Reaction mass of (+-)-(1RS,2SR,5SR,7RS,8SR)-5-METHYLTRICYCLO[6.2.1.02,7]UNDECAN-4-ONE and (+-)-(1RS,2SR,5RS,7RS,8SR)-5-METHYLTRICYCLO[6.2.1.02,7]UNDECAN-4-ONE

Endpoint summary

Description of key information

Acute toxicity: oral: Rat LD50 (combined) = 410 mg/kg bw (K, rel. 2)
Acute toxicity: dermal: Rabbit LD50 = 2000 mg/kg bw (K, rel. 2)

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 October 02 to December 14, 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to standard guideline.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study was performed according to procedure suggested by Hagan (1959) and is similar to the OECD Test Guideline No. 401.

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Summit View Farm, Belvidere, New Jersey, USA.
- Weight at study initiation: 150-300 g
- Fasting period before study: Animals were fasted overnight prior to administration of test material.
- Diet: Wayne animal feed, ad libitum
- Water: Water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS: Animals were maintained under standard laboratory conditions.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.26 mL/kg bw

Doses:

Range-finding study: 500, 1000 and 2000 mg/kg bw
Main study: 100, 500, 600, 750 and 1260 mg/kg bw

No. of animals per sex per dose:

1 male/dose (range-finding study)
3/sex/dose (main study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for signs of pharmacologic activity and toxicity at 1, 3, 6 and 24 h after test material administration and then daily for 14 days. Initial and final body weight of each animal was recorded.
- Necropsy of survivors performed: Yes; animals were sacrificed at the end of the 14-day observation period and were subjected to gross necropsy.

Statistics:

Litchfield and Wilcoxon (1949)

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

410 mg/kg bw

Based on:

test mat.

95% CL:

273 - 615

Mortality:

- In the range finding study, a male animal treated with 100 mg/kg bw dose was died at 1 h after dosing and another male animal treated with 200 mg/kg bw dose was died at 30 minutes after dosing. 0, 100 and 100 % mortality were observed at 500, 1000 and 2000 mg/kg bw, respectively
- In the main study, mortality was observed at all dose levels: 1/6 (1 female), 2/6 (2 females), 5/6 (3 males + 2 females), 6/6 (3 males + 3 females) and 6/6 (3 males + 3 females) at 100, 500, 600, 750 and 1260 mg/kg bw, respectively. 17, 33, 83, 100 and 100 % mortality were observed at 100, 500, 600, 750 and 1260 mg/kg bw, respectively.

Clinical signs:

other: - Range-finding study: Slight depression was observed in a male animal treated with 500 mg/kg bw after 1 h of dosing and appeared normal thereafter. - Main study: Slight depression and convulsions were observed in 5/6 animas treated with 1260 mg/kg bw wit

Gross pathology:

- No abnormality was observed at necropsy.

Other findings:

None

None

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Oral LD50 Combined = 410 mg/kg bw (95 % confidence limits of 273-615 mg/kg bw)

Executive summary:

In an acute oral toxicity study, groups of Wistar rats (3/sex/dose) were administered a single oral (gavage) dose of test material at 100, 500, 600, 750 and 1260 mg/kg bw. Animals 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. Range finding study was conducted at the dose levels of 500, 1000 and 2000 mg/kg bw (1 male/dose) to determine the dose for main study.

In the range finding study, 0, 100 and 100 % mortality were observed at 500, 1000 and 2000 mg/kg bw, respectively. Slight depression was observed in a male animal treated with 500 mL/kg bw.

In the main study, 17, 33, 83, 100 and 100 % mortality were observed at 100, 500, 600, 750 and 1260 mg/kg bw, respectively. Slight depression and convulsions were observed in all animals at 1260 mg/kg bw. Surviving animals showed slight increase in body weight gain over the 14 day observation period. No abnormality was observed at necropsy.

Oral LD50 Combined = 410 mg/kg bw (95 % confidence limits of 273-615 mg/kg bw)

 

Under the test conditions, the test material is classified as ‘Category 4: Harmful if swallowed’ according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

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

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Quality of whole database:

The key study is GLP compliant and of good quality (Klimisch score = 2)

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 October 16 to November 30, 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was performed prior to the OECD test guideline No. 402 but the protocol is similar to the TG with the following exeptions: occlusive dressing (worst-case condition) was used and only 3 animals per sex were included. However, a repeat study under standard conditions is unlikely to show worse effects, therefore this study was considered sufficiently robust to cover this endpoint.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline followed

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

occlusive dressing

Principles of method if other than guideline:

Study was performed according to a modification of the techniques described in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, compiled by the staff of the Division of Pharmacology, Food and Drug Administration.

GLP compliance:

no

Remarks:

(pre-GLP)

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Summit View Farm, Belvidere, New Jersey, USA.
- Weight at study initiation: 1.33-2.17 kg
- Diet: Wayne animal feeds, ad libitum
- Water: Water, ad libitum
- Acclimation period: Animals were conditioned prior to use.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Mid-dorsal area of the trunk.
- % coverage: Approximately 10 % of the body surface
- Type of wrap if used: Test material was applied under gauze and then covered with an impermeable plastic wrapping for 24 h.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Test material was removed and skin gently cleansed with water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw

Duration of exposure:

24 h

Doses:

Range-finding study: 500, 1000, 3000 and 5000 mg/kg bw
Main study: 2000 mg/kg bw

No. of animals per sex per dose:

1 male/dose (range-finding study)
3/sex/dose (main study)

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for signs of pharmacologic activity and toxicity at 1, 3, 6 and 24 h after dosing and daily thereafter for 14 days.
- Necropsy of survivors performed: Yes; non-survivors and animals sacrificed at the end of the 14-day observation period were subjected to gross necropsy.

Statistics:

None

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 3/6 animals were died.

Mortality:

- In the range-finding study, no mortality was observed at 500, 1000 and 3000 mg/kg bw. At 5000 mg/kg bw, one male animal was died (100 % mortality) within 3 h of dosing.
- In the main study, 2 animals (1 male + 1 female) treated with 2000 mg/kg bw were died within 24 h of dosing. Another female animal was died on Day 5 of dosing. 50 % mortality (3/6 animals, all with intact skin) was observed.

Clinical signs:

other: - Range-finding study: Depression was observed in a male animal treated with 3000 mg/kg bw between 3-6 h of dosing. Skin dryness, flaking and redness was observed in male animals treated with 1000, 3000 and 5000 mg/kg bw dose, respectively. - Main study:

Gross pathology:

- Range-finding study: A male animal treated with 5000 mg/kg bw showed enlargement of right kidney at anterior end (15 cm in diameter), thickened capsule and sub capsular space was filled with grey-white pus.
- Main study: No abnormality was observed at necropsy in animals treated with 2000 mg/kg bw.

Other findings:

None

None

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Dermal LD50 Combined = 2000 mg/kg bw

Executive summary:

In an acute dermal toxicity, the intact or abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material at dose of 2000 mg/kg bw for 24 h. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations. Range finding study was conducted at the dose levels of 500, 1000, 3000 and 5000 mg/kg bw (1 male/dose, intact skin) to determine the dose for main study.

In the range-finding study, 0, 0, 0 and 100 % mortality were observed at 500, 1000, 3000 and 5000 mg/kg bw, respectively. Depression was observed at 3000 mg/kg bw; skin dryness, flaking and redness was observed at 1000, 3000 and 5000 mg/kg bw dose, respectively. Gross necropsy of dead animal showed enlargement of right kidney at anterior end, thickened capsule and sub capsular space was filled with grey-white pus. 

In the main study, 3/6 animals (1 male + 2 females, all with intact skin) died (50 % mortality) at 2000 mg/kg bw. Clinical signs observed in animals were slight to severe depression and skin blanching. One female with intact skin showed sign of irritation (skin moderately reddened) and faeces loose. In animals with abraded skin, sloughing and scab formation were observed. Surviving animals (2/3) showed decreased body weight gain over the 14 day study period. No abnormality was observed at necropsy.

Dermal LD50 Combined = 2000 mg/kg bw

Under the test conditions, the test material is classified as ‘Category 4: Harmful in contact with skin’ according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

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

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP compliant and of good quality (Klimisch score = 2)

Additional information

Acute toxicity: oral:

A key study was identified (Consumer Product Testing, 1978). This acute oral toxicity study was performed prior to the OECD test guideline No. 401 but the protocol is similar to that guidance.

In the range finding study (1 rat/dose), 0, 100 and 100 % mortality were observed at 500, 1000 and 2000 mg/kg bw, respectively. Slight depression was observed in a male animal treated with 500 mL/kg bw.

In the main study (3 rats/sex/dose), 17, 33, 83, 100 and 100 % mortality were observed at 100, 500, 600, 750 and 1260 mg/kg bw, respectively. Slight depression and convulsions were observed in all animals at 1260 mg/kg bw. Surviving animals showed slight increase in body weight gain over the 14 day observation period. No abnormality was observed at necropsy.

Oral LD50 Combined = 410 mg/kg bw (95 % confidence limits of 273-615 mg/kg bw)

Acute toxicity: dermal:

A key study was identified (Consumer Product Testing, 1978). This acute dermal toxicity study was performed prior to the OECD test guideline No. 402 but the protocol is similar to that guidance with the following exeptions: occlusive dressing (worst-case condition) was used and only 3 animals per sex were included. However, a repeat study under standard conditions is unlikely to show worse effects, therefore this study was considered sufficiently robust to cover this endpoint.

Rabbits were given a single dermal application of the undiluted test material to intact or abraded skin for 24 hours.

In the range-finding study (1 male/dose, intact skin), 0, 0, 0 and 100 % mortality were observed at 500, 1000, 3000 and 5000 mg/kg bw, respectively. Depression was observed at 3000 mg/kg bw; skin dryness, flaking and redness was observed at 1000, 3000 and 5000 mg/kg bw dose, respectively. Gross necropsy of dead animal showed enlargement of right kidney at anterior end, thickened capsule and sub capsular space was filled with grey-white pus. 

In the main study (3 animals/sex/dose, half with intact/half with abraded skin), 3/6 animals (1 male + 2 females, all with intact skin) died (50 % mortality) at 2000 mg/kg bw. Clinical signs observed in animals were slight to severe depression and skin blanching. One female with intact skin showed sign of irritation (skin moderately reddened) and faeces loose. In animals with abraded skin, sloughing and scab formation were observed. Surviving animals (2/3) showed decreased body weight gain over the 14 day study period. No abnormality was observed at necropsy.

Dermal LD50 Combined = 2000 mg/kg bw

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

Justification for selection of acute toxicity – inhalation endpoint
Not required for substances at the REACH Annex VII tonnage level.

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

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP6.

Self-classification:

Acute toxicity (Oral):

Based on the available data, the substance is classified as H302: Harmful if swallowed (Category 4) according to the Regulation (EC) No. 1272/2008 as the LD50 is between 300 and 2000 mg/kg bw.

Acute toxicity (Dermal):

Based on the available data, the substance is classified as H312: Harmful in contact with skin (Category 4) according to the Regulation (EC) No. 1272/2008 as the LD50 is equal to 2000 mg/kg bw.

Acute toxicity (Inhalation):

No information was 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≤ 3000 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, 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) for a Category 1 classification (C≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw≥ C > 1000 mg/kg bw). No classification is required.

Specific target organ toxicity: single exposure (Inhalation):

No information was available.