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Toxicological information

Toxicity to reproduction

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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

Reference
Name:
Unnamed
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Groups I, Ia: 0.015%
Basis:
nominal in water
Remarks:
Doses / Concentrations:
Group II: 0.075%
Basis:
nominal in water
Remarks:
Doses / Concentrations:
Group III: 0.3%
Basis:
nominal in water
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)

open allclose all
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
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.