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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
The physiological response of rabbits to cyclohexane, methylcyclohexane, and certain derivatives of these compounds. I Oral Administration and Cutaneous Administration
Author:
Treon, J. et al.
Year:
1943
Bibliographic source:
J. Indust. Hygiene Toxicol. 25(6), 199-214

Materials and methods

Principles of method if other than guideline:
Determination of the minimum lethal dose after single oral exposure by gavage
GLP compliance:
no
Test type:
other: minimum lethal dose
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): methylcyclohexane
- Substance type: pure substance
- Physical state: colourless liquid
- Analytical purity: 97%
- Impurities (identity and concentrations): toluene, 3%
- Specific gravity: 0.767

Test animals

Species:
rabbit
Strain:
other: White
Sex:
not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 13 mL/kg bw (based on a reported specific gravity of 0.767)
Doses:
1000 to 10000 mg/kg bw
No. of animals per sex per dose:
1 animal per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: up to 14 days
- Frequency of observations and weighing: based on the reported results, animals were regularly observed for clinical signs and mortality. Body weight was recorded daily until death or until such a time as the lost weíght had been regained; the weights of survivors were then recorded weekly.
- Necropsy performed: yes, in animals found dead.
- Other examinations performed: clinical signs, body weight, blood cellular elements (not further specified), urinary sulphates.

Results and discussion

Effect levels
Sex:
not specified
Dose descriptor:
other: minimum lethal dose
Effect level:
4 000 - 4 500 mg/kg bw
Based on:
test mat.
Mortality:
4 rabbits given methylcyclohexane at 1000 to 4000 mg/kg bw survived.
4 rabbits given methylcyclohexane at 4500 to 10000 mg/kg bw died between 5.3 and 84 h post-administration (see Table 1).
The minimum lethal dose was therefore considered to be between 4000 and 4500 mg/kg bw.
Clinical signs:
Severe diarrhea occurred within 1-1.5 h after treatment. Other symptoms were reported to be similar to those described for cyclohexane: these included increased respiratory rate remaining elevated for a few hours, within few minutes after administration, the ears became reddened and slightly cyanotic, ear veins were distended and conjuctival congestion was observed at higher doses. Animals were generally lethargic without exhibiting true narcosis. Convulsions were not observed.
Body weight:
Rabbits given methylcyclohexane at 1000 to 4000 mg/kg bw lost weight (226-550 g) within 8-10 days after administration. Body weight was regained in the ensuing 10-14 days.
3/4 rabbits given methylcyclohexane at 4500 to 10000 mg/kg bw lost weight (221-579 g) before they died. The weight loss among the rabbits that died correlated with the length of survival irrespective of the dose level. Survival time was, however, not always determined by the dose level (see Table 1).
Gross pathology:
According to the authors, when administered orally in sufficient dosage (not further specified), the test material produced severe widespread vascular damage, with fibrinocellular thrombi in the capillaries and venules, and toxic coagulation necrosis in the heart muscle, liver spleen and kindneys.
Other findings:
A decrease in the ratio of inorganic sulphates to total sulphates in the urine was observed.
The results of blood examinations obtained during two months prior to and two months following administration showed no treatment-related abnormalities in the cellular elements of the blood.
A urine sample obtained from a rabbit 6 days post-administration (dose level not specified) contained 68.2% inorganic sulphates in relation to total sulphates in urine. An average of 87.5% inorganic sulphates was determined at 5 later measurements.
In another experiment, inorganic sulphates and total glucuronic acid in urine were determined on 2 consecutive days prior to and 1, 2 and 13 days following administration of 2130 mg methylcyclohexane/kg bw. A moderate decrease in inorganic sulphates and a strong increase in glucuronic acid excretion were observed on the 2 days following the treatment. Values returned to normal levels on Day 13 post-dose (see Table 2).

Any other information on results incl. tables

Table 1. Relationship between dose, retention time and survival time.

 

Animal No.

Dose (mg/kg)

Time interval before onset of diarrhea (h)

Dose x retention time

Time interval before death (h)

1

4500

3.0

13.5

5.33

2

10000

1.33

13.3

20

3

5000

2.0

10.0

60

4

8000

1.0

8.0

84

 

Table 2. Inorganic sulphates and glucuronic acid excretion in urine.

 

Day

Inorganic sulphates in 24-hour sample (%)

Total glucuronic acid in 24-hour sample (mg)

-2

77.5

47

-1

89.6

53

0 (dosing)

2130 mg methylcyclohexane/kg bw

1

51.9

384*

2

40.0

451

13

90.0

34

* 48-hour sample

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The minimum lethal dose of methylcyclohexane following oral administration was determined in rabbits. The animals (1 per dose) were given the undiluted test substance by gavage at doses ranging from 1000 to 10000 mg/kg bw and observed for up to 14 days. Rabbits given methylcyclohexane at 1000 to 4000 mg/kg bw survived. Rabbits given methylcyclohexane at 4500 to 10000 mg/kg bw died between 5.3 and 84 h post-administration. The minimum lethal dose was therefore considered to be between 4000 and 4500 mg/kg bw.
Severe diarrhoea occurred within 1-1.5 h after treatment. Other symptoms were reported to be similar to those described for cyclohexane: these included increased respiratory rate remaining elevated for a few hours, within few minutes after administration, the ears became reddened and slightly cyanotic, ear veins were distended and conjunctival congestion was observed at higher doses. Animals were generally lethargic without exhibiting true narcosis. Convulsions were not observed.
Rabbits given methylcyclohexane at 1000 to 4000 mg/kg bw lost weight (226-550 g) within 8-10 days after administration. Body weight was regained in the ensuing 10-14 days. 3/4 rabbits given methylcyclohexane at 4500 to 10000 mg/kg bw lost weight (221-579 g) before they died. The weight loss among the rabbits that died correlated with the length of survival irrespective of the dose level. Survival time was, however, not always determined by the dose level.
According to the authors, when administered orally in sufficient dosage (not further specified), the test material produced severe widespread vascular damage, with fibrinocellular thrombi in the capillaries and venules, and toxic coagulation necrosis in the heart muscle, liver spleen and kindneys. The results of blood examinations obtained during two months prior to and two months following administration showed no treatment-related abnormalities in the cellular elements of the blood (no details reported).

In this study, mortality and signs of systemic toxicity were observed only at very high dose levels of methylcyclohexane, which are above the limit dose values of the currently valid test methods. Therefore, based on expert judgement, the study results do not fulfil the classification criteria for acute toxicity via the oral route according to Regulation (EC) No 1272/2008 and Directive 67/548/EEC.

CLP: not classified
DSD: not classified