 cm2 area on the ventral surface of the body and left uncovered for 4 hours after every dose. Blood samples were taken for analysis of thyroid function (TBG, TSH, FT4, FT3, T4 and T3) on days 1, 4, 7, 12, 14, 16 and 21 and thyroid volume was estimated pre-study and post-study using ultrasound data. The test item was well-tolerated in the dose and application regime. There were no statistically significant differences between the test item and placebo for any of the thyroid function measurements (TSH, FT4, FT3, T4, T3 and TBG). Gender, smoking and the use of hormonal contraceptives had no effect on any of the thyroid function measurements. The total thyroid volume for the test item treatment was statistically lower compared to the placebo, however post-study volumes were not statistically significant from pre-test volumes for both treatments. Thyroid volume is likely of little clinical relevance when considered together with the thyroid hormone determinations and the limitations of the accuracy of the method used. This study is considered to be reliable with restriction (Klimisch 2) as it is a non-standard study, however it was well-designed and adequately reported.