2-(3,5-dimethylhex-3-en-2-yloxy)-2-methylpropyl cyclopropanecarboxylate

Endpoint summary

Description of key information

Oral

Oral LD50 > 2000 mg/kg bw (OECD 423, K, Rel.1)

Inhalation

Not required

Dermal

Dermal LD50 > 2000 mg/kg bw (OECD 402, K, Rel.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:

From 22 May To 11 August, 2008.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study conducted in compliance with OECD Guideline No. 423 without any deviation.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

December 2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

adopted 17 December 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

29 April 2004

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Remarks:

Swiss legislation on Good Laboratory Practice (signed in September 04, 2008)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

- Storage conditions: In the refrigerator at +2 to +8°C, protected from light

Species:

rat

Strain:

other: HanRCC: WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 184-202 g
- Fasting period before study: Animals were fasted approximately 18 to 19 hours (access to water was permitted) prior to incubation of the test substance by gavage, and 3 hours after the dosing.
- Housing: Animals were housed in groups of 3 in Makrolon type-4 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz)
- Diet: Pelleted standard Provimi Kliba 3433 rat maintenance diet, batch number 21/08 (Provimi Kliba AG, CH-4303, Kaiseraugst, Switzerland), ad libitum.
- Water: Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: 7 days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/-3 °C
- Humidity: 30-70 %
- Air changes: 10-15 changes/h
- Photoperiod: 12 h dark / 12 h light
- Music was played during the light period.

IN-LIFE DATES: From 27 May To 19 June, 2008.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

VEHICLE
PEH 30 was chosen after a non-GLP solubility trial.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: Test material was prepared shortly before each dosing occasion using a magnetic stirrer as homogenizer. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight/volume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using available information on the toxicity of the test material, 2000 mg/kg bw was chosen as the starting dose.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighting: On test days 1 (prior to administration), 8 and 15.
- Frequency of observations:
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.
Clinical observations: 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: Yes; 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.

Statistics:

None

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths occurred during the study.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: One female showed slightly ruffled fur 2 to 5 hours after treatment and on test days 3 to 6. In the other five females the slightly ruffled fur was observed from test day 2 or 3 up to test days 5, 6, 7 or 8. Additionally, hunched posture was recorded in f

Gross pathology:

No macroscopic findings were recorded at necropsy

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.

Executive summary:

In an acute oral toxicity study (limit test) performed according to OECD Guideline No. 423 and in compliance with GLP, female HanRCC: WIST (SPF) rats were administered a single oral dose of test material diluted in PEG-300 by gavage.

The animals (6 females) received a single dose of the test item on a 2000 mg/kg bw and were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

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. One female showed slightly ruffled fur 2 to 5 hours after treatment and on test days 3 to 6. In the other five females the slightly ruffled fur was observed from test day 2 or 3 up to test days 5, 6, 7 or 8. Additionally, hunched posture was recorded in five females 2, 3 or 5 days post-treatment and persisted up to test days 3, 4, 5 or 6. Otherwise, no clinical signs were recorded in any animal at any observation.

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

No macroscopic findings were recorded at necropsy.

Under the test conditions, the oral LD50 of the test substance is > 2000 mg/kg bw in rats. In accordance with OECD Guideline 423, the LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw by oral route in the rat. Therefore it is not classified according to the Regulation (EC) N° 1272-2008 and according to the GHS. No signal word or hazard statement is required.

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 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:

From 22 May To 11 August, 2008.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

According to the OECD Guideline No. 402 and in compliance with GLP practices.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

August 1998

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

Adopted 24 February 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

July 31, 1992

Deviations:

no

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Remarks:

Swiss legislation on Good Laboratory Practice (signed in September 04, 2008)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

- Storage conditions: In the refrigerator at +2 to +8°C, protected from light

Species:

rat

Strain:

other: 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: male: 9 weeks; female: 11 weeks
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet (batch 21/08), ad libitum
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum
- Housing: groups of five per sex in Makrolon type-4 cages with standard sotwood bedding during acclimatisation ; then individually in Makrolon type-3 cages with standard softwood bedding during treatment and observation period.
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Music during the daytime light period.

IN-LIFE DATES: From 27 May To 17 June, 2008

Type of coverage:

semiocclusive

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on dermal exposure:

TEST SITE
- % coverage: 10
On day 1, the test item was applied at a dose of 2000 mg/kg bw evenly on the intact skin 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): yes. Twenty-four hours after the application 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/Kg

VEHICLE
- Lot/batch no. (if required): 1310049 (FLUKA Chemie GmbH, CH-9471 Buchs)
- Purity: no data

Duration of exposure:

The application period was 24 hours.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males
5 females

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- 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, and twice daily during days 2-15.
- Body weights: On test days 1 (prior to administration), 8 and 15.
- Frequency of observations included local 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: yes; 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.

Statistics:

No statistical analysis was used.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths occured during the study

Mortality:

No deaths ocurred during the study

Clinical signs:

other: No clinical signs were observed during the course of the study.

Gross pathology:

No macroscopic finding were observed at necropsy

Other findings:

Local signs: at removal of the application patch, no local signs were visible in all males and females. However, on test day 3, a very slight erythema was observed in all females and persisted up to test day 5. On test day 7, slight focal scabs were visible in all males and four females which persisted up to test days 10 or 11 and in one female up to test day 9. Additionally, in this female the slight focal scabs were present again on test day 11. On test day 12, slight scabs were noted in all males and two females which persisted up to test day 13 in one female and two males. Additionally, one female showed slight scabs on test days 10, 12 and 13. Slight scaling was recorded in one male 7 to 11 days after test item exposure.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, the dermal LD50 for the registered substance is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Executive summary:

In an acute dermal toxicity study (limit test) performed according to the OECD test guideline No. 402 and in compliance with GLP, five male and five female rats were treated with the substance at 2000 mg/kg by dermal application. The test item was applied diluted in vehicle (PEG 300) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The test site was covered with a semi-occlusive dressing for 24 hours. Animals were observed for mortality, clinical signs, local signs and body weights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

No deaths occurred during the study. No clinical signs were observed during the course of the study.

At removal of the application patch, no local signs were visible in all males and females. However, on test day 3, a very slight erythema was observed in all females and persisted up to test day 5. On test day 7, slight focal scabs were visible in all males and four females which persisted up to test days 10 or 11 and in one female up to test day 9. Additionally, in this female the slight focal scabs were present again on test day 11. On test day 12, slight scabs were noted in all males and two females which persisted up to test day 13 in one female and two males. Additionally, one female showed slight scabs on test days 10, 12 and 13. Slight scaling was recorded in one male 7 to 11 days after test item exposure.

One female did not gain weight at the end of the study. Otherwise, the body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

Dermal LD50 Combined > 2000 mg / kg bw

Under the test conditions, the dermal LD50 for the registered substance is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

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

A key study was identified (RCC, 2008, rel. 1). In this acute oral toxic class method study performed according to the OECD guideline No. 423 and in compliance with GLP, six female HanRCC: WIST (SPF) rats received a single oral (gavage) dose of the test substance diluted in PEG-300 at a dose level of 2000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination.

All animals survived until the end of the study period. One female showed slightly ruffled fur 2 to 5 hours after treatment and on test days 3 to 6. In the other five females the slightly ruffled fur was observed from test day 2 or 3 up to test days 5, 6, 7 or 8. Additionally, hunched posture was recorded in five females 2, 3 or 5 days post-treatment and persisted up to test days 3, 4, 5 or 6. Otherwise, no clinical signs were recorded in any animal at any observation. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

Oral LD50 > 2000 mg/kg bw

 

DERMAL

A key study was identified (RCC, 2008, rel. 1). In this acute dermal toxicity study (limit test) performed according to the OECD test guideline No. 402 and in compliance with GLP, five male and five female rats were treated with the substance at 2000 mg/kg by dermal application. The test item was applied diluted in vehicle (PEG 300) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The test site was covered with a semi-occlusive dressing for 24 hours. Animals were observed for mortality, clinical signs, local signs and body weights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

No deaths occurred during the study. No clinical signs were observed during the course of the study.

At removal of the application patch, no local signs were visible in all males and females. However, on test day 3, a very slight erythema was observed in all females and persisted up to test day 5. On test day 7, slight focal scabs were visible in all males and four females which persisted up to test days 10 or 11 and in one female up to test day 9. Additionally, in this female the slight focal scabs were present again on test day 11. On test day 12, slight scabs were noted in all males and two females which persisted up to test day 13 in one female and two males. Additionally, one female showed slight scabs on test days 10, 12 and 13. Slight scaling was recorded in one male 7 to 11 days after test item exposure.

One female did not gain weight at the end of the study. Otherwise, the body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

Dermal LD50 Combined > 2000 mg / kg bw

 

INHALATION

Not required

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity (Oral)

Based on the available information, the substance is:

- not classified according to the CLP as the oral LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Acute toxicity (Dermal)

Based on the available information, the substance is:

- not classified according to the CLP as the dermal LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Acute toxicity (Inhalation)

No data available - waiver

Specific target organ toxicity: single exposure (Oral)

The classification criteria according to the CLP and to the GHS as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral).

Specific target organ toxicity: single exposure (Dermal)

The classification criteria according to the CLP and to the GHS as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal).

Specific target organ toxicity: single exposure (Inhalation)

No data available - waiver

Aspiration hazard

The substance is not a hydrocarbon and no effects were observed on lungs in oral studies, therefore the criteria for aspiration toxicity according to the CLP and to the GHS are not met.