Diethyl carbonate

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: only two one-sentence statements without background data; data from HSDB database

As stated in HSDB database (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB):

Mildly toxic by subcutaneous route. Questionable carcinogen with experimental tumorigenic and teratogenic data.

[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1171] **PEER REVIEWED**

Conclusions:

Data not sufficient in extent and quality to draw conclusions from.
No information on background data.

Reference 2

Endpoint:

carcinogenicity

Remarks:

other: oral: gavage; intraperitoneal injection

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Description of the method often not very clear. The experimental results are doubtful, because the mortality rate in the control group was rather high.

GLP compliance:

no

Species:

mouse

Strain:

Swiss

Sex:

male/female

Route of administration:

other: oral: gavage; intraperitoneal injection

Vehicle:

other: distilled water; saline

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

40 weeks

Frequency of treatment:

twice per week

Remarks:

Doses / Concentrations:
12.5 mg
Basis:
nominal in water
dose for oral gavage

Remarks:

Doses / Concentrations:
11.4 mg
Basis:
other: nominal in saline; dose for intraperitoneal injection

No. of animals per sex per dose:

20 animals for oral gavage study (no information on sex distribution);
30 animals for intraperitoneal injection study (no information on sex distribution)

Control animals:

other: yes, croton oil

Conclusions:

Male and female mice were administered the test substance diethylcarbonate orally (12.5 mg/mouse) and intraperitoneally (11.4 mg/mouse) twice a week for a 40 weeks. After the test period (oral administration) 73 % of the mice had skin tumours, 1/15 had a lung tumor. After intraperitoneal injection 40 % had skin tumors and non lung tumours. The author is speaking of a "weak effect" among the positive results.

In the opinion of the author of this IUCLID data set, the effect of the test substance cannot be regarded as weak. 48 % of the treated animals showed skin tumours when the high tumour rate of the control animals is subtracted (73 % - 25%). Although the tumour rate in the control animals was rather high, a tumour initiating effect of the test substance cannot be excluded according to this publication. In a review of the BG Chemie the publication of Berenblum et al. 1959 was also discussed and the author mentioned that this study is "unsuitable for use in evaluation of the possible
carcinogenic potential of carbonic acid diethyl ester" because of the small numbers of animals involved and the sometimes low survival rate.

Reference 3

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: No information was given concerning the gender of the animals. The description of the conducted methods was not layed out in detail in Salaman 1956, but were only referred to in another publication (Roe 1955).

Principles of method if other than guideline:

Method: other: subacute dermal toxicity

GLP compliance:

no

Species:

mouse

Strain:

other: strain "S"

Sex:

not specified

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Frequency of treatment:

thrice per week, in total 10 applications

Remarks:

Doses / Concentrations:
2.9 g
Basis:
other: pure substance

No. of animals per sex per dose:

25 (no information on sex distribution)

Control animals:

other: yes, croton oil

2 animals died during the subacute dermal treatment with 2.9 g of the pure test substance diethylcarbonate. Two surviving animals showed tumours at the end of the croton oil treatment. In the corresponding control group (0.17 % croton oil only) all animals survived and no animal beared any tumours.

Conclusions:

Dermal application of the test substance diethyl carbonate to the clipped backs of mice (10 applications in total, thrice a week) resulted in 2 dead animals and 2 animals with tumours (total of 25 animals). Thus the results of this study were evaluated as negative by the authors. In the opinion of the author of this IUCLID dossier this result on dermal toxicity cannot be concluded as absolutely negative as two animals died and two showed tumors. Therefore a cancerogenic effect of the test substance diethyl carbonate cannot be excluded completely.

Reference 4

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable publication

Principles of method if other than guideline:

Method: other: long-term oral toxicity

GLP compliance:

not specified

Species:

mouse

Strain:

other: ASH/CS1

Sex:

male/female

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Frequency of treatment:

83 weeks

Remarks:

Doses / Concentrations:
50, 250, 1000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

48 males
50 females

Control animals:

yes, concurrent vehicle

Dose descriptor:

LOAEL

Effect level:

50 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on testicular tumours found in every dose group (50, 250, 1000 ppm; 7, 35, 140 mg/kg) without similar findings in the controls. Interpretation of the given data by the author of this IUCLID dossier.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

The mice given water containing the test substance diethyl carbonate showed no abnormalities of appearance or behaviour. No statistically significant differences occurred at any time between the number of mice dead in the control and test groups of either sex. The incidences of histological findings were similar in all groups of mice including the controls. Similarily most of the tumours encountered were found with a similar frequency in the treated and control mice. 1 or 2 testicular interstitial-cell tumours were found in each group of treated male mice without comparable findings in the controls, but there was no dose-relationship in the incidences nor was the overall incidence significantly different from the control value. The incidence of histological lesions, including tumours of the ovaries was not influenced by treatment with the test substance.

Remark of the author of this IUCLID dossier: Regarding the fact that in every dose group (50, 250, 1000 ppm) 1 to 2 testicular interstitial-cell tumours were found in male mice without similar findings in the control groups, the author of this IUCLID dossier decided to set the lowest dose (50 ppm, approximately 7 mg/kg/d) as LOAEL for the test substance diethyl carbonate.

Conclusions:

Male and female mice of the ASH/CS1-strain were administered the test substance diethyl carbonate at concentrations of up to 1000 ppm in the drinking water for 83 weeks. According to the results of this study, the authors concluded that no carcinogenic effect could be detected. The authors mentioned that histological lesions including tumours of interstitial-cell in testis (1 or 2 of each treatment group) and ovaries were not increased in a dose-dependent manner by treatment with the test substance or were not even influenced by the treatment with diethyl carbonate. Although the authors found these tumours with a similar incidence in mice of the same strain in an other experiment, in the opinion of the author of this IUCLID data set a cancerogenic potential of diethyl carbonate to the reproductive system cannot be completely excluded.
Regarding the fact that in every dose group (50, 250, 1000 ppm) 1 to 2 testicular interstitial-cell tumours were found in male mice without similar findings in the control groups, the author of this IUCLID dossier decided to set the lowest value (50 ppm, 7 mg/kg) as the oral LOAEL of the test substance diethyl carbonate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

7 mg/kg bw/day

Justification for classification or non-classification

The oral no-untoward-effect-level (male/female mice) pointed out in the publication of Brown et al. (1978) was ca. 140 mg/kg/d.

There were some statistically significant findings in single treatment groups not found in the control group:

haematological examination:

lower packed cell volume (males, 1000 ppm, wk 27), higher packed cell volume (females, 50 ppm and 1000 ppm, wk 53); higher total leucocyte count (females, 50 ppm, wk 27), lower mean erythrocyte count (females, 1000 ppm, wk 53; males, 250 ppm, at end of study)

Organ weights:

higher absolute liver weights but not liver weights relative to body weight (some females of all groups: 50, 250, 1000 ppm; but no histopathological findings).

Histological lesions including tumours:

1 or 2 testicular interstitial-cell tumours in each treatment group (50, 250, 1000 ppm), 1 uterine fibroma at 250 ppm and 1000 ppm, 1 sarcoma of bladder (males, 50 ppm), 1 subcutaneous leiomyosarcoma (males, 250 ppm), 1 subcutaneous leiomyoma (1000 ppm).

In the discussion part of Brown et al. (1978) it is laid out that the found effects were not seen as related to the intake of diethyl carbonate. This conclusion was based on the following summarised arguments: the effects were not more pronounced the higher the intake of diethyl carbonate, the effect was not the same for both sexes, the inclusion of "background incidence" about the health of the utilised mice strain (in particular concerning tumours) leads to the conclusion that the found incidences in the treatment groups would not be meaningful.

In the opinion of the author of this IUCLID data set, it is possible to challenge the results as the inclusion of "background incidence" about the health of the utilised mice strain (in particular concerning tumours) means that the control group was extended using data produced before the actual study was conducted. The data of the treatment groups on the other hand was not extended.

In the opinion of the author of this IUCLID data set, a final conclusion about the effect of diethyl carbonate on the generaton of histological lesions and tumours can not be drawn from the given study results. A cancerogenic effect appears not impossible. Regarding the fact that in every dose group (50, 250, 1000 ppm) 1 to 2 testicular interstitial-cell tumours were found in male mice without similar findings in the control groups, the author of this IUCLID dossier decided to set the lowest value (50 ppm, 7 mg/kg) as the oral LOAEL of the test substance diethyl carbonate.

However, the fact that the intepretation of the study results is contradictory between the author of this IUCLID dossier and the authors of the published data and that only 1 or 2 tumours were found in each treatment group (with 48 male animals per group) suggest that classification of the test substance diethyl carbonate as carcinogenic is conclusive but not sufficient.

Additional information

Justification for selection of carcinogenicity via oral route endpoint:
Most extensive data source on possible cancerogenic effects. Brown et al. (1978) concluded there were no cancerogenic effects. However, it can be argued about this interpretation of the results in the opinion of the author of this IUCLID data set. Although the data is not sufficient for classification, a LOAEL of 7 mg/mg bw/d can be pointed out in a conservative approach.

Carcinogenicity: via oral route (target organ): urogenital: testes