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Description of key information

LD50 for acute oral toxicity (male and female; rat): = 3313 mg/kg bw. LD50 acute dermal toxicity (male and female; rat): > 2000 mg/kg bw

 

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
Study period:
April 14, 1981 - May 18, 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(acclimation period)
Principles of method if other than guideline:
Animals fasted overnight were treated orally, with a single dose, by means of a stomach tube. Physical condition and rate of deaths were monitored throughout the whole 14 days observation period.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: PP 126/1
Species:
rat
Strain:
other: RAIf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 7 to 8 weeks
- Weight at study initiation: 171.6 g - 195.8 g
- Fasting period before study: overnight
- Housing: housed in groups of 5 in Macrolon cages (type 3), marked individually with picric acid
- Diet: NAFAG No. 890, NAFAG, Gossau SG; ad libitum
- Water: ad libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 20
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 12 /12
Route of administration:
oral: gavage
Vehicle:
other: distilled water containing 0.5 % carboxymethylcellulose + 0.1 % Tween 80
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw
Doses:
1000, 2500, 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: day 1, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50, including the 95 % confidence limits were calculated by the logit model.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 313 mg/kg bw
95% CL:
> 2 405 - < 5 333
Mortality:
- 2500 mg/kg bw: 1/5 females and 0/5 males died (24 h after treatment)
- 5000 mg/kg bw: 5/5 females died (1 h (1), 24 h (1) and 4 d (3) after treatment) and 4/5 males died (3 h (1), 24 h (2) 4 d (1) after treatment)
Clinical signs:
other: Exophthalmos, dyspnoea, ruffled fur and curved body position which are unspecific signs of toxicity in acute oral study mostly occurred transient. All surviving animals recovered latest on day 8. Sedation, diarrhoea and ventral body position was only seen
Gross pathology:
No compound related gross organ changes were observed.

Mean body weights (g):

Dose (mg/kg bw)

Males

Females

Day 1

Day 7

Day 14

Day 1

Day 7

Day 14

1000

180

227

268

164

187

205

2500

178

204

243

159

154

190

5000

190

-

-

162

-

-

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 of the test material in rats of both sexes observed over a period of 14 days is 3313 (2405-5333) mg/kg.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
3 313 mg/kg bw
Quality of whole database:
Study comparable to guideline.

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:
November 05, 2012 - December 06, 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
other: Japan MAFF 8147
GLP compliance:
yes (incl. QA statement)
Remarks:
Bioassay Labor für biologische Analytik GmbH, Im Neuenheimer Feld 515/519, 69120 Heidelberg
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, avoid temperature < 0°C
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks
- Weight at study initiation: males animals approx. 230 g, female animals approx. 212 g
- Housing: single housing in Makrolon cage, type III; bedding: H 15005-29; Ssniff, Spezialitäten GmbH (Experimental Animal Diets Inc., 59494 Soest, Germany); enrichment: NGM E-022; ABEDD® LAB & VET Service GmbH, Hasnerstraße 84/6; 1160 Wien – Austria
- Diet: VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: about 40 cm²
- % coverage: 10
- Type of wrap if used: air-permeable dressing (4 layers of absorbent gauze (Ph. Eur. supplied by Lohmann GmbH & Co., KG) and stretch bandage (Fixomull® Stretch (adhesive fleece) supplied by Beiersdorf AG)

REMOVAL OF TEST SUBSTANCE
- Washing: warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 2.11 mL/kg bw
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation. Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
- Necropsy of survivors performed: yes
- Other examinations performed: Scoring of skin findings: Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), several times until the last day of observation. The evaluation of skin reactions was performed according to Draize, J.H. (1959).
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
other: No systemic clinical signs were observed during clinical examination. Local effects: In all male animals well-defined erythema (grade 2) was noted on study day 1 and persisted in one animal until study day 3. In the other four animals moderate erythema
Gross pathology:
No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, the acute dermal median lethal dose (LD50) was determined to be greater than 2000 mg/kg bw,
Executive summary:

In an acute dermal toxicity study (Limit Test) following OECD guideline 402 and in compliance with GLP, young adult Wistar rats (5 males and 5 females) were dermally treated with a single dose of 2000 mg/kg bw of the undiluted test item to the clipped skin (dorsal and dorso-lateral parts of the trunk) and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days. No mortality occurred and no signs of systemic toxicity were observed. The following test item-related local effects were recorded during the course of the study: very slight to moderate erythema (grade 1 to 3), very slight to slight edema (grade 1 to 2), incrustations and scaling. The mean body weight of the animals increased within the normal range throughout the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study. Accordingly, the acute dermal median lethal dose (LD50) was determined to be > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Study comparable to guideline.

Additional information

Acute Oral Toxicity  

In a standard acute oral toxicity study performed similarly to OECD TG 401, groups (5 rats/sex/dose) of young RAIf rats were administered the test substance (no data on purity) after an overnight fasting period. The test substance was administered at doses of 1,000, 2,500 and 5,000 mg/kg bw in water containing 0.5% CMC and 0.1% Tween 80. Animals were subsequently observed for 14 days and clinical signs of toxicity, body weight changes and cases of mortality were noted. In the low dose group, no animal died. In the mid and high dose group 1/10 and 9/10 animals died, respectively. Hence the LD50 is 3,313 mg/kg bw. Besides unspecific signs of toxicity, sedation, diarrhoea and ventral body position was seen in the first 5 h after treatment. Tremor was only seen in the mid dose group at day 1. All surviving animals recovered latest on day 8. No compound related findings were observed during necropsy and changes in body weight were within the normal range.

Acute Dermal Toxicity  

In an acute dermal toxicity study (Limit Test) performed according to OECD guideline 402 and under GLP, young adult Wistar rats (5 males and 5 females) were dermally exposed to a single dose of 2000 mg/kg bw of the undiluted test substance to the clipped skin (dorsal and dorso-lateral parts of the trunk) and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days. No mortality occurred and no signs of systemic toxicity were observed. The following test item-related local effects were recorded during the course of the study: very slight to moderate erythema (grade 1 to 3), very slight to slight edema (grade 1 to 2), incrustations and scaling. The mean body weight of the animals increased within the normal range throughout the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study. Based on the results of this study, the acute dermal median lethal dose (LD50) was determined to be > 2000 mg/kg bw

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. LD50 for acute oral toxicity was greater than 2000 mg/kg bw. As a result the substance is not considered to be classified for acute toxicity under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/218.