1,2-epoxycyclohexane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

ABSORPTION, DISPOSITION KINETICS, AND METABOLIC PATHWAYS OFCYCLOHEXENE OXIDE IN THE MALE FISCHER 344 RAT AND FEMALE B6C3F1 MOUSE

Author:

Sauer JM et al.

Year:

1996

Bibliographic source:

Drug Metabolism and Disposition, 25: 3 371-378

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Peer- reviewed publication assessing the absorption, distribution, metabolism, and excretion of the test item.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,2-epoxycyclohexane

EC Number:

206-007-7

EC Name:

1,2-epoxycyclohexane

Cas Number:

286-20-4

Molecular formula:

C6H10O

IUPAC Name:

7-oxabicyclo[4.1.0]heptane

Test animals

Species:

other: Rat and Mouse

Details on species / strain selection:

B6C3F1 Mice
Fischer 344 Rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Male JVC F-344 rats were obtained from Hilltop Lab Animals, Inc. (Scottsdale, PA). Female
B6C3F1 mice were obtained from Harlan Sprague-Dawley, Inc. (Indianapolis, IN).
- Weight at study initiation: Rats (175-250 g), Mice (21-27 g)
- Housing: Nalgene metabolism cages
- Diet (e.g. ad libitum): Teklad 4% Mouse-Rat Diet, Teklad, Madison, WI) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Animals were acclimated for 5–7 days in a temperature-controlled 12-hr light/
dark cycle facility before any treatment.

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12-hr light/dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

0.5%

Details on oral exposure:

- PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared every 2 weeks.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Capillary GC, within 10% of the target concentration.

Duration of treatment / exposure:

28 days

Frequency of treatment:

5 days a week. Treatment was not performed on weekends or holidays, and animals were dosed at least two consecutive days before the terminal sacrifice.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

6.25 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

12.5 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

25 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 5

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5 animals per sex per species per dose

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Animals were weighed on the first day of test item administration, once each week and at euthanasia. After euthanasia, organ weights (liver, thymus, right kidney, right testicle, heart, and lungs) were determined for all animals. Histopathological evaluation was performed on heart, ovary, forestomach

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights (liver, thymus, right kidney, right testicle, heart, and lungs) were determined for all animals
HISTOPATHOLOGY: Yes, heart, ovary, forestomach

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

Very few gross lesions were found at necropsy, and none were considered compound-related. Microscopic examination of the gross lesions demonstrated no compound-related pathological alterations.
The test item appeared to increase lung weight in female F-344 rats, this measurement was not statistically significant due to a large variance between samples.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

The publication does not provide a NOEL, but no effects were observed in any of the parameters evaluated

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Table 1. Weight gain and relative organ weights for rats and mice after oral exposure to 100 mg/kg of Test Material

Test Animal		Body weight	Organ Weights % of control
		% of control	Liver	Heart	Kidney	Lung
Rats F-344	Male	102	106 ± 3	105 ± 3	100 ± 1	97 ± 23
	Female	101	100 ± 6	102 ± 5	99 ± 6	128 ± 30
Mice B6C3F1	Male	98	108 ± 5	100 ± 4	106 ± 4	99 ± 7
	Female	99	96 ± 6	105 ± 6	103 ± 3	99 ± 6

Applicant's summary and conclusion

Conclusions:

The test test item showed no signs of toxicity at concnetrations up to 100 mg/kg on the test organims after 28 days of oral exposure.

Executive summary:

B6C3F1 Mice and Fischer 344 Rats were exposed orally by gavage to five concentrations of the test item and a vehicle control. The study was carried for 28 days. Regular weighing of the organisms plus systemic and histological effects after the organisms were euthanised were recorded. No relevant effects were seen in any of the parameters recorded, therefore, we can establish a NOEL of 100 mg/kg, the greatest concentration of test item used. These data are consistent with the demonstration that the test item is rapidly hydrolyzed and conjugated after both oral and dermal administrations.