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Effects on fertility

Link to relevant study records

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Endpoint:
multi-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable publication with very detailed description of the conducted methods.
Principles of method if other than guideline:
chronic oral administration of the test substance with regard to offspring development.
GLP compliance:
not specified
Species:
rat
Strain:
other: Wistar-Stamm II BR 46
Sex:
male/female
Route of administration:
oral: drinking water
Vehicle:
water
Details on mating procedure:
Preliminary mating occurred during 20 days (daily changing of sexual partners) with 10 males and 10 females from two groups (treated with 0.015 % test substance, and control without test substance)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
100 weeks
Remarks:
Doses / Concentrations:
0.0 % (w/v), 0.0 mg/kg bw (males, females) -> control group
0.015 % (w/v), 3 mg/day, 6.5 mg/kg bw (males), 10.7 mg/kg bw (females);
0.075 % (w/v), 10 mg/day, 20.7 mg/kg bw (males), 35.7 mg/kg bw (females);
0.3 % (w/v), 60 mg/day, 130 mg/kg bw (males), 214.3 mg/kg bw (females);
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
>= 130 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: histopathological examination of reproduction organs and fertility
Remarks on result:
other: Generation not specified (migrated information)
Dose descriptor:
NOAEL
Effect level:
>= 214.3 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: histopathological examination of reproduction organs and fertility
Remarks on result:
other: Generation not specified (migrated information)
Dose descriptor:
NOAEL
Generation:
other: F3
Effect level:
10.7 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: weights of ovaries were slightly lower in the two higher dosage groups compared to control
Remarks on result:
other:
Remarks:
F3 generation; according to publication, however, no clear treatment-related signs of toxicity or of macroscopic or microscopic effects on the organs
Reproductive effects observed:
not specified

The only diseases related to the reproductive system in the parental animals were vulvar cancers in one female of group III (administration of 0.3 % diethylcarbonate) and one female of the control group (possibly also a tumour of the intestine). Ovarian cysts were not taken into account as these are observed frequently in rats and were therefore not regarded as relevant. Fertility was not affected in treatment groups compared to the controls in any generation.

In group III of the F3 -generation the weights of the ovaries were slightly decreased compared to the control group and group II (25.0 mg/100 g bw in group II, 0.075 %; 20.5 mg/100 g bw in group III, 0.3 %; 26.1 mg/100 g bw in control group); 10 females per group.

According to the publication no clear treatment-related signs of toxicity or of macroscopic or microscopic effects on the organs were found in any of the treated groups.

The authors of the publication summarised that there were no indications of diethyl carbonate having an organotropic effect.

Conclusions:
Rats were administered the test substance diethyl carbonate chronically at concentrations of up to 0.3 % (w/v) in drinking-water and possible effects on the reproduction system analysed. Histopathological analysis of testes and ovaries resulted in vulvar cancers in one treated female and one control female. Ovarian cysts were not taken into account as these would be frequently observed in rats. They were therefore not relevant in the opinion of the authors of the publication.

Another part of the experiment was a fertility-study over 3 generations (parent -> F1 -> F2 -> F3) in which the offsprings were always treated with the corresponding dose of the test substance of their parents. Compared to the controls the fertility of the treated animals was not affected by the test substance as stated in the publication. A lower weight of the ovaries in F3-females was observed in the highest dose group compared to the control group and the next lower treatment group (20.5 mg/100 g bw at 0.3 % versus 25.0 mg/100 g bw at 0.075 % and 26.1 mg/100 g bw in the control group). There was no statement made about the statistical significance of this data nor was it discussed in the results or discussion section. The data was only presented in a table. A concluding statement about the effect of the substance on ovary weight appears therefore not possible for this study. Other effects related to ovaries were not reported. There was no generation F4 bred with generation F3 as parents to investigate further influences on reproduction.

Date conclusive but not sufficient for classification.
Endpoint:
toxicity to reproduction
Remarks:
other: subacute: 7 hours at 5 subsequent days for 4 weeks
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:
rat
Sex:
male/female
Details on test animals and environmental conditions:
Animals: 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;
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
other: probably whole body
Vehicle:
air
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.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
7 hours at 5 subsequent days
Remarks:
Doses / Concentrations:
18.995 mg/L
Basis:
no data
average analytical concentration
No. of animals per sex per dose:
10
Control animals:
yes
Dose descriptor:
NOAEC
Effect level:
>= 18.995 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absolute and relative weights of testes and ovaries not different to control group
Remarks on result:
other:
Remarks:
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.
Dose descriptor:
other: -
Generation:
other: no F1 generation
Effect level:
0 mg/kg bw/day (nominal)
Based on:
other:
Remarks:
-
Sex:
male/female
Basis for effect level:
other: -
Remarks on result:
other:
Remarks:
-
Dose descriptor:
other: -
Generation:
other: no F2 generation
Effect level:
0 mg/kg bw/day (nominal)
Based on:
other:
Remarks:
-
Sex:
male/female
Basis for effect level:
other: -
Remarks on result:
other:
Remarks:
-
Reproductive effects observed:
not specified

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.

Absolute weight of testes:

Control 2835 mg; treated 2743 mg

Relative weight of testis (per 100 g bw):

Control 1162 mg/100g; treated 1226 mg/100g

Absolute weight of ovaries:

Control 78.1 mg; treated 70.8 mg

Relative weight of ovaries (per 100 g bw):

Control 41.0 mg/100g; treated 38.7 mg/100g

There were no significant differences between the absolute and relative weights of the reproductive systems of the animals (testes and ovaries).

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. There were no significant differences between the absolute and relative weights of the reproductive systems of the animals (testes and ovaries).
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
214.3 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
18 995 mg/m³
Additional information
Short description of key information:
Oral exposure:
oral administration of 0.015, 0.075, 0.3 % (w/v) in drinking water to rats (approximately 6.5, 20.7, 130 mg/kg/d for male rats with an average weight of 460 g; 10.7, 35.7, 214.3 mg/kg/d for female rats); no effects on the reproduction and fertility of the animals was seen in any dose group (see endpoint record 7.8.1.001 (key data) for more details)

Inhalation exposure:
Male and female rats were exposed to 18.995 mg/L of diethyl carbonate for 4 weeks (7 h/d). No effects to the reproductive organs of the animals were observed (see endpoint records 7.8.1.003 and 7.5.2.001 for more details, key data each).

Justification for selection of Effect on fertility via oral route:
the only data on fertiliy via the oral route

Justification for selection of Effect on fertility via inhalation route:
the only data on fertiliy via the inhalation route

Effects on developmental toxicity

Description of key information
In a study from Bayer (1969), diethyl carbonate was not toxic to mother animals, embryotoxic or teratogenic in the rat when exposed via drinking water ad libitum at a concentration < 1 % (10000 ppm, 956 mg/kg/day) during day 6 to 15 of gestation (see endpoint record 7.8.2.001 for more details (key study)).
However, in a publication from 1966, some effects on the weight development of organs in female rats (thyroid, adrenal glands, ovaries) may have occurred. This was not conclusively discussed in the publication. The data is not deemed to be sufficient for a classification. Conservatively, a LOAEL of 35.7 mg/kg bw was pointed out (7.8.2.002, key study).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable publication with very detailed description of the conducted methods.
Principles of method if other than guideline:
Method: other: multigeneration toxicity study
GLP compliance:
no
Species:
rat
Strain:
other: Wistar II BR 46
Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
>= 214.3 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: other
Remarks on result:
other: -
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
LOAEL
Effect level:
35.7 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: weight of organs, F3 generation
Remarks on result:
other: -
Abnormalities:
not specified
Developmental effects observed:
not specified

In summary it is stated in the publication that the administration of the test substance in every treatment group (I-III) and every generation (F1 -F3) did not affect the fetal development nor the development of the newborns compared to the control.

In an additional experiment male and female animals from the F1 -generation of the lowest treatment group and control group (10 weeks old, average weight 230 g) were used to measure the respiration of oxygen. In both groups no differences were observed (respiratory quotient 0.82 for both groups).

In 20 weeks old F3 -animals of the two highest treatment groups (0.075, 0.3 % (w/v)) and the control group analysis of the blood sugar was conducted. The obtained values did not differ between the treatment groups and the control.

In the publication it is summarised that the histological analysis of treatment animals and control animals including weights of endocrine organs did not show any differences between treated and control animals for the generation F1 -F3.

However, for the F3 generation it is in addition referred to a table where organ weights are listed upon treatment.

There is no info about the statistical significance of this table data. This data is also not further discussed. Abnormalities in shape etc. have apparentyl not occurred.

Overview of organ weights for F3 generation:

Dose group Sex Number of animals Pituitary average weight (mg) Pituitary average weight (mg/100 g bw) Thyroid average weight (mg) Thyroid average weight (mg/100 g bw) Adrenal gland average weight (mg) Adrenal gland average weight (mg/100 g bw) Ovaries average weight (mg) Ovaries average weight (mg/100 g bw)
Control m 10 11.3 2.4 20.9 4.5 49.2 10.4 / /
0.075 % m 10 11.1 2.3 20.5 4.3 37.8 7.9 / /
0.3 % m 10 11.3 2.4 21.2 4.5 42.8 9.0 / /
Control f 10 11.8 4.0 14.7 4.9 64.3 21.7 77.1 26.1
0.075 % f 10 12.1 4.2 16.7 5.8 56.7 19.5 72.3 25.0
0.3 % f 10 11.4 3.8 18.1 6.0 53.0 17.6 61.8 20.5
Control m+f 20 11.6 3.2 17.8 4.7 56.8 16.1 / /
0.075 % m+f 20 11.6 3.2 18.6 5.0 47.3 13.7 / /
0.3 % m+f 20 11.4 3.1 19.7 5.2 47.9 13.3 / /

For the author of the IUCLID dossier, it may be disputable if there was some effect of the substance on weight development for the following organs (boldly marked numbers): thyroid, adrenal gland, ovaries.

Conclusions:
In this study rats administered the test substance diethyl carbonate via drinking-water (0.015, 0.075, 0.3 % (w/v)) were mated and the resulting offsprings treated as their parents. In total three generations were bred like this and all offsprings received the corresponding parental concentration of the test substance. The authors of the publication summarised that they never found any differences in fetal development, development of the newborns, blood sugar composition, oxygen respiration and histopathological analysis, including weights of endocrine organs, in the treated groups and the control. The authors of the publication concluded that the test substance diethyl carbonate had no embryotoxic or teratogenic effects. They also pointed out that it may, however, not possible to fully exclude the possibility of teratogenicity.

For the author of the IUCLID dossier, it may be disputable if there was some effect of the substance on weight development of the following organs (boldly marked numbers in the table, in results section): thyroid, adrenal gland, ovaries. These data on the F3 generation were presented in a table of the publication but was not further discussed in respect of their significance.

Data conclusive but not sufficient for classification.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
35.7 mg/kg bw/day
Additional information
Justification for selection of Effect on developmental toxicity: via oral route:
See also discussion under "Short description of key information". The data under 7.8.2.001 (study from Bayer (1969)) is regarded as more profound than this data source. However, in a conservative approach this data delivers a lower effect level, LOAEL of 35.7 mg/kg bw/d.

Justification for classification or non-classification

The data is regarded as conclusive but not sufficient for a classification as reproductive toxicant.