Producto P0310

Endpoint summary

Description of key information

Oral: Key study: OECD guideline 423 and EU method B.1 tris. GLP study.

The oral LD50 (female) is greater than 2000 mg/kg bw.

Dermal: Key study: OECD guideline 402 and EU method B.3. GLP study.

The dermal LD50 is greater than 2000 mg/kg bw.

Inhalation: Route to route extrapolation:  4-h LC50 would be greater than 10 mg/l.

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

(Directive 2004/73/EC)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Test system Rat, HanRcc:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Fasting period before study: The animals received a single dose of the test item by oral gavage after being fasted for approximately 18 to 19 hours
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse mainte-nance diet, batch no. 67/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum.
- Acclimation period: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30-70 %
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): automatically controlled light cycle of 12 hours light and 12 hours dark,

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:
The dosing volume was 10 mL/kg body weight.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

Number of animals per group 3 females
Total number of animals 6 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: All animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived until the end of the study period.

Clinical signs:

A slightly ruffled fur was noted in all animals on the day of treatment starting 1 or 2 hours after dosing. This persisted up to the 3- and 5-hour reading in two animals, respectively, and up to test day 2 in four animals. Five animals expressed a hunched posture starting at the 1-hour reading in three animals and the 2-hour reading in two animals. This was present until the 3-hour reading in one animal and the 5-hour reading in four animals, respectively.

Body weight:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

No macroscopic findings were recorded at necropsy.

Interpretation of results:

GHS criteria not met

Remarks:

CLP Implementation.

Conclusions:

The oral LD50 (female rat) is greater than 2000 mg/kg body weight

Executive summary:

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test substance by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (purified water) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. A slightly ruffled fur was noted in all animals on the day of treatment starting 1 or 2 hours after dosing. This persisted up to the 3- and 5-hour reading in two animals, respectively, and up to test day 2 in four animals. Five animals expressed a hunched posture starting at the 1-hour reading in three animals and the 2-hour reading in two animals. This was present until the 3-hour reading in one animal and the 5-hour reading in four animals, respectively. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. The oral LD50 (female rat) is greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has a Klimisch score 1.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

other: extrapolation from results obtained by the oral route

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.

Principles of method if other than guideline:

Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.

Test type:

other: extrapolation

Key result

Sex:

not specified

Dose descriptor:

LC50

Effect level:

> 10 mg/L air

Exp. duration:

4 h

Based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals, an extrapolation based on the acute oral toxicity data is calculated for the inhalation route.

From the available data on the acute oral toxicity data, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw. As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 100% of an orally administered dose is systemically available. Since no data is available on inhalation absorption, the most precautionary default would be to assume 100% absorption by this route.

Based on this acute oral toxicity data, an oral NOAEL may be identified as greater than 2000 mg/kg bw. This NOAEL can be modified into an inhalation NOAEL using a route-to-route extrapolation based on the assumptions stated above. Taking into account an exposure of 4 hours for the acute inhalation toxicity study, the value of 2000 mg/kg bw is divided by the default physiological parameter under the allometric scaling principle which is approximately 0.2 m3/kg bw for rats. This extrapolation leads to a value of 10000 mg/m3 (10 mg/l). Therefore, the 4 -h LC50 would be greater than 10 mg/l (dust/particles inhalation).

Interpretation of results:

GHS criteria not met

Remarks:

CLP Implementation.

Conclusions:

Based on the assumptions for the extrapolation from the acute oral toxicity data, the inhalation 4-h LC50 would be greater than 10 mg/l.

Executive summary:

Based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals, an extrapolation based on the acute oral toxicity data is calculated for the inhalation route.

From the available data on the acute oral toxicity data, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw. As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 100% of an orally administered dose is systemically available. Since no data is available on inhalation absorption, the most precautionary default would be to assume 100% absorption by this route.

Based on this acute oral toxicity data, an oral NOAEL may be identified as greater than 2000 mg/kg bw. This NOAEL can be modified into an inhalation NOAEL using a route-to-route extrapolation based on the assumptions stated above. Taking into account an exposure of 4 hours for the acute inhalation toxicity study, the value of 2000 mg/kg bw is divided by the default physiological parameter under the allometric scaling principle which is approximately 0.2 m3/kg bw for rats. This extrapolation leads to a value of 10000 mg/m3 (10 mg/l). Therefore, the 4 -h LC50 would be greater than 10 mg/l (dust/particles inhalation).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

10 mg/m³

Quality of whole database:

Extrapolation (Klimish =2) from results obtained in a GLP compliant study with Klimish =1 conducted by the oral route.

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Rat, HanRcc:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: Males: 8 weeks; Females: 11 weeks
- Housing: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observation.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse mainte-nance diet, batch no. 67/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) ad libitum.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum.
- Acclimation period: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30-70 %
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): automatically controlled light cycle of 12 hours light and 12 hours dark

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: One day before treatment, the backs of the animals were clipped with an electric clipper.
- % coverage: 10 % of the total body surface.
- Type of wrap if used: The test item was applied with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL
- Preparation: The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The formulation was prepared shortly before the application using a magnetic stirrer, a spatula and an Ultra-Turrax.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
Local signs: Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: All animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

No clinical signs of toxicity were noted during the course of the study.

Body weight:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

At the scheduled necropsy one male was observed with enlarged kidneys. Otherwise, there were no macroscopic findings in the animals.

Other findings:

- Local effects: At removal of the application patch, two animals expressed a slight erythema which was present at that observation, only.

Interpretation of results:

GHS criteria not met

Remarks:

CLP Implementation.

Conclusions:

The dermal LD50 (rat) is greater than 2000 mg/kg body weight

Executive summary:

Five male and five female HanRcc:WIST (SPF) rats were treated with the test item at 2000 mg/kg by dermal application. The test item was diluted in vehicle (purified water) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. No deaths occurred during the study. No clinical signs of toxicity were noted during the course of the study. At removal of the application patch, two animals expressed a slight erythema which was present at that observation, only. The body weight of the animals was within the range commonly recorded for this strain and age. At the scheduled necropsy one male was observed with enlarged kidneys. Otherwise, there were no macroscopic findings in the animals. The dermal LD50 (rat) is greater than 2000 mg/kg body weight

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has a Klimisch score 1.

Additional information

Oral: Key study: OECD guideline 423 and EU method B.1 tris. GLP study.

The oral LD50 (female) is greater than 2000 mg/kg bw.

Dermal: Key study: OECD guideline 402 and EU method B.3. GLP study.

The dermal LD50 is greater than 2000 mg/kg bw.

Inhalation: Route to route extrapolation: 4-h LC50 would be greater than 10 mg/l.

Justification for classification or non-classification

Based on the available information, the substance is not classified for acute toxicity in accordance to CLP Regulation (EC) 1272/2008.