Carbonic acid, ethyl methyl ester

Toxicity to reproduction

Administrative data

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study of a close chemical analogue. Study design not in accordance with OECD guideline 416 (giving less detailed information on male fertility effects), but a 3-generation reproduction study with results described in sufficient detail to assess validity of study conclusions.

Data source

Reference

Reference Type:

publication

Title:

Untersuchungen zur Toxikologie von Diaethylcarbonat

Author:

G. Bornmann. A. Loeser

Year:

1966

Bibliographic source:

Archiv fur Toxikologie 22, 98-114

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 10 female rats (exposed for a minimum of 9 weeks) were mated with similarly treated males (P generation): F1, F2 and F3 progeny produced by similar matings. Exposure to test substance in drinking water continued throughout. Fertility, post-implantation losses and developmental indicators were assessed.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diethyl carbonate

EC Number:

203-311-1

EC Name:

Diethyl carbonate

Cas Number:

105-58-8

Molecular formula:

C5H10O3

IUPAC Name:

diethyl carbonate

Details on test material:

Purity >99.5%, specific weight 0.9667 at 23 degrees C

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Initial group mean bodyweights 160-165g (males), 145g (females).
Individually housed (except for mating) in wire cages, fed (dry food) and given water (containing test substance, except for controls) ad libitum; room maintained at 26-28 degrees C.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Drinking (tap) water bottles were filled daily with amounts far in excess of daily consumption

Details on mating procedure:

10 females for each group were paired with 10 males from the same group. Partners were changed daily: females were paired for a total period of 20 days

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No analytical verification of test substance concentration in drinking water is specified. However all test solutions were prepared freshly each day

Duration of treatment / exposure:

Continuous from experimental start to 18 weeks post-partum for the F3 generation. P generation males and females were exposed for 9 weeks (groups Ia, IVa) or 27 weeks (all other groups) prior to mating; subsequently exposure continued throughout mating, gestation, weaning and into the following generation.

Frequency of treatment:

Continuous intake via drinking water

Details on study schedule:

F1, F2 generations separated from mothers at 4 weeks, mated at sexual maturity

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
Groups I, Ia: 0.015%
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
Group II: 0.075%
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
Group III: 0.3%
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
Groups IV, IVa: water controls
Basis:

No. of animals per sex per dose:

Total group sizes 30 males + 30 females (Groups I - IV), 40 males + 40 females (Groups Ia, IVa). From these groups, sub-groups of 10 males + 10 females were selected for P generation mating.

Control animals:

yes, concurrent vehicle

Details on study design:

Assessment of effects on reproduction was supplementary to a chronic toxicity study

Examinations

Parental animals: Observations and examinations:

Bodyweights and general observations of behaviour were recorded. After 16 and 32 weeks blood samples (8 rats/sex/group) were analysed for haematology parameters. Urine samples from males (10/group, groups I-IV) were analysed in week 38.
Implantation sites in the uteri of F1 and F2 females were counted and compared with numbers of live offspring produced.

Oestrous cyclicity (parental animals):

Vaginal swabs were inspected in weeks 8-9 (Groups IA, IVa P females, 20/group: Allen-Doisy test).

Litter observations:

Numbers of offspring born and survival up to 4 weeks post-partum.
Resting metabolism (oxygen consumption) of 6 F1 males/gp, bodyweight ca 230g, was measured in groups Ia and IVa.
Blood sugar levels measured in F3 males (groups II-IV).

Postmortem examinations (parental animals):

Gross observations at necropsy

Postmortem examinations (offspring):

Bodyweights and organ weights (pituitary, thyroid, adrenals, ovaries) of F3 rats were measured (10/sex/group, groups II-IV)

Reproductive indices:

Fertility rate (mated females).
Average litter size in all 3 generations.
Resorption rate (implantation sites/live young born).
% of foetuses becoming live progeny.

Offspring viability indices:

Post-partum survival at 4 weeks (end of weaning - separation from mother).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not specified

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

No adverse effects reported. Postimplantation losses (incidence of resportions) was not affected by treatment.
Haematology parameters and vaginal swabs showed no effects of treatment. Necropsy of rats in the concurrent chronic toxicity study found no gross abnormalities.

Effect levels (P0)

1

Dose descriptor:

NOAEC

Effect level:

0.3 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Daily intake/rat from 0.03% in water was at least 60 mg, corresponding to ca. 200 mg/kg bodyweight

2

Dose descriptor:

NOAEC

Effect level:

0.3 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Daily intake/rat from 0.03% in water was at least 60 mg, corresponding to ca. 200 mg/kg bodyweight

Remarks on result:

other: Generation: F3 (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Examined in F3 generation

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Examined in F3 generation

Gross pathological findings:

no effects observed

Description (incidence and severity):

Examined in F3 generation

Histopathological findings:

not specified

Details on results (F1)

No adverse effects reported.

Effect levels (F1)

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

0.3 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Daily intake/rat from 0.03% in water was at least 60 mg, corresponding to ca. 200 mg/kg bodyweight

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEC

Generation:

F2

Effect level:

0.3 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Daily intake/rat from 0.03% in water was at least 60 mg, corresponding to ca. 200 mg/kg bodyweight

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Table 1: Fertility and developmental data

Experimental group & generation	Mated females pregnant	Litter mean size, next generation	Mean 4-week survival in litter
Ia P	9/10	10.3	74.5%
Ia F1	10/10	9.9	42.4%
Ia F2	8/10	10.6	90.6%
IVa P	10/10	9.5	48.8%
IVa F1	10/10	10.9	74.3%
IVa F2	9/10	11.6	71.2%
II P	7/10	8.0	21.4%
II F1	7/10	10.3	93.1%
II F2	10/10	10.3	81.8%
III P	7/8	9.0	65.1%
III F1	10/10	9.8	93.9%
III F2	10/10	11.0	97.3%
IV P	10/10	9.5	43.2%
IV F1	10/10	10.1	95.0%
IV F2	9/10	9.1	97.6%

Table 2: Post-implantation loss data

Group & generation	Females with implants	Total implantation sites (X)	Live progeny born (Y)	Number of re-absorbed foetuses (X–Y)	Resorption rate (X/Y)	% foetal survival to parturition
Ia	9	111	85	26	1.306	76.6
Iva	9	123	104	19	1.183	84.6
II	7	85	72	13	1.181	84.7
III	10	140	98	42	1.429	70.0
IV	10	138	101	37	1.366	73.2
II	9	111	88	23	1.261	79.3
III	10	125	110	15	1.136	88.0
IV	10	108	82	26	1.317	75.9

Applicant's summary and conclusion

Conclusions:

Exposure to diethyl carbonate produced no evidence of reproductive toxicity in this study. It is reasonable to assume that ethyl methyl carbonate would produce closely similar results in a study of this type.