2,2,5-trimethyl-5-pentylcyclopentan-1-one

Endpoint summary

Description of key information

Acute toxicity: oral: LD50 > 6834 mg/kg bw (similar to OECD 401 in rats, K, rel.2);
Acute toxicity: dermal: LD50 > 2000 mg/kg bw (similar to OECD 402 in rabbits, WoE);
Acute toxicity: inhalation: waiver. 

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:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-guideline and pre-GLP study. Only basic data given but the study is comparable to OECD TG 401 with a deviation: 2 animals/sex/dose were used instead of 5 animals of the same sex/dose. This deviation is not considered to have affected the reliability of the study.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

2 animals/sex/dose were used, no details test animals, environmental condition of animal room

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Remarks:

(pre-GLP)

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Charles River CD® Strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts, USA.
- Weight at study initiation: Males: 152-226 g; females: 146-162 g
- Fasting period before study: Animals were fasted for 24 h before dosing.
- Housing: Animals were housed in suspended, wire-mesh stock cages.
- Diet: Purina® Rat Chow® 5012 (Ralston Purina Company, St. Louis, Missouri, USA), ad libitum
- Water: Water, ad libitum
- Acclimation period: 5 days

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

900, 3038 and 6834 mg/kg bw

No. of animals per sex per dose:

2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
Animals were observed for mortality and clinical signs daily for 14 days. Initial and final bodyweights of animals were recorded.
- Necropsy of survivors performed: Yes; animals were subjected to gross necropsy.

Statistics:

None

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 6 834 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality was observed.

Mortality:

- No mortality was observed.

Clinical signs:

other: - No clinical signs were observed in animals treated with 900 mg/kg bw dose. - Hypoactivity was observed in animals within 15 minutes of dosing at 3038 mg/kg bw, and all animals were recovered after 6-22 h. - Hypoactivity, muscular weakness, laboured brea

Gross pathology:

- Enlarged uterine horns was observed in one female at 3038 mg/kg bw.
- No abnormalities were noted at necropsy in other animals.

Other findings:

None

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Oral LD50 Combined > 6834 mg/kg bw

Executive summary:

In an acute oral toxicity study, 3 groups of Charles River CD® Strain rats (2/sex/dose) were administered a single oral dose of test material at 900, 3038 and 6834 mg/kg bw by gavage. 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.

No mortality was observed. Hypoactivity was observed in animals within 15 minutes of dosing at 3038 mg/kg bw, and all animals were recovered after 6-22 h. Hypoactivity, muscular weakness, laboured breathing, lacrimation, diuresis and prostration were observed at 6834 mg/kg bw and animals recovered from clinical signs within 5 days after dosing. All animals showed expected gains in bodyweight over the 14-day study period. No abnormalities were noted at necropsy except enlarged uterine horn in one female at 3038 mg/kg bw dose.

Oral LD50 Combined > 6834 mg/kg bw

Under the test conditions, the test material is not classified 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:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 834 mg/kg bw

Quality of whole database:

The key study performed on the registered substance in rats was pre-guideline and pre-GLP, but was similar to OECD Test guideline No 401. This study was considered sufficiently robust to cover this endpoint.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study on the registered substance was not sufficiently robust. Therefore a weight-of evidence using data on a supporting substance was followed to cover this endpoint.

Additional information

Acute toxicity: oral

A key study was identified (Bio-Test, 1978, rel.2). This study was non-GLP, but was similar to OECD Test guideline No 401 except that 2 animals/sex/dose were used instead of 5 animals of the same sex/dose. This deviation is not considered to have affected the reliability of the study. Groups of rats (2/sex/dose) were administered a single oral dose of test material at 900, 3038 and 6834 mg/kg bw. Animals were then observed for mortality and clinical signs for 14 days.

No mortality was observed. Hypoactivity was observed in animals within 15 minutes of dosing at 3038 mg/kg bw, and all animals were recovered after 6-22 h. Hypoactivity, muscular weakness, laboured breathing, lacrimation, diuresis and prostration were observed at 6834 mg/kg bw and animals recovered from clinical signs within 5 days after dosing. All animals showed expected gains in bodyweight over the 14 day study period. No abnormalities were noted at necropsy except enlarged uterine horn in one female at 3038 mg/kg bw dose.

Rat Combined Oral LD50 = 6834 mg/kg bw.

Acute toxicity: dermal

A study was identified on the registered substance (Bio-Test, 1979, rel. 4). In this acute dermal toxicity study (limit test), a group of New Zealand Albino rabbits (2/sex) were given a single dermal application of test material at 2025 mg/kg bw. The test material was applied topically to the clipped skin area with intact skin (1/ sex) and abraded skin (1/sex) of the animals and covered with occlusive binding for 24 h.

No mortality or clinical signs were observed.

Skin reactions observed at 24 h were beet red erythema, severe oedema and second degree burns. Escharosis was observed at the test skin sites at Day 7 and 14. It has to be highlighted that half of the animals had abraded skin and individual results were not reported in the study report to confirm whether abraded and/or non-abraded skin were concerned.

All animals showed expected gains in bodyweight over the 14-day study period. Necropsy examinations revealed moderate desquamation and superficial escharosis at the test skin sites. No other gross pathologic alterations were observed.

Dermal LD50 Combined > 2025 mg/kg bw.

In this study, only 2 animals/sex were used instead of 5 animals/sex as required by the OECD guideline No. 402. Therefore, a weight-of evidence approach using data from a supporting substance, 2-Pentylcyclopentan-1-one, was used to conclude on acute dermal toxicity of the registered substance (see IUCLID section 13 for read-across justification).

The study on the supporting substance, 2-Pentylcyclopentan-1-one, (Biosearch, 1979, rel.2) was performed similarly to the OECD guideline No. 402. The abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 h at dose of 2000 mg/kg bw.

No mortality or clinical signs were observed.

No abnormalities were noted at necropsy. Dermal LD50 Combined > 2000 mg/kg bw.

Taken together, these data confirm the absence of dermal toxicity of the test substance. The LD50 is considered to be > 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. The choice for the second route will depend on the nature of the substance and the likely route of human exposure
In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (9.2 Pa at 25°C) and a low freezing point (< -20°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 4.7 at 20°C, WS = 18.9 mg/L at 20°C).

Justification for selection of acute toxicity – dermal endpoint
No study was selected since a weight-of-evidence approach was followed.

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 via Oral route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Acute toxicity via Dermal route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Acute toxicity (Inhalation):

No data 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≤ 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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

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.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available. However, the registered substance is not a skin or an eye irritant, therefore respiratory tract irritation is not expected.