Registration Dossier

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1970

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): "DIÄTHYLCARBONAT"
- Analytical purity:
German, original statement: "Für die Untersuchungen wurde eine chemisch reine Verbindung verwendet."
English, original statement translated: For the examinations a chemically pure compound was used.

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levels

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.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.