Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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))
Principles of method if other than guideline:
chronic oral toxicity of diethyl carbonate
GLP compliance:
not specified
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.
Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
83 weeks
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
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.
Critical effects observed:
not specified

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.

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.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
7 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Publication of acceptable quality standard.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: subacute: 7 hours at 5 subsequent days for 4 weeks (see Trial 4)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No official guideline method but methodology and results well documented; no GLP
Principles of method if other than guideline:
Inhalation studies were carried out according to methods from Farbenfabriken Bayer A.G., Werk Wuppertal-Elberfeld, Germany.
GLP compliance:
no
Species:
other: mouse, rat, rabbit
Details on test animals and environmental conditions:
Animals: Male NMRI-mice (weight 18-24 g), male and female Wistar-II-rats (weight 160-200 g), male and female Wistar-II-SPF-rats (weight 130-150 g) from the breeder Winkelmann, Kirchborchen, Germany; rabbits, male and female (weight 2,3 - 3,2 kg), of no specific breed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Details on methodology see under 8 Analytical methods in this IUCLID dossier:
"DIÄTHYLCARBONAT - KONZENTRATIONSBESTIMMUNG IN DER INHALATIONSLUFT NACH VERDAMPFUNG" (original German title of the study)
Diethyl carbonate - determination of concentration in inhalation air after evaporation (German title translated into English)
Author: Dipl.-Chem. A. Eben, FARBENFABRIKEN BAYER AG, INSTITUT FÜR TOXIKOLOGIE
Report Nr.: 2182
Date: 31.07.1970

Summary air analyses:
Diethyl carbonate was determined in the air being inhaled according to a modified method of H. GARSCHAGEN (Z. analyt. Chem. 241, 32, 1868; Weinberg and Keller 14, 131, 1967). The air being inhaled was conveyed through a vessel cooled down to -30 °C (absorption vessel). Determination by gas chromatography.
Dose descriptor:
NOAEC
Effect level:
> 18.995 mg/L air (analytical)
Basis for effect level:
other: 18.995 mg/l was the average measured concentration. The term "NOAEC" was not used in study report. The NOAEC was spotted out by the author of the IUCLID dossier.
Critical effects observed:
not specified

Explanation term "toxicological result" in the tables (.../.../...):

1.      Number = Number of died animals

2.      Number = Number of animals with symptoms

3.      Number = Number of animals used for the test

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1. Toxicity of aerosols

Results Trial 1:

Male rats        
theoretical substance concentration in air (mg/l) analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days number of subsequent exposure days toxicological result after 14 d
2.0 0.452 4 1 0/0/20
5.0 1.83 7 1 0/0/20
2.0 0.499 4 5 0/0/10
5.0 1.593 7 5 0/0/10
Female rats        
theoretical substance concentration in air (mg/l) analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days toxicological result after 14 d
5.0 1.268 4 1 0/0/20
2.0 0.499 7 5 0/0/10
5.0 1.593 4 5 0/0/10

LC50, male rats, 1 day * 7 h exposure, > 1.83 mg/l

LC50, male rats, 5 days * 7 h exposure, > 1.593 mg/l

LC50, female rats, 1 day * 7 h exposure, > 1.268 mg/l

LC50, female rats, 5 day * 7 h exposure, > 1.593 mg/l

In Trial 1 no signs of toxicity or irritation were found in the rats.

Results Trial 2:

theoretical substance concentration in air (mg/l) analytically determined substance concentration in air (mg/l) type of animal toxicological result
1.0 0.235 rabbit 0/0/2
1.0 0.235 rat 0/0/10
1.0 0.235 mouse 0/0/20
5.0 2.179 rabbit 0/0/2
5.0 2.179 rat 0/0/10
5.0 2.179 mouse 0/0/20

In Trial 2 no signs of toxicity or signs of irritation for the mucosas of eyes and noses were found.

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2. Toxicity of vapours

Results Trial 3:

No indication of toxicity or irritation was found in rats exposed to diethyl carbonate. At the section of the animals the inner organs were unchanged.

Male rats      
analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days toxicological result after 14 d
17.75 4 1 0/0/20
19.50 7 1 0/0/20
20.971 7 5 0/0/10
Female rats      
analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days toxicological result after 14 d
18.30 4 1 0/0/20
19.50 7 1 0/0/20
20.971 7 5 0/0/10

Results Trial 4:

Rats exposed to the test substance did not show a different behavior to the rats of the control group.

The weight gain of organs was also not significantly different in the rats treated with the test substance.

The hematological examinations did also give no evidence of a difference between rats exposed or not exposed to the substance. The measured values were within the range of normal physiological values.

 

The average activities and measured concentrations of values indicating the function of liver and kidney were also found to be the same in the test group and the control group. The values were all within the normal physiological range.

 

At the autopsy of the animals the organ weights of the treated and untreated group were not significantly different (average absolute organ weights in mg and average relative organ weights in mg/100 g of body weight; comparison of males and females separately; comparison of the different types of organs separately). Examined organs were: thyroid, heart, lung, liver, spleen, both kidneys, adrenal glands, testes, ovaries.

Table 1

Male rats      
analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days toxicological result after 14 d
17.75 4 1 0/0/20
19.50 7 1 0/0/20
20.971 7 5 0/0/10
Female rats      
analytically determined substance concentration in air (mg/l) daily exposure time (h) number of subsequent exposure days toxicological result after 14 d
18.30 4 1 0/0/20
19.50 7 1 0/0/20
20.971 7 5 0/0/10

Table 2

Male rats        
concentration of the substance in air (mg/l) body weight at the beginning of the test period (g) body weight after 4 weeks (g) weight difference after 4 weeks - beginning (g) p (= probability)
control 143 245 102 -
18.995 143 224 81 > 0.05
Female rats        
concentration of the substance in air (mg/l) body weight at the beginning of the test period (g) body weight after 4 weeks (g) weight difference after 4 weeks - beginning (g) p (= probability)
control 139 190 51 -
18.995 139 182 43 > 0.05

Table 3

Male rats              
concentration of the substance (mg/l) hemoglobin % (weight/weight) Erythrocytes 10^6 HbE (average hemoglobin content of cells) Leukocytes 10^3 Thrombocytes 10^3 Haematocrit % MCV (average cell volume of erythrocytes) (µm³)
control 14.6 7.65 19 5.4 918 50 66
18.995 14.1 7.15 20 3.9 744 46 64
Female rats              
concentration of the substance (mg/l) hemoglobin % (weight/weight) Erythrocytes 10^6 HbE (average hemoglobin content of cells) Leukocytes 10^3 Thrombocytes 10^3 Haematocrit % MCV (average cell volume of erythrocytes) (µm³)
control 12.5 6.23 20 5.1 782 41 65
18.995 12.4 6.41 19 5.4 698 41 65

Table 4

Male rats          
concentration of the substance (mg/l) liver function: GOT (mU/ml) liver function: GPT (mU/ml) liver function: SDH (mU/ml) kidney function: urea (mg/100 ml) kidney function: creatinine (mg/100 ml)
control 27.3 13.4 0.5 40.3 1.85
18.995 26.5 13.2 0.7 37.5 1.50
Female rats          
concentration of the substance (mg/l) liver function: GOT (mU/ml) liver function: GPT (mU/ml) liver function: SDH (mU/ml) kidney function: urea (mg/100 ml) kidney function: creatinine (mg/100 ml)
control 28.1 11.2 1.2 45.8 1.40
18.995 28.4 11.7 1.1 39.7 1.32

Table 5

Male rats                  
concentration of the substance (mg/l) body weight (g) thyroid average absolute weight (mg) heart average absolute weight (mg) lung average absolute weight (mg) liver average absolute weight (mg) spleen average absolute weight (mg) both kidneys average absolute weight (mg) adrenal glands average absolute weight (mg) testes average absolute weight (mg)
control 245 11.8 650 1281 10084 577 1541 42.0 2835
18.995 224 11.8 628 1122 9240 500 1450 44.6 2743
concentration of the substance (mg/l) / thyroid average relative weight (mg/100 g bw) heart average relative weight (mg/100 g bw) lung average relative weight (mg/100 g bw) liver average relative weight (mg/100 g bw) spleen average relative weight (mg/100 g bw) both kidneys average relative weight (mg/100 g bw) adrenal glands average relative weight (mg/100 g bw) testes average relative weight (mg/100 g bw)
control / 4.8 266 530 4114 237 631 17.1 1162
18.995 / 5.2 281 502 4109 223 647 20.0 1226
Female rats                  
concentration of the substance (mg/l) body weight (g) thyroid average absolute weight (mg) heart average absolute weight (mg) lung average absolute weight (mg) liver average absolute weight (mg) spleen average absolute weight (mg) both kidneys average absolute weight (mg) adrenal glands average absolute weight (mg) ovaries average absolute weight (mg)
control 190 9.9 527 892 7219 506 1110 60.8 78.1
18.995 183 10.2 526 879 7024 495 1093 62.6 70.8
concentration of the substance (mg/l) / thyroid average relative weight (mg/100 g bw) heart average relative weight (mg/100 g bw) lung average relative weight (mg/100 g bw) liver average relative weight (mg/100 g bw) spleen average relative weight (mg/100 g bw) both kidneys average relative weight (mg/100 g bw) adrenal glands average relative weight (mg/100 g bw) ovaries average relative weight (mg/100 g bw)
control / 5.2 278 469 3793 266 583 32.0 41.0
18.995 / 5.5 287 478 3824 270 596 27.9 38.7
Conclusions:
In respect of the 28d study it was concluded in the study report:
In male and female groups of rats, exposed to diethyl carbonate for 7 h on 5 d for 4 weeks at a concentration of 18.995 mg/l air, no significant differences were found compared to the control group in respect of behaviour, body weight gain, blood status, functionality of liver and kidneys and organ weights.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
18 995 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
No official guideline method but methodology and results well documented, good quality standard.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
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
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
thrice per week, in total 10 applications
Dose / conc.:
2.9 other: g/kg bw/day (nominal)
Remarks:
Doses / Concentrations:
Basis: per animal dose of pure substance diethyl carbonate

No. of animals per sex per dose:
25 animals (no information on sex distribution)
Control animals:
other: yes, 0.17 % croton oil in acetone
Dose descriptor:
LOAEL
Effect level:
48.3 - 145 other: g/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
mortality
gross pathology
Remarks on result:
other:
Remarks:
Treated animals: of the 25 animals, 2 animals with tumours (papillomas), 2 other animlas died
Dose descriptor:
dose level: control group
Effect level:
0 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
mortality
gross pathology
Remarks on result:
other:
Remarks:
Control group (0.17 % croton oil in acetone): of 20 animals, 3 animals died, no animals with tumours (papillomas)
Critical effects observed:
not specified
Lowest effective dose / conc.:
48.3 other: g/kg bw/day (nominal)
System:
other: papillomas, tumours, lethality

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 (papillomas).

Conclusions:
Dermal application of the test substance diethylcarbonate to the clipped backs of mice (10 applications in total, thrice a week) resulted in 2 dead animals and 2 further animals with tumours (papillomas) (total of 25 animals). In the control group 17 mice survived, and none had tumours. In the review of BG Chemie (1994) was stated "In another control group which underwent comparable treatment with croton oil, 4/19 mice had papillomas. The results of the study were evaluated as negative by the authors (Salaman and Roe, 1956).". In the opinion of the author of this IUCLID dossier the results on the repeated dose toxicity (dermal) cannot be concluded as absolutely negative as two animals died and two showed tumors. Therefore a toxic effect of the test substance diethyl carbonate cannot be excluded completely. It should also be remarked when evaluating the above mentioned data that therein definitions and distinctions of "papillomas" and "tumours" are not fully clear.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
48 300 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Publication of acceptable quality.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Lowest effect level of all data. Only publication where testicular interstitial-cell tumours were found after chronic oral administration.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only study available on repeated inhalation toxicity

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Only study available on repeated dermal toxicity

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: testes

Repeated dose toxicity: inhalation - systemic effects (target organ) other: all gross lesions and masses

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

Justification for classification or non-classification

In both key references for the endpoints repeated dose toxicity oral and repeated dose toxicity dermal the terms "LOAEL" and "NOAEL" were not used. The terms were spotted out by the author of the IUCLID dossier. In every dose group (50, 250, 1000 ppm) of the oral study 1 to 2 testicular interstitial-cell tumours were found in male mice without similar findings in the control groups. Thus the author of this IUCLID dossier decided to set the lowest dose (50 ppm in water, approximately 7 mg/kg/d) as LOAEL for the test substance diethyl carbonate. In contrast the authors of the published data (Brown D. et al. 1978, endpoint record 7.5.1.001) set the highest administered dose (50 ppm in water, ca. 140 mg/kg/d) as the oral no-untoward-effect-level (male/female mice).

In the inhalation study the author concluded according to the obtained results that the test substance diethyl carbonate had no organotropic effects.

In the key reference for the endpoint repeated dose toxicty inhalation the term "NOAEC" was not used. The NOAEC was spotted out by the author of the IUCLID data set.

Regarding these results and the corresponding interpretation of the data, classification of the test substance diethyl carbonate for repeated dose toxicity is conclusive but not sufficient.