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Description of key information

- LD50 acute oral toxicity (male and female; rat): = 3313 mg/kg bw (Ciba Geigy Ltd.; reliability score: 2)
- LD50 acute dermal toxicity (male and female; rat): > 2000 mg/kg bw (Bioassay, reliability score: 1)

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:
other: Comparable to guideline study with acceptable restrictions (incomplete characterization of test substance, e.g. no data on substance purity), no GLP
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
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.
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:
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 in the first 5 h after treatment. Tremor was only seen on day 1 in dose group 2500 mg/kg bw.
Body weight:
Body weight changes were within the normal range.
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:
not classified
Remarks:
Migrated information
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

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:
other: GLP compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment.
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
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).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
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 (grade 3) was noticed on study day 2 and 3.
Slight erythema (grade 1) was observed on study day 6 in four animals and persisted in 3 males until study day 7.
Slight edema (grade 2) was noted in all males on study day 1; decreased to very slight edema (grade 1) and was noted from study day 2 up to study day 3 in four animals and up to study day 6 in the fifth animal.
On study day 3 incrustations were observed in all animals. This finding persisted in one animal until study day 7, in another one until study day 8 and in a third one up to study day 14.
Scaling was noticed in all male animals on study day 3. In two animals this finding persisted until study day 9 or 14, respectively.

In all female animals well-defined erythema (grade 2) was noted on study day 1 and increased on study day 2 and 3 to moderate erythema (grade 3). Thereafter well-defined erythema (grade 2) was noted in two out of five animals at study day 6, which decreased to very slight erythema (grade 1) on study day 7. Two other animals revealed very slight erythema (grade 1) on study day 6 and 7, while the last animal showed very slight erythema (grade 1) on study day 6 only.
Slight edema (grade 2) was noted in all females on study day 1 after administration and persisted in three of these animals until study day 3. In two of these three animals very slight edema (grade 1) was noted on study day 6. In the two remaining animals very slight edema was noted from study day 2 up to day 3.
Incrustations were observed in two animals on study day 3 and persisted in one animal until study day 7.
Scaling was observed in all females on study day 3 up to study day 7 and persisted in three animals until study day 8, 9 or 14, respectively.
Body weight:
The mean body weight of the animals increased within the normal range throughout the study period.
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:
practically nontoxic
Remarks:
Migrated information
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

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 (Ciba Geigy Ltd. 1981).

This study is suitable for assessment of acute oral toxicity as it was performed using a protocol which is similar and equivalent to the deleted OECD guideline (401).

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 (Bioassay, 2012). 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 selection of acute toxicity – oral endpoint
Study comparable to guideline.

Justification for selection of acute toxicity – dermal endpoint
Study comparable to guideline.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data are considered reliable and suitable for the purpose of classification. Based on the criteria for classification of Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC, classification for acute toxicity is not warranted.

 

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

The available experimental test data are reliable and suitable for the purpose of classification. Based on the criteria laid down in Regulation (EC) No. 1272/2008, as amended for the 2nd time in Directive EC 286/2011, classification for acute toxicity is not warranted.