Cyclohexanemethanol, 4-(1-methylethyl)-

Endpoint summary

Description of key information

1)  The oral LD50 was considered to be greater than 10,000 mg/kg bw in the albino rat.

2) Acute toxicity via inhalation route : waiver

3) The dermal LD50 of the test compound was determined to be greater than 2,000 mg/kg.

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:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study appears to follow OECD 401 with the following deviation: Sex of the animal and purity of the test substance not reported.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Sex of the animal and purity of the test substance not reported.

GLP compliance:

no

Remarks:

Study pre-dates GLP

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: AMR Biological Research, Inc .
- Age at study initiation: no data
- Weight at study initiation: see table 1
- Fasting period before study:24 hours
- Housing: individually housed
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: To: no data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE: no data
MAXIMUM DOSE VOLUME APPLIED: 10,000 mg/kg
CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: no data

Doses:

10,000 mg/kg bw

No. of animals per sex per dose:

18

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weight were recorded

Statistics:

not required

Preliminary study:

not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Mortality:

no

Clinical signs:

other: no effects

Gross pathology:

no effects

Other findings:

Food consumption and water intake were normal.

Table 1. Summary of animal data from an acute oral toxicity study in rat
Animal No.	Initial weight (grams)	Final weight (grams)	Dose (g/kg)	Mortality
5	340	349	10	euthanized
6	234	245	10	euthanized
39	233	241	10	euthanized
40	241	246	10	euthanized
41	226	242	10	euthanized
42	230	242	10	euthanized
43	218	230	10	euthanized
44	222	226	10	euthanized
45	226	227	10	euthanized
46	239	248	10	euthanized
47	231	229	10	euthanized
48	221	227	10	euthanized
49	218	230	10	euthanized
50	248	262	10	euthanized
51	212	220	10	euthanized
52	228	235	10	euthanized
53	237	245	10	euthanized

observation of toxic symptoms
Animal No.	Time post admin.	Observation	Necropsy observation
5,6, 39-53	15 minutes	none	-
5,6, 39-53	8 hours	none	-
5,6, 39-53	24 hours	none	-
5,6, 39-53	48 hours	none	-
5,6, 39-53	72 hours	none	-
5,6, 39-53	4 days -7 days	none	-
5,6, 39-53	8 days -10 days	none	-
5,6, 39-53	11 days -14 days	none	none

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 oral, rat >10,000 mg/kg.

Executive summary:

The acute toxicity of the test substance was evaluated in an oral (gavage) study in albino rats. The test compound was administered at a single dose level of 10,000 mg/kg body weight via oral gavage. The animals were observed over a period of 14 days for clinical signs of toxicity. No mortalities or toxic effects were induced by the administration of the test compound at this dose level. Therefore, the oral LD50 of the substance was considered to be greater than 10,000 mg/kg body weight in rats. 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

10 000 mg/kg bw

Quality of whole database:

Klimisch 2 study similar to guideline study. The information is reliable and consistent with the database as a whole.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Clinical signs:

other:

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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

OECD guideline equivalent study with deviations from current methodology. 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:

purity, solubility, melting/boiling point, pH of the test material not reported; sex, acclimatization period, randomization not reported; fur was removed from ventral surface; skin abraded; shaved area not measured.

GLP compliance:

no

Remarks:

Study pre-dates GLP

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: New England Rabbitry Supply Inc.
- Age at study initiation: no data
- Fasting period before study: 24 hours
- Housing: no data
- Diet :ad libitum
- water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Hair was removed from the ventral surface of the four animals and shaved areas were abraded. Note that the report description of methods and data values clearly show 6 animals in the test group but describes shaving and abrasion of the test site for 4 animals. The status of the remaining 2 animals is unclear and the report does not provide information on these remaining animals. Therefore it seems likely that all 6 animals had shaved and abraded skin and the statement regarding just 4 was erroneous.

TEST SITE
- Area of exposure: ventral surface
- % coverage: no data
- Type of wrap if used: gauze bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data
- Constant concentration used: 100% test material

VEHICLE: no

Duration of exposure:

24 hours

Doses:

2,000 mg/kg

No. of animals per sex per dose:

6 per group

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily observations for signs of dermal irritation.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (recorded 2 and 4 hours post-application and daily thereafter) and body weight (recorded prior to application, 7 days post-application, and at termination).

Statistics:

not required

Preliminary study:

not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 mg/kg bw

Based on:

test mat.

Mortality:

One animal died on Day 8 (post-application).

Clinical signs:

other: At 24 hours post-application, all animals were noted to be lethargic and these observations persisted until Day 4 post-application. There also was a decrease in food and water consumption observed from Day 1 to Day 5 post-application.

Gross pathology:

At necropsy, findings in the premature decedent were limited to an enlarged gall bladder. Macroscopic examinations of the remaining animals did not reveal any adverse findings.

Other findings:

The test compound induced dermal irritation (erythema and edema) in the treated animals; see Table 1 and Table 2 below.

Table 1       Erythema Scores of Test Compound 0778/3 in the Rabbit*

Animal No.	19	20	21	22	23	24
Day No.
1	2	2	1	2	2	1
2	4	4	2	3	2	3
3	4	4	2	3	2	3
4	4	4	2	3	2	3
5	4	4	2	3	2	3
6	4	4	1	3	2	3
7	4	4	1	3	2	3
8	3	3	0	-	1	3
9	3	3	0	-	1	2
10	2	2	0	-	0	2
11	2	2	0	-	0	2
12	1	1	0	-	0	1
13	1	1	0	-	0	1
14	1	0	0	-	0	0

* The degree of dermal irritation was scored according to the Draize method.

Table 2       Edema Scores of Test Compound 0778/3 in the Rabbit*

Animal No.	19	20	21	22	23	24
Day No.
1	2	2	0	1	1	0
2	3	3	0	1	2	2
3	3	3	0	1	2	2
4	4	4	0	1	2	2
5	3	3	0	0	1	1
6	2	2	0	0	1	1
7	0	0	0	0	0	0
8	0	0	0	-	0	0
9	0	0	0	-	0	0
10	0	0	0	-	0	0
11	0	0	0	-	0	0
12	0	0	0	-	0	0
13	0	0	0	-	0	0
14	0	0	0	-	0	0

  * The degree of dermal irritation was scored according to the Draize method.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 dermal, rabbit > 2,000 mg/kg

Executive summary:

The dermal LD50 of the test compound was determined to be greater than 2,000 mg/kg body weight in this study. The one mortality noted during this study was considered unrelated to the application of the test compound as similar gross pathological findings (enlarged gall bladder) were not observed in the remaining animals at necropsy. While dermal irritation (erythema and/or edema) was observed in all animals, it should be noted that the test compound was applied to the ventral surface of the animals on shaved and abraded skin (a deviation according to OECD Guideline 402). It is worth noting that there is an apparent inaccuracy in the study report. The report states that there were six animals in the treatment group while a subsequent sentence states that "the four" animals were shaved and had shaved skin abraded. As the remainder of the report does not differentiate between animals with shaved/abraded skin and any that might have been unshaven/unabraded, it is assumed that all animals were in fact shaved and their shaved skin was abraded. Abrading the skin could have altered its permeability. It also was unclear in the study report whether residual test substance was removed (with water or an appropriate solvent) at the end of the 24-hour exposure period. Despite the deviations noted in the study design, the LD50 is considered not to be affected.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 2 study similar to guideline study. The information is reliable and consistent with the database as a whole.

Additional information

The acute toxicity of the substance was evaluated in an oral (gavage) study and in a dermal study. The oral study was compared to OECD Guideline No. 423 and the dermal study was compared to OECD Guideline No. 402. Neither of the studies were Good Laboratory Practices (GLP) compliant.

Acute Toxicity: Oral

In the oral study (AMR Biological Research Inc, 1978), eighteen healthy albino rats (sex not reported) were administered the test compound at a single dose level of 10,000 mg/kg body weight via oral gavage. The animals were observed over a period of 14 days for clinical signs. No mortalities or toxic effects were induced by the administration of the test compound at this dose level. Therefore, the oral median LD50 was reported to be greater than 10,000 mg/kg body weight in rats. 

Acute Toxicity: Dermal

The acute dermal toxicity of the substance was assessed in a group of six healthy albino rabbits (AMR Biological Research Inc, 1979). The animals were fasted 24 hours prior to the test application and hair was shaved from the ventral surface of four animals; the shaved areas also were abraded.  [It is worth noting that there is an apparent inaccuracy in the reporting since, although the report states there were six animals in the treatment group, a subsequent sentence states that “the four” animals were shaved and had shaved skin abraded. As the remainder of the report does not differentiate between animals with shaved/abraded skin and any that might have been unshaved, it is thus assumed that, in fact, all animals were shaved and the shaved skin abraded.]

The test material (2000 mg/kg body weight) was applied and held in contact with the shaved abdominal area for 24 hours using a damming and gauze bandage; the animals were restrained during this 24-hour period. One animal died on Day 8 post-application, but this mortality was considered unrelated to the application of the test compound as similar gross pathological findings (enlarged gall bladder) were not observed in the remaining animals at necropsy. There were no adverse clinical signs noted at 2 or 4 hours post-application, however, at 24 hours post-application, all animals appeared lethargic and decreased food and water consumption were noted. Lethargy was noted in all animals until Day 4 post-application and decreased food and water consumption was noted until Day 5 post-application. Notable body weight loss (39%) was observed in only the premature decedent.  The test compound induced dermal irritation (erythema and/or edema) in all animals, reaching maximum scores in some animals, but this observation resolved by the end of the 14-day observation period (with the exception of one animal that exhibited minimal erythema on Day 14 post-application). While dermal irritation was observed in all animals, it should be noted that the test compound was applied to the ventral surface of the animals on shaved and abraded skin (a deviation according to OECD Guideline 402). Abrading the skin could have altered its permeability. It also was unclear in the study report whether residual test substance was removed (with water or an appropriate solvent) at the end of the 24-hour exposure period. Taking into consideration the study design deviations and the lack of a Control group, the dermal irritation findings in this study should be interpreted with care. That being said, there were no adverse findings noted at necropsy examinations of the surviving animals. The dermal LD50 of the test compound was considered to be unaffected by these deviations as it was determined to be greater than 2,000 mg/kg/body weight. The endpoint conclusion is that although there was an adverse effect observed, it was not based on the evidence of systemic toxicity, but on consideration of the dermal findings following application of the substance to the abraded ventral skin of the rabbits.

Acute Toxicity: Inhalation

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 (2.2 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 = 3.48 at 30°C, WS = 213,7 mg/L at 20°C).

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):

While gall bladder effects were noted in one dead animal in the acute dermal study, there is no indication from the remaining animals that there is a clear effect to the gall bladder after single dermal exposure to the test substance. There were no clinical or gross pathological effects noted after oral exposure.

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.

Aspiration hazard:

The dynamic viscosity at 40°C is 18 mm²/s (below the threshold of 20.5 mm²/s.). However the substance is neither hydrocarbon, nor n-primary alcohol, nor isobutyl alcohol or nor ketone & no aspiration-related effects were observed in the available toxicity studies so the substance is not classified according to the Regulation (EC) No. 1272/2008 and to the GHS.