1-o-tolylbiguanide

Endpoint summary

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:

weight of evidence

Study period:

Single dose

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

Performed to acute toxic class method, but only with males
Some mortality at the single dose tested.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: Charles River (UK) Ltd, Margate, Kent
- Age at study initiation: five to eight weeks old
- Weight at study initiation: At the start of the main study the males weighed 143 to 172g, and the females 131 to 149g
- Fasting period before study:
- Housing: Solid-floor polypropylene cages furnished with woodflakes.
- Diet: Rat & Mouse Expanded Diet no. 1, Special Diets Services Limites, witham, Essex, UK
- Water: Free access to mains drinking water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 24
- Humidity (%): 46 - 63
- Air changes (per hr): 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours darkness.

Route of administration:

oral: gavage

Doses:

- dosed once by gavage using a metal cannula attached to a graduated syringe

No. of animals per sex per dose:

5 fasted male were given a single dose

Dose descriptor:

LD50

Effect level:

2 390 mg/kg bw

Mortality:

Deaths were noted one or two days after dosing

Clinical signs:

other: Ataxia, hunched posture and increased salivation with additonal signs or incidents of lethargy, ptosis, decreased respiratory rate, laboured respiration, red/brown stains around the eyes, mouth or snout and toptoe gait. Surviving animals recovered four t

Other findings:

Necropsy: Common abnormalities noted at necropsy of animals that died during the study were haemorrhage or pallor of the gastric mucosa. Slight haemorrhage of the large and/or small intestines was also noted at necropsy of animals treated with 2000 mg/kg that died during the study. Additonal abnormalities noted at necropsy of one male treated with 2000 mg/kg that died during the study were haemorrhage of the non-glandular epithelium of the stomach and slight haemorrhage of the bladder. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) and 95% confidence limits of the test material, CASAMINE OTB, in the Sprague-Dawley CD strain rat were calculated by a probit method of Finney D J to be:

Males only: 2390 (1446 - 3950 mg/kg/bodyweight)
No symbol and risk phrase required.

Test material was given evaluation number 1 according to the German Water Hazard Classification Scheme.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 390 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

other:

Reason / purpose for cross-reference:

data waiving: supporting information

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

a)Compound and formulation

TK 11786 was suspended with carboxymethyl-cellulose 2 %. Before treatment the suspension was homogeneously dispersed with an Ultra-Turrax and during treatment it was kept stable with a magnetic stirrer.

b)Animals

Healthy random bred rats of the Tif RAIf (SPF) strain raised on our premises were used for these experiments. They were kept at a room temperature of 22 + 1° C, at a relative humidity of 55 + 5 % and on a 14 hours light cycle day. They received ad libitum rat food - NAFAG, Gossau SG - and water. Prior to treatment the animals were adapted to our laboratories for a minimum of 4 days and the initial body weight ranged from 180 to 200 grams. 


c) Treatment* and observations

During the treatment and observation period the rats were housed individually in Macrolon cages (type 2). Approximately 2 4 hours before treatment an area on the back of the rats of approximately 60 square cm was shaved with an electric clipper, For treatment the substance was evenly dispersed on the skin with a syringe and was covered with an occlusive dressing which was fastened around the trunk with an adhesive elastic bandage. After 24 hours the dressing was removed, the skin was cleaned with lukewarm water and the reaction of the skin was appraised.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 180-200 g
- Housing: housed individually in metal cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): constant room temperature of 18 +/- 1° C
- Humidity (%): 55 +/- 5 %
- Photoperiod (hrs dark / hrs light): 10 hours dark / 14 hours light

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

TEST SITE
- Area of exposure: 60 cm2
- % coverage: ~25%
- Type of wrap if used: covered with an occlusive dressing which was fastened around the trunk with an adhesive elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The dressing was removed and the skin was cleaned with lukewarm water
- Time after start of exposure: After 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2150mg/kg .: ~0.4g // 2780mg/kg .: ~0.5g // 3170 mg/kg .: ~0.6g
- Concentration (if solution): 50%

Duration of exposure:

24 hours

Doses:

single application, 3 concentrations.
2150 mg/kg
2780 mg/kg
3170 mg/kg

No. of animals per sex per dose:

3 male, 3 female per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: obs. at 1hr , 24hrs , 48 hrs, 7d and 14d.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 100 mg/kg bw

Based on:

test mat.

Other findings:

Within 24 hours after treatment the rats in all dosage groups showed dyspnoea, exophthalmus, curved position and ruffled fur. Three to six days after treatment a severe erythema developed into necrosis.
The surviving animals recovered from systemic symptoms within 8 to 13 days. They were submitted to a necropsy whenever they died, survivors on day 14.
No substance related gross organ changes were seen

Dose (mg/kg)	Concentration % of formulation	Number of Animals		Died within
				1 hour		24 hours		48 hours		7 days		14 days
		♂	♀	♂	♀	♂	♀	♂	♀	♂	♀	♂	♀
2150	50	3	3	0	0	0	0	0	0	0	0	0	0
2780	50	3	3	0	0	0	0	0	0	0	0	0	0
3170	50	3	3	0	0	0	0	0	0	1	0	1	0
No higher doses were possible

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 > 3170mg/kg bw .: not classified under CLP

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 170 mg/kg bw

Additional information

Justification for selection of acute toxicity – inhalation endpoint

nnex VIII, section 8.5.2, of the REACH Regulation states “Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.” The particle size of OTB has been demonstrated to have a median particle size of , which, being relatively large, is likely to make the risk of inhalation relatively unlikely.

Annex VIII, section 8.5.2, of the REACH Regulation states “Testing by the dermal route is appropriate if: (1) inhalation of the substance is unlikely…” As an acute dermal toxicity study has already been completed (giving a result of LD50 > 2500mg/kg), the acute inhalation study is demonstrated to be unnecessary.