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Administrative data

Description of key information

In acute oral toxicity study, mice (5/sex/dose) received orally 125, 250, 500, 1000 and 2000 mg/kg bw. One of five male and 3 of five females died within 2 hours after dosing. No mortality occurred among the lower dose groups and no other compound-related effects were observed. This data is in line with the harmonized classification of propyl gallate (Acute Tox 4, H302). Supporting information was presented in the review publications by EFSA, 2014 and by CIR, 2007. In both publications an oral LD50 of 1700 mg/kg bw was reported for mice, which further supports the harmonized classification.

 

In an acute dermal toxicity study (OECD 402) a group of young adults Wistar rats (5 /sex) were dermally exposed to propyl gallate for 24 hours to approximately 10% of body surface area at dose of 2000 mg/kg bw. Animals then were observed for 14 days. No mortality 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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
see box "Principles of method if other than guideline"
Principles of method if other than guideline:
Dose ranges are not given relative to body weight but in ppm.
GLP compliance:
not specified
Test type:
acute toxic class method
Test material information:
Composition 1
Specific details on test material used for the study:
TEST MATERIAL
- Name: Propyl gallate
- CAS no.: 121-79-9
- Batch: 2185
- Appearance: white, odorless powder, slightly bitter taste
- Purity: >98%
- Source: Harshaw Chemical Co. (Philadelphia, PA)
- Storage: dark, 5°C
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Center (Frederick MD)
- Number of animals per group: 5 female & 5 male
- Age at start of treatment: approx. 5 weeks
- Acclimatization: 8 days
- Housing: stainless steel cages, Hahn Roofing & Steel Metal Co. (Birmingham, AL); cages changed twice weekly
- Animals per cage: 5
- Diet: ad libitum, Wayne Lab Blox, Allied Mills inc., Chicago, IL
- Water: automatic watering system, Edstorm Industries (Waterford, WI)

ENVIRONMENTAL CONDITIONS
- Temperature: 21 - 23°C
- Humidity (%): (relative) 40 - 60%
- Photoperiod (hrs dark / hrs light): 12/12
- Air changes per hour: 15
Route of administration:
oral: gavage
Vehicle:
ethanol
Details on oral exposure:
Weighed amount of propyl gallate and a solution of 20% ethanol in distilled water with a plunger attached to a high-speed drill until a suspension was obtained.
Doses:
125, 250, 500, 1000, or 2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

OBSERVATION
- Weighing: at start of study, then weekly
- Mortality/Viability: there was five death out of five female & male animales in the 100,000 ppm and one male death out of five in the 50,000 ppm dose range.
- Clinical signs: twice daily for mortality
- Necropsy of survivors performed: yes, all animals were sacrificed
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
1/5 male and 3/5 female mice receiving 2000 mg/kg bw Propyl gallate died within 2 hours of dosing.
Clinical signs:
Survivors in 2000 mg/kg bw group were slightly inactive for 1 day after dosing.

One of five male and 3/5 female mice receiving 2,000 mg/kg body weight propyl gallate died within 2 hours of dosing; the survivors in this group were slightly inactive for 1 day after dosing. No death ocured among the 125, 250, 500, or 1,000 mg/kg bw groups, and no other compound-related effects were observed.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
One of five male and 3 of 5 female mice receiving 2000 mg/kg body weight propyl gallate died within 2 hours of dosing. The surviving animals in this group were slightly inactive for 1 day after dosing. No death occurred among the 125, 250, 500 or 1000 mg/kg bw dose groups. No other compound-related effects were observed.
Executive summary:

In a single dose acute toxicity study conducted similar to OECD Guideline 401, 5 male and 5 female mice received 125, 250, 500, 1000, or 2000 mg/kg body weight propyl gallate (98% purity).

The animals were observed for a total of 14 days. One of five male and 3 of 5 female mice receiving 2000 mg/kg body weight propyl gallate died within 2 hours of dosing. The surviving animals in this group were slightly inactive for 1 day after dosing. No death occurred among the 125, 250, 500, or 1000 mg/kg bw dose groups. Moreover, no other compound-related effects were observed. Based on the results, the LD50 can be considered to be greater than 1000, but lower than 2000 mg/kg bw in female mice.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Quality of whole database:
Comparable to guideline study

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
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
Reference:
Composition 0
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 information:
Composition 1
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.
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
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.
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.

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

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
GLP guideline study

Additional information

In acute oral toxicity study, mice (5/sex/dose) received orally 125, 250, 500, 1000 and 2000 mg/kg bw. One of five male and 3 of five females died within 2 hours after dosing. No mortality occurred among the lower dose groups and no other compound-related effects were observed. This data is in line with the harmonized classification of propyl gallate (Acute Tox 4, H302). Supporting information was presented in the review publications by EFSA, 2014 and by CIR, 2007. In both publications an oral LD50 of 1700 mg/kg bw was reported for mice, which further supports the harmonized classification.

 

In an acute dermal toxicity study (OECD 402) a group of young adults Wistar rats (5 /sex) were dermally exposed to propyl gallate for 24 hours to approximately 10% of body surface area at dose of 2000 mg/kg bw.  Animals then were observed for 14 days. No mortality 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.

Justification for classification or non-classification

Based on the available results and in line with the harmonized classification (Annex VI of CLP Regulation (EC) No 1272/2008), the test item propyl gallate is classification for acute oral toxicity (Acute Tox. 4, H302). No classification for acute dermal toxicity is necessary, as the LD50 in an acute dermal toxicity study (OECD 402) was considered to exceed 2000 mg/kg bw.