Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-01-05 to 2017-04-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

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
Test material form:
solid: particulate/powder
Details on test material:
- Source and lot/batch No.of test material: 201601004
- Expiration date of the lot/batch: 01.01.2019
- Purity: 99.93 %
- Storage condition of test material: room temperature
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
Test item was used as deliverd by the sponsor. In order to ensure good skin contact, it was moistened with the vehicle.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: males: 9-10 weeks old, females 12-13 weeks old
- Weight at study initiation: males: 233-259 g, females: 214-227 g
- Fasting period before study:
- Housing: The animals were kept individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Free access to Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): Free access to tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- Acclimation period: Adequate acclimatisation period (at least five days) under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): relative humidity of 55 ± 10%
- Air changes (per hr): 10 air changes per hour
- Photoperiod (hrs dark / hrs light): Artificial light, sequence being 12 hours light, 12 hours dark

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
other: Aqua ad injectionem
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 10% of the total body surface.
- % coverage: approximately 10% of the total body surface.
- Type of wrap if used: The test item was held in contact with the skin by a dressing throughout a 24-hour period. This consisted of a semi-occlusive dressing made of a porous gauze and non-irritating tape and was fixed with an additional dressing in a suitable manner.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, the residual test item will be removed by using water or another appropriate solvent if practicable.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): single dose of 2000 mg/kg body weight.
- For solids, paste formed: yes

VEHICLE
- Lot/batch no. (if required):AlleMan Pharma, Lot. No. 605070, expiry date 2019-04-30
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were weighed on day 1 (prior to the application), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed:
- clinical signs: several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose), and once daily thereafter, until the end of the observation period. Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- histopathology: In absence of gross pathological changes no tissues were preserved for a possible histopathological evaluation.
- primary skin irritation: Signs of erythema and oedema were assessed using the scoring system (Table 1 in "Any other information on material and methods") laid down in OECD Guideline 404.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortality occurred
Clinical signs:
No specific findings were determined
Body weight:
A slight weight loss was recorded for 3 out of 5 female animals during the first week, but all of the female animals showed weight gain during the second week. The effects on weight development might be secondary to the dressing, and toxicological relevance of this finding cannot clearly be concluded.
The male animals showed weight gain during the first and the second week of the observation.
The individual data is presented in Table 2 (Any other information on results)
Gross pathology:
No specific gross pathological changes were recorded for any animal.

Any other information on results incl. tables

Table 2: Absolute Body Weights in g and Body Weight Gain in %.

Test Group Animal No. Dose (mg/kg bw) Body Weight (g) on Day BW gain in Comparison to Day 1 (%)
1 8 15
Males 21 2000 245 269 299 22
22 2000 255 290 326 28
23 2000 259 292 335 29
24 2000 245 270 308 26
25 2000 233 252 275 18
Females 26 2000 214 227 240 12
27 2000 224 223 236 5
28 2000 216 213 210 -3
29 2000 227 223 234 3
30 2000 214 220 237 11

bw = body weight

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of Propyl gallate in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

In an acute dermal toxicity study (OECD 402, limit test), a group of young adult Wistar rats (5 males and 5 females) were dermally exposed to Propyl gallate (purity 99%) moistened with Aqua ad injectionem for 24 hours to approximately 10% of body surface area at doses of  2000 mg/kg bw.  Animals then were observed for 14 days. No mortality and neither signs of toxicity nor signs of irritation occurred. The dermal LD50 value of Propyl gallate in Wistar rats was established to exceed 2000 mg/kg body weight.

Propyl gallate is of low toxicity based on the results of this study and does therefore not warrant for classification according to CLP criteria.