Ethylene carbonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Older study. No guideline followed: number of animals and duration of study did not correspond to the guidelines currently recommended. Limited documentation on results. However, the study is considered to be reliable with restrictions (nephrotoxicity in the long-term feeding study).

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Carcinogenicity tests of certain environmental and industrial chemicals

Author:

Weisburger EK Ulland BM, Nam J, Gart JJ, Weisburger JH

Year:

1981

Bibliographic source:

J Nat Cancer Inst 67: 75-88

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Screening study: the carcinogenic potential of several chemicals is studied via a long term feeding study in rats.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethylene carbonate

EC Number:

202-510-0

EC Name:

Ethylene carbonate

Cas Number:

96-49-1

Molecular formula:

C3H4O3

IUPAC Name:

1,3-dioxolan-2-one

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): Ethylene carbonate
- Purity: > 99%
- Physical state: fine crystals

Test animals

Species:

rat

Strain:

other: Charles River CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, USA
- Age at study initiation: approx. 5 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2 rats per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7-10 days


ENVIRONMENTAL CONDITIONS: no data
- air-conditioned

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: feed: Wayne Lab Blox Meal

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): twice weekly
- Mixing appropriate amounts with (Type of food): Wayne Lab Blox meal
- Storage temperature of food: 4°C

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

78 weeks

Frequency of treatment:

continuously (at libitum access to feed)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
25000 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
50000 (40000 males) ppm
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
approx 1250 mg/kg bw/d
Basis:
actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:
approx 2500 (2000 males) mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

26

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based dose range finding study.
Acute study with single dose given by gavage. If no effects were noted, daily doses were administered up to 14 days.
Maximum tolerated dose for the chronic study is determined in a repeated dose study: 5 dose levels were administered via the diet to groups of 3 animals each over 30 days + 30 days post-exposure observation. No further details documented.

Positive control:

Two groups of positive control animals received N-2-Fluorenylacetamide in the diet at 80 ppm (32 rats) or 250 ppm (20 rats).

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, 7 days a week for toxicological effects or deaths


BODY WEIGHT: Yes
- Time schedule for examinations: weekly (1st month), biweekly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption determined during the initial week and the fourth week of each subsequent 4-week period.


OPHTHALMOSCOPIC EXAMINATION, HAEMATOLOGY, CLINICAL CHEMISTRY, URINALYSIS, NEUROBEHAVIOURAL EXAMINATION:
No data

Sacrifice and pathology:

Moribund rats were killed.
At the end of week 78, 5 femals of the higher dose group are killed, necropsied, histopathology performed. The animals were used for calculation of tumor incidence but not survival rate.
All rats were necropsied and tissues were examined histopathologically.
Following tissues are examined: cerebrum, cerebellum, pituitary gland, spinal cord and vertebrae, lung, heart, mediastinum, thymus, thyroid gland, parathyroid gland, liver, spleen, pancreas, adrenal galnd, kidney, urinary bladder, ovary, uterus or testis, accessory sex organ, esophagus, stomach, intestinal tract and any abnormal tissue or mass.

Other examinations:

no

Statistics:

survival: product-limit procedure of Kaplan and Meier (life table method)
one-tailed Fisher's exact probability test for tumor incidence (significance level 0.05)
Bonferroni inequality
Cochran-Armitage test for linear trend

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Males: increased mortality in high-dose males. Three (this might be a typing error in the document: 50% is stated in the text. This would mean 13 rats(13/26)) survived to week 52; all died by week 60. Treatment was stopped at week 42 and resumed at 40000 ppm at week 44. Twenty males (20/16) in the low dose group survived to 52 weeks. Only 10 survived to 78 weeks.
Females: no mortality at week 52. In the low dose group, 23/26 rats survived until week 78, in the high dose group, 20/16 rats survived until week 78. There were no effects compared to control. Females remained unaffected clinically.

BODY WEIGHT AND WEIGHT GAIN
Males: male treatment groups had substancially lower mean weights than the matched controls.
Females: mean weights similar to those of the control groups


HISTOPATHOLOGY:
Severe nephrotoxicity in high-dose males, evidenced by diffuse severe chronic nephritis. Strongly birefringent crystals (probably oxalic acid) found in the convoluted tubules of the kidney, the collecting tubules, and sometimes in the renal pelvis and urinary bladder. Low-dose males were not affected appreciably untill week 60.

Under the conditions of the study, the treated groups did not show any increase in the incidence of tumors over that of the controls.

The difference in toxicity and survival between males and females may relate to differences in metabolims as a function of sex, similar to that of the hydrolysis product ethylene glycol.

No further details presented in the paper.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

25 000 other: ppm in diet

Sex:

male

Basis for effect level:

other: 25000 ppm = ~1250 mg/kg bw/d basis for effect: nephrotoxicity

2

Dose descriptor:

NOAEL

Effect level:

50 000 other: ppm in diet

Sex:

female

Basis for effect level:

other: 50000 ppm =~ 2500 mg/kg bw/d no effects observed at the highest dose

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a long-term feeding study in rats (78 weeks), no carcinogenic effects were detected (M/F).
In males, nephrotoxic effects were observed at 25000 ppm (diet) (~1250 mg/kg bw/d).
In females, no effects observed the NOAEL was determined to be 50000 ppm (~2500 mg/kg bw/d).

Executive summary:

Male and Female CD rats were exposed via the diet to 25000 or 50000 ppm (corresponding to approx. 1250 or 2500 mg/kg bw/d) for 78 weeks (N=26 per dose per sex, presumably N=18 in controls).

The study was terminated after a 26 weeks post exposure observation period at week 104. Due to an increased mortality rate at the high dose, exposure was terminated in males at week 42 and continued at week 44 with 40000 ppm.

In males, even the low dose resulted in reduced survival and decreased body weight; dose dependent nephrotoxic effects were detected.

No effects were found in females. Under the condidtions of this study, treated groups did not show any increase in tumor incidence.

The difference in toxicity and survival between males and females may be related to differences in metabolism.

Data on nephrotoxicity in this study do support cross read of the results of ethylene glycol.

In conclusion: in a long-term feeding study in male and female rats, the LOAEL for males = 25000 ppm, while the NOAEL for females is 50000 ppm. No carcinogenic effects were observed.