Registration Dossier

Acute toxicity, oral in rats: LD50 > 2000 mg/kg bw (OECD 401, GLP, K, Rel. 2)

Acute toxicity, dermal in rabbits: LD50 > 2000 mg/kg bw (OECD 402, GLP, K, Rel. 2)

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

24 February 1987

Deviations:

yes

Remarks:

Some housing conditions are not reported (temperature, humidity, air changes); lack of details on the test item; no (historical) control group

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Name in the study report: Elemi resinoid (Canarium spp.)
Test article label: #1259-93
Date of reception: 13 July 1993
Storage: in refrigerator and protected from light
Description: yellow solid

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals
- Females nulliparous and non-pregnant
- Weight at study initiation: 236-256 g for males; 237-250 g for females
- Fasting period before study: yes (16-20 hours before dosing)
- Housing: 5/sex/cage in suspended wire mesh cages
- Diet (e.g. ad libitum): Fresh Purina Rodent Chow (Diet #5012), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS

- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 July 1993 To: 03 August 1993

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test article was melted (heated) in to a liquid state and the dose was based on the sample weight as calculated from the specific gravity (1.01).

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Animals were observed 1, 2 and 4 h post dose and once daily for 14 days. They were observed twice daily for mortality. Bodyweights were recorded before dosing, weekly and at termination.
All animals were examined for gross pathology.

Statistics:

The LD50 and 95% confidence limits were calculated, if possible, by the method of Litchfield and Wilcoxon (JPET 96:99, 1949) or Horn (Biometrics 12:311, 1956)

Preliminary study:

Not applicable

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the observation period.

Clinical signs:

other: Chromodacryorrhea was noted in one male on days 4 and 5. All other animals appeared normal throughout the study.

Gross pathology:

All animals were normal.

Other findings:

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 therefore it is not classified according to the Regulation (EC) N° 1272-2008 and potentially not classified according to GHS as no mortality and no adverse clinical signs were observed at 2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study performed according to OECD guideline 401 and GLP, single oral dose of 2000 mg/kg bw of the undiluted test substance, melted (heated) into a liquid state, was administered to 5 male and 5 female Wistar rats. Animals were then observed for mortality twice daily and for clinical signs of toxicity 1, 2 and 4 h after dosing and then daily for 14 days. Bodyweights were recorded before dosing, weekly and at termination.

No mortality occured during the observation period. Chromodacryorrhea was noted in one male on days 4 and 5. All other animals appeared normal throughout the study. Bodyweight changes and necropsy were normal.

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw therefore it is not classified according to the Regulation (EC) N° 1272-2008 and potentially not classified according to GHS as no mortality and no adverse clinical signs were observed at 2000 mg/kg bw.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Adequate for hazard assessment

Reference

Endpoint:: acute toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Basic data given, but considered sufficiently reliable for the purpose of hazard assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Some housing conditions are not reported (temperature, humidity, air changes); lack of details on the test item; no (historical) control group

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Name in the study report: Elemi resinoid (Canarium spp.)
Test article label: #1259-93
Date of reception: 13 July 1993
Storage: in refrigerator and protected from light
Description: yellow solid
Sample preparation: the test article was placed in a water bath and heated to 45-50°C in order to make a liquid

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals
- Males and nulliparous and non-pregnant females
- Weight at study initiation:2.5-2.7 kg for males; 2.3-2.6 kg for females
- Age: animals were born on 11 and 25 April 1993
- Fasting period before study: No
- Housing: individually in suspended wire mesh cages
- Diet (e.g. ad libitum): Fresh Purina Rabbit Chow (Diet #5321), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS

- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21 July 1993 To: 04 August 1993

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximatively 24 h prior to administration, the dorsal area of the trunk of each animal was clipped free of hair. The prepared site was approximatively 10% of the body surface and remained intact.
The test article was melted into a liquid and the dose was based on the sample weight as calculated from the specific gravity. The test article was applied to the dermal site, one time, by seringue type applicator at a dose level of 2.0 g/kg. The test site was covered with a gauze patch, secured with non-irritating tape. At 24 h, the patches were removed. Any residual test article was wiped with gauze prior to observations.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5/dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- The test sites were scored for dermal irritation at 24 h post dose and on days 7 and 14 using the numerical Draize scale. Additional signs were described.
- The animals were observed 1, 2 and 4 h post dose and once daily for 14 days for toxicity and phamaclogical effects. The animals were observed twice daily for 14 days for mortality.
- Bodyweights were recorded pretest, weekly and at death or termination.
- All animals were examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination.

Statistics:

The LD50, 95% confidence limits, dose response curve and slope were calculated, if possible, by the method of Litchfield & Wilcoxon, 1949.

Preliminary study:

Not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One male was found dead on Day 14 with predeath signs of diarrhea and few feces.

Clinical signs:

other: Instances of diarrhea and few feces were noted in some surviving animals (2 males and 1 female)

Gross pathology:

Necropsy of the dead animal revealed abnormalities of the gastrointestinal tract and lungs as well as soiling of the anogenital area. Necropsy of survivors revealed treated skin abnormalities in all animals, one of which also exhibited excess fluid in the peritoneal cavity.

Other findings:

- Dermal reactions: dermal reactions were absent to well defined on days 1 and 7; slight to well defined on day 14. However, it was not possible to completely remove the test item from the dose site without injuring the skin.

See attached document

Interpretation of results:

other: not classified according to CLP

Conclusions:

Under the test conditions, the dermal LD50 of the test substance is > 2000 mg/kg bw in rabbits therefore it is not classified according to the Regulation (EC) N° 1272-2008. One death occurred at this dose level with clinical signs such as diarrhea in survivors therefore it is possible that LD50 is < 5000 mg/kg bw and classified Category 5 according to the GHS.

Executive summary:

In an acute dermal toxicity study, 5 New Zealand white rabbits/sex/dose were administered a single dermal dose of the test substance at 2000 mg/kg bw for 24 h under semi-occlusive conditions. Animals were then observed for mortality, clinical signs of toxicity and dermal reactions for 14 days.

One male was found dead on Day 14 with predeath signs of diarrhea and few feces. Instances of diarrhea and few feces were noted in some surviving animals (2 males and 1 female). Dermal reactions were absent to well defined on days 1 and 7; slight to well defined on day 14. However, it was not possible to completely remove the test item from the dose site without injuring the skin. Bodyweight changes were normal in 8/9 survivors. One male lost weight during the second week of the observation period. Necropsy of the dead animal revealed abnormalities of the gastrointestinal tract and lungs as well as soiling of the anogenital area. Necropsy of survivors revealed treated skin abnormalities in all animals, one of which also exhibited excess fluid in the peritoneal cavity.

Under the test conditions, the dermal LD50 of the test substance is > 2000 mg/kg bw in rabbits therefore it is not classified according to the Regulation (EC) N° 1272-2008. One death occurred at this dose level with clinical signs such as diarrhea in survivors therefore it is possible that LD50 is < 5000 mg/kg bw and classified Category 5 according to the GHS.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Adequate for hazard assessment

Acute toxicity: via oral route

In an acute oral toxicity study performed according to OECD guideline 401 and GLP, single oral dose of 2000 mg/kg bw of the undiluted test substance,melted (heated) into a liquid state, was administered to 5 male and 5 female Wistar rats. Animals were then observed for mortality twice daily and for clinical signs of toxicity 1, 2 and 4 h after dosing and then daily for 14 days. Bodyweights were recorded before dosing, weekly and at termination.

No mortality occured during the observation period. Chromodacryorrhea was noted in one male on days 4 and 5. All other animals appeared normal throughout the study. Bodyweight changes and necropsy were normal.

Under the test conditions, the oral LD50 of the test substance is >2000 mg/kg bw therefore it is not classified according to the Regulation (EC) N° 1272-2008 and potentially not classified according to GHS as no mortality and no adverse clinical signs were observed at 2000 mg/kg bw.

Acute toxicity: via dermal route

In an acute dermal toxicity study, 5 New Zealand white rabbits/sex/dose were administered a single dermal dose of the test substance at 2000 mg/kg bw for 24 h under semi-occlusive conditions. Animals were then observed for mortality, clinical signs of toxicity and dermal reactions for 14 days.

One male was found dead on Day 14 with predeath signs of diarrhea and few feces. Instances of diarrhea and few feces were noted in some surviving animals (2 males and 1 female). Dermal reactions were absent to well defined on days 1 and 7; slight to well defined on day 14. However, it was not possible to completely remove the test item from the dose site without injuring the skin. Bodyweight changes were normal in 8/9 survivors. One male lost weight during the second week of the observation period. Necropsy of the dead animal revealed abnormalities of the gastrointestinal tract and lungs as well as soiling of the anogenital area. Necropsy of survivors revealed treated skin abnormalities in all animals, one of which also exhibited excess fluid in the peritoneal cavity.

Under the test conditions, the dermal LD50 of the test substance is > 2000 mg/kg bw in rabbits therefore it is not classified according to the Regulation (EC) N° 1272-2008. One death occurred at this dose level with clinical signs such as diarrhea in survivors therefore it is possible that LD50 is < 5000 mg/kg bw and classified Category 5 according to the GHS.

Harmonized classification:

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

Self-classification:

Acute toxicity via Oral route:

Based on the available information, the registered substance is:

- not classified according to the Regulation (EC) No. 1272/2008 and GHS.

Acute toxicity via Dermal route:

Based on the available information, the registered substance is:

- not classified according to Regulation (EC) No. 1272/2008 and potentially classified as category 5 according to GHS.

Acute toxicity via Inhalation: This information is not available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 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) for a Category 1 classification (C ≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification is required.

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 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) for a Category 1 classification (C ≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification is required.

Specific target organ toxicity: single exposure (Inhalation): This information is not available.

Based on its physical state, the registered substance is not classified for aspiration hazard acording to CLP Regulation and GHS.