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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: publication of acceptable quality standard (Brown et al. (1978))

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Long-Term Toxicity of Diethyl Carbonate in Mice
Author:
Brown, D. et al.
Year:
1978
Bibliographic source:
Toxicology, 10, 291-295
Reference Type:
publication
Title:
Untersuchungen zur Toxikologie von Diäthylcarbonat; [english translation: Investigations on the toxicity of diethyl carbonate]
Author:
Bornmann, G., Loeser, A.
Year:
1966
Bibliographic source:
ARCH TOXICOL 22, 98.
Reference Type:
publication
Title:
No information
Author:
Brantom, P.G., Gaunt, L.F. and Grasso, P.
Year:
1973
Bibliographic source:
Food Cosmet. Toxicol., 11 (1973) 735
Reference Type:
other: referred to in Brown et al. (1978)
Title:
No information
Author:
P.L. Mason, I.F. Grant, K.R. Butterworth and J. Hardy
Year:
1974
Bibliographic source:
BIBRA Research Report No. 1, 1974

Materials and methods

Principles of method if other than guideline:
chronic oral toxicity of diethyl carbonate
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of the test substance as stated in the publication: diethyl carbonate (DEC).
Obtained from: Farbenfabrik Bayer AG, Werk Uerdingen
Purity of the test substance: > 99.5 %
(for info about supplier and purity has been referred to Bornmann and Loeser (1966) in the original publication of Brown et al. (1978))

Test animals

Species:
mouse
Strain:
other: ASH/CS1
Sex:
male/female
Details on test animals and environmental conditions:
males caged individually, females caged in groups of 5; cages were in a room maintained at 20 +/- 1 °C.
The animals were allowed unlimited access to Spillers Laboratory Small Animal Diet and water.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
83 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250, 1000 ppm
Basis:
nominal in water
No. of animals per sex per dose:
48 males
50 females
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

open allclose all
Dose descriptor:
other: no-untoward-effect level
Effect level:
1 000 ppm
Based on:
other: nominal concentration in drinking water
Sex:
male/female
Basis for effect level:
other: Based on the data interpretation of Brown et al. (1978)
Dose descriptor:
other: no-untoward-effect level
Effect level:
ca. 140 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the data interpretation of Brown et al. (1978)
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.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Results as laid out in the publication:

The treated mice showed no abnormalities of appearence or behaviour. No statistically significant differences occurred at any time between the numbers of mice dead in the control and test groups of either sex. No statistically significant difference between body weights of treated and non-treated mice. The weights of the livers of all treated female mice, but not of the males, were greater than those of the controls to a statistically significant degree (but not significant when expressed relative to body weight). There were also no statistically different weights and relative weights of any examined organs in the comparison of control to treatment groups.

A lower value for the packed cell volume in male mice given 1000 ppm diethyl carbonate was significantly greater than that of the controls at week 53. At week 27 there was a statistically significant increase in the total leucocyte count in female mice given 50 ppm of the test substance, but this difference was not apparent at week 53 or at the higher level (1000 ppm). The erythrocyte count was for some treatment groups lower than for the control but this appeared not to be dependent on the dose level or the sex.

Histological findings similar in all groups of mice including controls. Most tumours were also encountered in 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. There was a single uterine fibroma in each of the groups on the 2 higher dose levels, a single sarcoma of the bladder in a male given 50 ppm DEC and a subcutaneous leiomyosarcoma in a male given 250 ppm. The only tumour found at the highest dose of DEC (1000 ppm) without similar findings at the lower levels or in the controls was a subcutaneous leiomyoma.

Discussion as laid out in the publication (in particular concerning histological lesions and tumours):

The differences between treated and contral mice apparent in the haematological examination were inconsistent and were not directly related to the length of treatment or to the dosage.

The slightly higher values for liver weight, found in all groups of female mice, did not appear to be related to treatment. This difference was found in mice with slightly higher body weights so that when the liver weight was expressed relative to body weight there were no statistically significant differences between controls and treated groups. There was no dose relationship in the magnitude of the differences from controls despite a 20-fold difference in the doses. The finding was not made for males. No indication of any histopathological effect on the liver. In fact, the incidence of the naturally occurring lesions tended to be lower in the treated females than in the controls.

The incidences of the histological lesions, including tumours of the lungs, liver, kidneys, ovary and reticuloendothelial system was not influenced by treatment with diethyl carbonate. Indeed the overall incidence of tumours, particularly of malignant types, was slightly lower in the test groups than in control animals. The few tumours found in treated animals without similar findings in the controls either were of types commonly encountered in mice or occurred only at the lower treatment levels. Primary tumours of the bladder are not

common in mice (Bornmann and Loeser (1966)). However, the sarcoma found in 1 male given 50 ppm DEC cannot he regarded as evidence of an effect of treatment since no tumours were found in the bladders of male mice given 250 or 1000 ppm or in any of the females. Thus this single tumour represents an incidence of 0.4% in all of the mice given DEC.

The incidences of fibroma of the uterus and subcutaneous sarcoma in this study were similar to those reported previously in control animals of this strain in our laboratories (Brantom et al. (1973); Mason et al. (1974)). Hence, although these tumours were found only in treated animals, comparison with the "background incidence" for the strain of mouse used does not indicate an effect of treatment. Although subcutaneous leiomyosarcomas have not been encountered previously in our laboratories in this strain of mouse, the single occurrence at the intermediate dose with no comparable finding at the higher level is not suggestive of an effect of treatment.

The incidence of interstitial-cell tumours of the testis was not increased in a dose-dependent manner by DEC treatment. Moreover, these tumours have been found with a similar incidence in control mice of this strain in this laboratory (Brantom et al. (1973)).

1 subcutaneous fibroma was found in a male mouse given 50 ppm DEC and, although no such tumours were found in the male control group, one fibroma was found in the female control group and 1 in a female given 250 ppm. This distribution of tumours does not suggest any effect of treatment.

The results of this study failed to indicate any effect of DEC on tumour incidence in mice given up to 1000 ppm in the drinking-water. This is in accordance with conclusions reached from a long-term study with rats (Bornmann and Loeser (1966)). The intake The intake of DEC in the 2 studies are comparable since Bommann and Loeser (1966) gave drinking-water containing 3000 ppm DEC and in terms of intake in relation to body weight this is similar to the highest level used in the present study (1000 ppm). Also the no-untoward-effect level in the present study was 1000 ppm in the drinking-water. In mice, this concentration represents an intake of approx. 140 mg/kg/day, which after application of the traditional 100-fold safety factor suggests an acceptable daily intake

of 1.4 mg/kg for man or 98 mg/day for a 70 kg adult.

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.

Applicant's summary and conclusion

Conclusions:
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.