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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Aug 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
Percutaneous absorption of the 14C-labelled test substance calculated from the amount of 14C eliminated already from the body (72 h after administration) plus the amount of 14C still being present in the carcass.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Thioglycolic acid (titrated with ammonia to give solutions of pH 6, 7 and 8)
- Physical state: liquid (slightly yellowish solution)
- Analytical purity: no data
- Purity test date: 15.07.1992 (radiochemical purity test date)
- Lot/batch No.: 2675-291
- Radiochemical purity (if radiolabelling): 97.55
- Specific activity (if radiolabelling): 0.149 mCi/mmol
- Stability under test conditions: unknown for the radioactive test substance, ca. 3 months for the inactive material accordinq to the sponsor, if stored in the deep freezer under nitrogen.
- Storage condition of test material: in the freezer at about -25 °C under nitroqen
- Labelling: 14C
- Preparation: synthesis by NEN, 549 Albany Street, Boston, USA
- Supplier: NEN-DU PONT WIEN, A-1020, Lasallestr. 2/20, Austria
Radiolabelling:
yes
Remarks:
14C-labelling

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Forschungsinstitut für Versuchstierzucht, A-2325 Himberg, Austria
- Age at study initiation: males ca. 6 - 7 weeks, females 9 - 10 weeks
- Weight at study initiation: approx. 200 g
- Fasting period before study:
- Housing: single caging. Metabolism cages (UNO B.V., Zevenaar,Holland)
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Altromin 1321ff, diet for rats, ad libitum
- Water (e.g. ad libitum): tap water in Makrolon bottles with stainless steel canules, ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): average of 23
- Humidity (%): average of 75
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
dermal
Vehicle:
other: A solution of 14C-thioglycolic acid was gradually neutralized with a 25 % solution of ammonia resulting in three final solutions of 11 % ammonium 14C-thioglycolate with pH 6, pH 7 and pH 8, respectively (concentration calculated as thioglycolic acid).
Details on exposure:
TEST SITE
- Area of exposure: 3x3 cm on the dorsal, median thoracic to lumbar area
- % coverage: 2.65% of body surface
- Type of wrap if used: After rinsing and neutralisation, the skin was covered with 4 layers of gauze fixed by adhesive tape. Additional covering by fixation of an air permeable, plastic, truncated cone to prevent licking of the treated area.
- Time intervals for shavings or clipplings: one day before application of the test substance


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The solution was rinsed off with water of about 37 °C. Then the skin was dabbed dry with absorbent cellulose tissue.
- Time after start of exposure: 30 min


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
Mean values
Study A: 0.295 g of the solution applied, corresponding to 32.5 mg of the test substance
Study B: 0.300 g of the solution applied, corresponding to 33.0 mg of the test substance
Study C: 0.304 g of the solution applied, corresponding to 33.4 mg of the test substance.
- concentration (if solution): 11% (w/w)
Duration and frequency of treatment / exposure:
30 min, one application
Doses / concentrations
Remarks:
Doses / Concentrations:
Mean values
Study A: 158 mg/kg bw
Study B: 164 mg/kg bw
Study C: 166 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Dose selection rationale: In humans a maximum of 75 ml of the 11 % test substance solution is applied to the hair. The scalp which has an estimated average surface of 500 cm2 is only reached by a small part of the solution estimated to be at most 1/10, corresponding to 0.015 ml per cm2.
In order to have reproducible conditions the fur of the rats was clipped, the test substance was therefore applied mainly on the skin. 0.3 ml were used on an area of 9 cm2, larger amounts of test substance solution would flow off during exposure time. The applied volume was with 0.033 ml per cm2 two times higher then in hunans which is a "worst case".
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, carcass, cage washes
- Time and frequency of sampling: daily
Statistics:
t-test was used for analysis of differences between the sexes and the studies. P = 0.05.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Study A: 0.27% of the applied dose
Study B: 0.24% of the applied dose
Study C: 0.26% of the applied dose
Details on excretion:
Urine: 76.5 - 80.3% of the eliminated 14C
Faeces: 19.7 - 23.5% of the eliminated 14C

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

No pH dependence of the results was detectable.
The majority of the applied 14C was removed from the skin by rinsing after the actual exposure and after the neutralization 

step (means of  96.1 to 96.8 % of the applied dose).
The mean 14C-content of the skin at the site of application was 0.82 %,  0.57 % and 0.60 % (study A, B and C, respectively) of the administered 14C-amount.
Means of 0.139 %, 0.119 % and 0.137 % of the applied 14C were recovered  in urine and faeces within 72 hours. 14C was 

excreted to a larger extent via urine (means 79 %, 76 % and 80 % of the eliminated amounts). The mean excretion was fast:

92 %, 83 % and 93 % of the totally eliminated amounts were excreted in the first 24 hours after application.
The remaining mean amounts of 14C in the carcass 3 days after the  application were 0.126 %, 0.116 % and 0.121 % of the 

administered  14C-amount. This corresponds to 46.7 %, 48.3 % and 46.5 % of the absorbed 14C-amount.
The red foci that appeared in the application site of several animals of all pH groups did not have a distinct influence on the 

absorption.
In the three studies the cutaneous absorption as well as the 14C-concentration found in urine, faeces and carcass were 

higher in males than in females without gaining statistical significance.
Means of 97 % to 97.9 % of the applied 14C-doses were recovered in the various types of samples in the three studies.
From these results the mean absorption was calculated to be 0.27 %, 0.24  % and 0.26 % of the applied dose.

Applicant's summary and conclusion