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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed in accordance with generally accepted scientific principles, with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
publication
Title:
Absorption, Disposition Kinetics, and Metabolic Pathways of Cyclohexene oxide in the Male Fischer 344 Rat and Female B6C3F1 Mouse
Author:
Sauer J M, Bao J, Smith R L, McClure T D, Mayersohn M, Pillai U, Cunningham M L & Spies I G
Year:
1997
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:
Groups of rats and mice received doses of test material, orally by gavage, five days per week for a period of 28 days. Animals were treated with 100, 50, 25, 12.5, 6.25 and 0 (vehicle control) mg/kg test material. Animals were weighed weekly and following sacrifice organ weights were determined. Histopathological evaluation was performed on the heart, ovary and forestomach since they demonstrated possible lesions of interest at gross pathology.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): cyclohexene oxide

Test animals

Species:
other: rats & mice
Strain:
other: F-344 rats and B6C3F1 mice
Sex:
male/female
Details on test animals and environmental conditions:
FEMALE RATS F-344
- Housed in groups of 5 per cage.
- Source: Hilltop Lab Animals, Inc. Scottsdale, PA, USA

MALE AND FEMALE MICE B6C3F1
-Males housed individually and females in groups of 5 per cage.
- Source: Harlan Sprague-Dawley, Inc. Indianapolis, IN, USA.

TEST ANIMALS
- Diet (e.g. ad libitum): Teklad 4% Mouse-rat diet, Teklad, Madison, WI, USA. ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 14 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled.
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hr dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% methyl cellulose.
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:
Performed by capillary GC and found to be within 10% of the target concentration.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Treatment performed performed 5 days a week. Treatment was not performed on weekends or holidays, however animals were dosed at least 2 consecutive days before the terminal sacrifice.
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 50, 25, 12.5 and 6.25 mg/kg
Basis:
actual ingested
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 weighted on the first day of administration, once a week and again at sacrifice.
Sacrifice and pathology:
- Post mortem the following organs were weighed for all animals; liver, thymus, right kidney, right testicle, heart and lungs.
- Histopathological evaluation was performed on the following organs; heart, ovary and 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
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
see the field " details on results".
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
Organ weight: A non-significant gain in lung weight was observed.
Lesions: some lesions were noted, however they were not thought to be related to treatment with test material.

Effect levels

Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were observed at this dose level.

Target system / organ toxicity

Critical effects observed:
not specified

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 28-day repeat dose oral toxicity study revealed no evidence of systemic toxicity up to 100 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that the test material is not readily absorbed without first being hydrolysed and conjugated, thus only a small amount of the test material will enter the blood, with less entering the tissue.
Executive summary:

Rats and mice were exposed daily via oral gavage to the test material in varying concentrations. The study was continued for 28 days before termination.The 28-day repeat dose oral toxicity study revealed no evidence of systemic toxicity up to 100 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that the test material is not readily absorbed without first being hydrolysed and conjugated, thus only a small amount of the test material will enter the blood, with less entering the tissue.