SILATRIZOLE

Endpoint summary

Description of key information

- Oral LD50 (Key study OECD 401, V1, 1996): > 2000 mg/kg bw in rats
- Dermal LD50 (Key study OECD 402, V1, 1996) > 2000 mg/kg bw in rats

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:

From 02 November 1995 to 29 April 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD Guideline 401 without any deviation.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

16-06-1994

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HanIbm: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories, Ltd. Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: 8 weeks old for males; 10 weeks old for females
- Weight at study initiation: 239.9-257.6 g for males; 196.0-212.3 g for females
- Fasting period before study: yes, overnight prior to application (approximately 16h)
- Housing: Groups of five rats in Makrolon type-4 cages with autoclaved standard softwood bedding ("Lignoce1", Scill AG, CH-4132 Muttenz).
- Diet (e.g. ad libitum): Pelleted standar Kliba 343, Batch no. 66/95 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad libitum (except for the overnight fasting period prior to application). Food was provided again approximately 3 hours after dosing.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, available ad libitum.
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 37-70 %
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12h dark/ 12h light

IN-LIFE DATES: From: 2 November 1995 To: 23 November 1995

Route of administration:

oral: gavage

Vehicle:

other: methylcellulose 4% + Tween 80R 1%

Details on oral exposure:

VEHICLE
- Concentration in vehicle: the test article was placed into a glass beaker on a tared Mettler PM 480 balance, and the vehicle (methylcellulose 4% + Tween 80R 1%) was added. A weight by volume dilution was prepared using a homogenizer (Ultra-Turrax, Janke & Kunkel, D-79219 Staufen). Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer (Janke&Kunkel, D-79219 Staufen). The preparation was made shortly before dosing.
- Amount of vehicle (if gavage): 10 ml/kg bw
- Justification for choice of vehicle: no data
- Purity: no data

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: reference control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality and viability were observed four times during test day 1 and daily during days 2-15, as well as clinical signs (changes in appearance and behaviour).
Body weights were measured on test day1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes; at the end of the observation period all animal were anesthetized by intraperitoneal injection of NARCOREN (Rhone Merieux GmBH, D-88471 Laupheim) at a dose of at least 2.0 ml/kg bw (equivalent to at least 320 mg sodium pentobarbitone/kg bw) and sacrificed by exsanguination. The animals were examined macroscopically and all abnormalities recorded.

Statistics:

None

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: No clinical signs of toxicity were observed during the observation period.

Gross pathology:

No organ abnormalities were observed at necropsy.

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the test conditions, the oral LD50 of the test item, Silatrizole (encoded "G4375"), was higher than 2000 mg/kg in rats and no mortality occurred at this concentration. Therefore Silatrizole should not be classified for acute oral toxicity according to the Regulation (EC) N° 1272-2008 (CLP) and the Directive 67/548/EEC.

Executive summary:

In an acute oral toxicity study, performed according to the OECD guideline No. 401, and GLP-compliant, groups of (HanIbm: WIST (SPF)) male and female rats (5 animals/sex/dose) were given a single oral dose (by gavage) of 2000 mg/kg bw of Silatrizole (encoded "G4375") . Clinical signs, mortality and body weight gain were checked for a period of up to 14 days.

 

There were no deaths as a result of treatment with the test article. No clinical signs of toxicity were observed during the observation period. The body weight of the animals was within the normal range for rats of this strain and age, when compared to the body weights from reference control. No organ abnormalities were observed at necropsy.

 

Oral LD50 in rats (male and female) > 2000 mg/kg bw.

 

Under the test conditions, Silatrizole  is not classified for Acute oral toxicity according to the criteria of the CLP regulation (EC) N°1272/2008.

 

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP-compliant and of high quality (Klimisch score = 1)

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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:

From 02 November 1995 to 30 January 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD Guideline 402 with some deviation: stability of the test article in the vehicle (acetone) is unknown

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Stability of the test article in the vehicle (acetone) is unknown

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

yes

Remarks:

Stability of the test article in the vehicle (acetone) is unknown

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

16-06-1994

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HanIbm: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories, Ltd. Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: 7 weeks old for males; 9 weeks old for females
- Weight at study initiation: 266.5-298.0 g for males; 228.2-247.3 g for females
- Housing:
During acclimatization: Groups of five rats in Makrolon type-4 cages with autoclaved standard softwood bedding ("Lignoce1", Scill AG, CH-4132 Muttenz).
During treatment and observation: individually in Makrolon type-3 cages with autoclaved standard softwood bedding.
- Diet (e.g. ad libitum): Pelleted standard Kliba 343, Batch no. 66/95 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad libitum.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, available ad libitum.
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 37-70 %
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12h dark/ 12h light

IN-LIFE DATES: From 02 November 1995 to 23 November 1995

Type of coverage:

semiocclusive

Vehicle:

acetone

Details on dermal exposure:

TEST SITE
- Area of exposure: Clipped backs of the animals
- % coverage: approximately10% of the total body surface.
- Type of wrap if used: semi-occlusive dressing wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Dressing was removed and the skin was washed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: 24h

TEST ITEM
- Constant volume or concentration used: no data
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 4.0 ml/kg bw
- Concentration (if solution): the test article was placed into a glass beaker on a tared Mettler PM 480 balance, and the vehicle (acetone) was added. A weight by volume dilution was prepared using a homogenizer (Ultra-Turrax, Janke & Kunkel, D-79219 Staufen). Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer (Janke&Kunkel, D-79219 Staufen). The preparation was made shortly before dosing.
- Purity: no data

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: reference control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality and viability were observed four times during test day 1 and daily during days 2-15, as well as clinical signs (changes in appearance and behavior with special emphasis on the application area, except for the time when the semi-occlusive dressing was in place).
Body weights were measured on test day1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes; at the end of the observation period all animal were anesthetized by intraperitoneal injection of NARCOREN (Rhone Merieux GmBH, D-88471 Laupheim) at a dose of at least 2.0 ml/kg bw (equivalent to at least 320 mg sodium pentobarbitone/kg bw) and sacrificed by exsanguination. The animals were examined macroscopically.

Statistics:

None

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study period

Clinical signs:

other: No clinical signs of systemic toxicity were observed during the observation period.

Gross pathology:

No findings were observed at necropsy

Other findings:

Skin reactions: no local effects of the test article on the skin at the application site were observed during the observation period

None

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the test conditions, the dermal LD50 of the test item, Silatrizole (encoded "G4375"), was higher than 2000 mg/kg in rats and no mortality occurred at this concentration. Therefore Silatrizole should not be classified for acute dermal toxicity according to the Regulation (EC) N° 1272-2008 (CLP) and the Directive 67/548/EEC.

Executive summary:

Silatrizole (encoded "G4375") was tested for acute dermal toxicity in (HanIbm: WIST (SPF)) male and female rats in a GLP-compliant limit dose assay according to OECD guideline 402. Groups of rats (5/sex) were administered a single dermal dose of undiluted test material at 2000 mg/kg bw on clipped skin (approximately 10 % of the total body surface area) using a semi-occlusive patch held in place for 24 h. Residual test item was removed at the end of the 24 h exposure period using lukewarm tap water and the application site was dried with disposable paper towels. Examinations for mortality, clinical signs, body weight gain and dermal reactions were performed during a 14-day observation period. All surviving animals were necropsied at the end of the observation period.

No deaths occurred during the observation period. No clinical signs of systemic toxicity were observed during the observation period. The body weight gain of the animals was within the normal range for rats of this strain and age, when compared to the body weights from reference control. A slight loss of body weight in one female animal during the first observation week was considered to be a consequence of the semi-occlusive dressing. Commonly female animals prove to be more sensitive in relation to the effects on body weight caused by semi-occlusive dressing than males. At necropsy, no findings were observed.

Dermal LD50 in rats (male and female) > 2000 mg/kg bw

No local effects of the test article on the skin at the application site were observed during the observation period.

Under the test conditions, Silatrizole should not be classified for acute dermal toxicity according to the Regulation (EC) N° 1272-2008 (CLP).

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP-compliant and of high quality (Klimisch score = 1)

Additional information

Oral:

In a GLP-compliant acute oral toxicity study performed in accordance with OECD guideline 401, no mortality was observed in HanIbm: WIST (SPF)) male and female rats given a single oral dose (gavage) of Silatrizole (encoded "G4375") at the limit test dose of 2000 mg/kg bw. Thus, Silatrizole oral LD50 is > 2000 mg/kg bw.

Dermal:

In a GLP-compliant acute dermal toxicity study performed in accordance with OECD guideline 402, no mortality was observed in HanIbm: WIST (SPF))male and female rats given a single dose of Silatrizole at the limit test dose of 2000 mg/kg bw. Thus, Silatrizole dermal LD50 is > 2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
Only one study available

Justification for selection of acute toxicity – inhalation endpoint
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. Based on the nature of the substance and the likely route of human exposure, the dermal route has been selected as the more likely route of exposure.

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

Under the test conditions, the oral LD50 of the test item, Silatrizole (encoded "G4375"), was higher than 2000 mg/kg in rats and no mortality occurred at this concentration. Therefore Silatrizole should not be classified for acute oral toxicity according to the Regulation (EC) N° 1272-2008 (CLP).

Under the test conditions, the dermal LD50 of the test item, Silatrizole, was higher than 2000 mg/kg in rats and no mortality occurred at this concentration. Therefore Silatrizole should not be classified for acute dermal toxicity according to the Regulation (EC) N° 1272-2008 (CLP).