Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 October 1994 to 20 October 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and extant test guidelines without deviation

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): PTH-Decahydroamid

- Physical state: colourles to pale yellow solid
- Analytical purity: 99.8% (GC method)
- Impurities (identity and concentrations): No data
- Composition of test material, percentage of components: No data

- Purity test date: no data
- Lot/batch No.: 25927
- Expiration date of the lot/batch: 30 June 1995

- Stability under test conditions: Stable
- Storage condition of test material: room temperature in the dark
- Other: stable in selected vehicle, 1% aq. carboxymethyl cellulose for at least 48 hours. Homogeneity confirmed visually prior to administration

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL Ltd, Basel, Switzerland. Outbred, SPF albino Wistar rats
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 210-223g males and 176-184g females
- Fasting period before study: Not applicable
- Housing:individual polycarbonate cages with sawdust bedding
- Diet (e.g. ad libitum): Kliba 343 supplied by Klingentalmuhle AG - a standard pelleted laboratory rodent diet
- Water (e.g. ad libitum): ad libitum access to tap water
- Acclimation period: at least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): circa 21°C
- Humidity (%): RH of 50%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12h/12h

IN-LIFE DATES: From: 6 October 1994 To:20 October 1994

Administration / exposure

Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Details on dermal exposure:
TEST SITE
- Area of exposure: 5 x5 cm for males and 3.5 x 3.5 cm for females approximating to circa 10% of body surface
- % coverage:circa 10% of body surface
- Type of wrap if used: gauze patch covered by aluminium foil and secured by adhesive flexible Coban bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): tap water used to rinse off residual test material after dressing removal
- Time after start of exposure:24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw in dose volume of 10 ml/kg bw
- Concentration (if solution):20%; 200 mg/ml
- Constant volume or concentration used: yes
- For solids, paste formed: no, solid dissolved/suspended in vehicle

VEHICLE
- Amount(s) applied (volume or weight with unit):10 ml/kg bw 1% aq, carboxymethyl cellulose (CMC)
- Concentration (if solution):1% aq, carboxymethyl cellulose (CMC)
- Lot/batch no. (if required):no data
- Purity:no data
Duration of exposure:
24 hours under an occlusive dressing
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Five males and five females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Twice daily checks for mortality/viability; weights recorded on Days 1,8 and 15 or at death
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs - assessed frequently on day 1 and once daily to day 15; body weights - recorded on Days 1, 8 and 15;macroscopic pathology at termination
Statistics:
Not required for limit test evaluation.

Results and discussion

Preliminary study:
Not applicable
Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks:
mortality among males treated at the limit dose did not exceed the 50% threshold that would indicate a median lethal dose level should be evaluated
Remarks on result:
other: two of five males died but the combined mortality at the limit dose was only 20%
Mortality:
Two males died approximately 1 hour after application. No specific ante-mortem signs were recorded and no macroscopic abnormalities were indicated during necropsy of the decedents.
Clinical signs:
The three surviving males and two of the five females were lethargic on days 1 and/or 2 but had recovered by day 3 in all cases.
Dermal reactions were assessed and two of the females developed erythema, scabs and/or desquamation during the observation period, although no details are available to attribute these reactions directly to an effect of treatment with PTH-decahydroamide.
Body weight:
Bodyweight gains during the first week following application were considered low for one male and two females but acceptable for the remaining rats. All surviving rats gained weight during the second week.
Gross pathology:
No macroscopic abnormalities revealed during necropsy of the decedents or rats surviving to day 15.
Other findings:
Dermal reactions were assessed and two of the females developed erythema, scabs and/or desquamation during the observation period, although no details are available to attribute these reactions directly to an effect of treatment with PTH-decahydroamide. The onset of the response was Day 5 and very slight erythema persisted to Day 15 for one female.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The dermal LD50 is greater than 2000 mg/kg bw in male and female rats.
The study was compliant with OECD and EC test methods. Although two males died approximately one hour after application, the median lethal dose for males and females separately or based on combined sexes results was greater than the limit dose level.
Executive summary:

Following test guideline compliant dermal application of PTH-decahydroamide for 24 hours, at 2000 mg/kg bw, to a group of five male and five female Wistar rats, two of the males died within an hour of completion of the topical exposure. Other effects noted included lethargy for several males and females on days 1 and/or 2; erythema, scabs and desquamation for one or two females from Day 5 and erythematous reactions persisting to termination for one female. Low bodyweight gains were recorded for several rats in the first week but gains were normal during the second observation week. Necropsy of the decedents and the rats surviving to Day 15 revealed no macroscopic abnormalities. The median lethal dermal dose in both sexes exceeded 2000 mg/kg bw and consequently PTH-Decahydroamide does not require classification for dermal toxicity according to the criteria laid out in Commission Regulation (EC) No. 1272/2008.