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:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Rat, Han: of Wistar origin
Sex:
male/female
Details on test animals and environmental conditions:
The rat is commonly used species for toxicological studies in accordance with international recommendations.
The Wistar rat was the system of choice because it has been the preferred and most commonly used species for oral gavage toxicity tests and is a well-known laboratory model with sufficient historical data.
Route of administration:
oral: gavage
Details on route of administration:
The test item was administered orally via gavage.
Vehicle:
vegetable oil
Remarks:
Sunflower oil
Details on oral exposure:
Diethyl carbonate was suspended in the vehicle (sunflower oil) in concentrations of 25, 75 and 250 mg/mL.
Formulations were prepared in the formulation laboratory of the Test Facility beforehand for not longer than 4 days and stored in a refrigerator (5±3 °C) until use.
Table 1 contains the group numbers, doses and concentration of formulations that were administered to the animals.

Table 1: Concentrations used in the study

Groups
Dose
(mg/kg bw/day) Nominal concentration of formulations (mg/mL)
Group 1 0 0
Group 1 R⃰ 0 0
Group 2 100 25
Group 3 300 75
Group 4 1000 250
Group 4 R⃰ 1000 250
⃰ = Recovery
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical control of dosing formulations (verification of concentrations and homogeneity) was performed in the Analytical Laboratory of Test Facility three times during the study.
Duration of treatment / exposure:
90/91 days
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control group
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15 animals/sex in the control and highest dose groups – including recovery animals – and 10 animals/sex in the low and middle dose groups
Control animals:
yes, concurrent no treatment
Positive control:
without positive control group
Clinical signs:
no effects observed
Description (incidence and severity):
Diethyl carbonate did not induce clinical signs at 100, 300 or 1000 mg/kg bw/day in male or female animals during the course of the 90/ 91-day administration or the four weeks recovery period.
Mortality:
no mortality observed
Description (incidence):
There was no mortality in the control, 100, 300, or 1000 mg/kg bw/day groups during the 90/91-day treatment (male/ female, respectively) period or during the following 4-week recovery period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no test item related changes in the mean body weight and body weight gain in the male and female animals at 100, 300 and
1000 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No adverse effects on the mean food consumption development were observed at 100, 300 or 1000 mg/kg bw/day in male or female animals (main and recovery groups).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No alterations were detected in the eyes of the animals of the high dose group at the end of treatment or recovery periods.
Haematological findings:
no effects observed
Description (incidence and severity):
There were no test item related adverse pathological changes in the investigated hematological or blood coagulation parameters in any group
(main and recovery groups).
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Pathological test item effects were not detected upon the evaluation of the clinical chemistry parameters in male or female animals at 100, 300 and 1000 mg/kg
bw/day (main and recovery groups).
In male and female animals at 100, 300 and 1000 mg/kg bw/day the level of FT3 (free T3) and FT4 (free T4) thyroid hormones
were normal at the end of treatment and recovery period. The levels of TSH were below the limit of detection.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment related alterations were found in the organ weight results (absolute weights, relative to the body weight and brain weight) in male and female animals
compared to the control parameters (main and recovery groups).
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Macroscopic alterations related to the test item were not detected at the necropsy at the termination of the treatment and at the end of the recovery period.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item related lesions in the organs or tissues of high dose animals (no general histopathological examination was performed for low and mid dose
animals).
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
A test item effect on the estrous cycle was not detected at any dose level. In accordance with this observation, histopathological examinations did not reveal
changes in the morphology of uterus or ovaries in this study.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects caused by the test item were observed during the study.
Key result
Critical effects observed:
no
Conclusions:
Under the conditions of the present study, Diethyl carbonate did not cause adverse
effects in male or female Han:WIST rats after 90/91-day consecutive oral (by gavage) administration of 100, 300 or 1000 mg/kg bw/day doses.

There were no toxic changes in the examined parameters (clinical signs, body weight
and body weight gain, food intake, ophthalmology, hematology, blood coagulation and clinical chemistry, serum levels of thyroid hormones, estrous cycle necropsy findings, organ weights or histopathological findings).

Based on the observations made in this toxicity study the No Observed Adverse Effect
Level (NOAEL) was determined as follows.

NOAEL: 1000 mg/kg bw/day for male and female animals
Executive summary:

The objective of this study was to obtain information on the possible health hazards likely to arise from repeated exposure of Diethyl carbonate over a 90/91-day period of time covering post-weaning maturation and growth well into adulthood followed by a 28-day recovery (post treatment) period in order to assess reversibility, persistence or delayed occurrence of potential toxic effects according to OECD 408.The study intended to provide information on the major toxic effects, indicate target organs and the possibility of accumulation, and an estimate of a no-observed-adverse-effect level (NOAEL) of exposure.

Four dose groups of Han:WIST ratsconsisting of15 animals/sex in the control and highest dose groups – including recovery animals – and 10 animals/sex in the low and middle dose groups were administered orally (by gavage) once daily at 0 (vehicle only), 100, 300and 1000 mg/kg body weight/day (mg/kg bw/day) doses in concentrations of 0, 25, 75and 250 mg/mL corresponding to a 4 mL/kg bw dosing volume. A group of vehicle (Sunflower oil) treated animals (n= 15/sex) served as a control.

The suitability of the chosen vehicle (recovery and stability) for the test item at the intended concentrations was analytically verified up front.

Diethyl carbonateconcentrations in the dose forms used for administration of animals varied within the range of 95 % to 100 % in comparison to the nominal values, thereby confirming proper dosing.

 

General clinical cage side observations were made once a day, at approximately the same time after treatment and during the course of the recovery period. Detailed clinical observations were performed weekly during the treatment and recovery period andfunctional observations were made during the last week of treatment and recovery periods. Body weights and food consumption were determined weekly during the entire study.Ophthalmologic examinations were performed on all animals being considered for study before the first treatment and on all animals of the control and high dose groups during the last week of treatment and recovery periods.Clinical pathology (hematology, blood coagulation, clinical chemistry andthyroid hormones) and gross pathology examinations were conducted on all animals one day after the last treatment and at the end of the recovery period. Selected organs were weighed. Full histopathological examinations were performed on the organs and tissues of the control and high dose groups (main and recovery groups). The estrous cycle of each female animal was examined on the day of necropsy.

The results of this study were summarized as follows:

Mortality: There was no mortality during the course of the study.

Clinical observations: No clinical signs related to the test item were found at general daily

or detailed weekly clinical observations at 100, 300 and 1000 mg/kg bw/day. The functional

observations did not reveal any test item influence on the animal behavior or neurological functions.

Body weight and body weight gain: There were no test item related changes in the mean body weight and body weight gain in the male and female animals at 100, 300 and

1000 mg/kg bw/day.

Food consumption: No adverse effects on the mean food consumption development were observed at 100, 300 or 1000 mg/kg bw/day in male or female animals (main and recovery groups).

Ophthalmoscopy: No alterations were detected in the eyes of the animals of the high dose group at the end of treatment or recovery periods.

Hematology and blood coagulation: There were no test item related adverse pathological changes in the investigated  hematological or blood coagulation parameters  in any group

(main and recovery groups).

Clinical chemistry: Pathological test item effects were not detected upon the evaluation of the clinical chemistry parameters in male or female animals at 100, 300 and 1000 mg/kg

bw/day (main and recovery groups).

Determination of serum levels of thyroid hormones: In male and female animals at 100, 300 and 1000 mg/kg bw/day the level of FT3 (free T3) and FT4 (free T4) thyroid hormones

were normal at the end of treatment and recovery period. The levels of TSH were below the limit of detection.

Organ weight: No treatment related alterations were found in the organ weight results (absolute weights, relative to the body weight and brain weight) in male and female animals

compared to the control parameters (main and recovery groups).

Histopathology: There were no test item related lesions in the organs or tissues of high dose animals  (no  general  histopathological  examination was performed  for  low and mid  dose

animals).

Estrous cycle examination: A test item effect on the estrous cycle was not detected at any dose level. In accordance with this observation, histopathological examinations did not reveal

changes in the morphology of uterus or ovaries in this study.

Necropsy: Macroscopic alterations related to the test item were not detected at the necropsy at the termination of the treatment and at the end of the recovery period.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
OECD 408 study is available.

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

-----------

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.

----------

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:
2 (reliable with restrictions)
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.