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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data is from safety assessment reports

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
MAK Value documentation for the test chemical
Author:
MAK Commission
Year:
2018
Bibliographic source:
The MAK Collection of Occupational Health and Safety, 2018
Reference Type:
other: Secondary Literature
Title:
Effect of maternal exposure to the chemical in rats
Author:
KRYSTYNA SITAREK et.al.
Year:
1992
Bibliographic source:
Polish Journal of Occupational Medicine and Environmental Health, 1992
Reference Type:
other: Authoritative database
Title:
HSDB for the TEST CHEMICAL
Author:
U S National Library of Medicine
Year:
2020
Bibliographic source:
HSDB, 2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
To determine the effects of maternal exposure to the test chemical during prenatal development phase
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-dioxolane
EC Number:
211-463-5
EC Name:
1,3-dioxolane
Cas Number:
646-06-0
Molecular formula:
C3H6O2
IUPAC Name:
1,3-dioxolane
Test material form:
liquid
Details on test material:
Name of the test chemical: 1,3-Dioxolane
Molecular Formula: C3H6O2
Molecular Weight: 74.07 g/mol
InChI: 1S/C3H6O2/c1-2-5-3-4-1/h1-3H2
Smiles Notation: C1COCO1
Substance type: organic
Physical state: liquid

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: breeding colony (Imp: DAK).
- Females (if applicable) nulliparous and non-pregnant: [yes/no] : yes, Nulliparous female rats
- Age at study initiation: (P) x wks; (F1) x wks : Nulliparous female rats, aged approximately 14 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g : Nulliparous female rats, aged approximately 14 weeks, weighing 199 + 12 g
- Fasting period before study:
- Housing: quarters
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): The animals were maintained on commercial pelleted chow (Fodder Factory, Motycz, Poland), ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: no daata available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled temperature (approx. 22°C)
- Humidity (%): Relative humidity varied between 45 — 55%.
- Air changes (per hr): no data available
- Photoperiod (hrs dark / hrs light): 12 hours cycle, illumination (light on between 6 a.m. and 6 p.m.)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: the inseminated females were divided into one control and three treatment groups receiving 0.025, 0.1 and 0.2 of median lethal dose of the test chemical which had been earlier found to be 5.8 g/kg.
Details on mating procedure:
- M/F ratio per cage: Females were mated overnight with 17-week-old male rats of the same strain.
- Length of cohabitation: Females were mated overnight with 17-week-old male rats of the same strain.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: The morning when copulation plugs or spermatozoa appeared in
vaginal smears was regarded as day 1 of gestation
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
The test chemical was administered orally, by gavage, every other day from day 8 do day 20 of gestation.
Frequency of treatment:
daily
Details on study schedule:
no data available
Doses / concentrations
Remarks:
Prenatal Phase study:0, 140, 580, 1150 mg/kg.day
Basis: 0.025, 0.1 and 0.2% of median lethal dose of the test chemical, LD50 = 5800 mg/kg
No. of animals per sex per dose:
exact number of rats not mentioned
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the inseminated females were divided into one control and three treatment groups receiving 0.025, 0.1 and 0.2 of median lethal dose of the test chemical which had been earlier observed to be 5.8 g/kg(5800 mg/kg).
Positive control:
no data available

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes / No / No data: YES
- Time schedule: DAILY
- Cage side observations checked in table [No.?] were included. : General appearance of the dosed rats was observed daily

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data: yes
- Time schedule: daily

BODY WEIGHT: Yes / No / No data: yes
- Time schedule for examinations: The maternal weight gain was observed throughout the gestation period

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data: The daily food and water
consumption intake were monitored throughout the gestation period.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: no data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data: yes
- Time schedule for examinations:The daily water consumption intake were monitored throughout the gestation period.
Oestrous cyclicity (parental animals):
no data available
Sperm parameters (parental animals):
no data available
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups, other. Particular attention should be paid to the external reproductive genitals which should be examined for signs of altered development; gross evaluation of external genitalia] : The uterus was opened and the number of live fetuses, dead fetuses, early and late resorption sites were recorded. A site was judged as a late resorption when macroscopic discrimination between fetal residues and placental material was possible. When this discrimination could not be made, the site was judged as an early resorption. Total implantation was calculated as the sum of the number of fetuses and resorption sites in each female. Live fetuses were measured for body weight, crown-rump length and examined for external malformations.

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead] :
Approximately half of the live fetuses from each litter were preserved in 95% ethanol for subsequent skeletal examination after staining with Alizarin S. The remaining fetuses were fixed in Bouin’s fluid for visceral examination
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]: The female rats were killed on day 21 of
gestation under ethyl ether anesthesia

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]: The uterus was opened and the number of live fetuses, dead fetuses, early and late resorption sites were recorded.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Statistics:
In the case of homogeneity of variance, one-way analysis of variance and Dunnett’s test were used: in the case of heterogeneity the Kruskal-Wallis analysis of variance was followed by non-parametric tests. Frequency data were analyzed with Fisher’s exact probability test. The effect of test chemical on behavioral performance, food and water consumption and body weight gain of the offspring was evaluated with two-way analysis of variance and Scheffe’s
test for multiple comparison.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
The general appearance and behaviour of the exposed and control animals did not differ significantly
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The toxic effect of the test chemical on the organism of the pregnant female rats was manifested by significantly smaller body weight gain during their pregnancy
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The daily intake of the food of the exposed and control animals did not differ significantly.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
The daily intake of the water of the exposed and control animals did not differ significantly.
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
the general appearance and behaviour of the exposed and control animals did not differ significantly.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Female rat fertility in terms of the percentage of the inseminated female rats found to be pregnant, and female rat fecundity in terms of the number of live fetuses in a litter were similar in the control group and in the groups exposed to the test chemical
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The test chemical when administered to the maternal rats at the dose of 1.15 g/kg (0.2 LD50) showed fetotoxic effect, causing a reduction of fetus body weights and length. The weight of the placenta in the female rats poisoned with 0.14 g/kg - 1.15 g/kg of this chemical was significantly higher than that in the controls. The dose-effect relationship, however, was not detected

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
580 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
reproductive function (oestrous cycle)
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
The number of live and dead litter per dose group didnot differ significantly from the controls
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The test chemical when administered to the maternal rats at the dose of 1.15 g/kg (0.2 LD50) showed fetotoxic effect, causing a reduction of fetus body weights and length.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macro evaluation of the internal organs of the fetuses did not reveal any macro pathology within the organs in any of the evaluated groups of the animals
Histopathological findings:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The frequency of occurrence of the delays in epicranial bones and sternum ossification was significantly higher in the groups which were prenatally exposed to higher doses of the test chemical

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
580 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

Table 1. Absolute and relative organ weights of female rats receiving daily by gevage test chemical on days 8—20 of gestation.

 

Control

0.14 g/kg

0.58 g/kg

1.15 g/kg

Liver

14

18

18

17

(g)

11.69 ± 1.5“

 11.68 ± 1.27

 11.62 + 1.08

 11.21 + 1.02

(g%)

3.91 + 0.24

 3.86 ± 0.24

3.87 + 0.24

3.85 + 0.23

Kidneys

14

18

18

17

(g)

1.36 + 0.15

1.40 ±0.11

1.37 ± 0.13

1.37 ± 0.12

(g%)

0.46 ± 0.03

0.47 + 0.04

0.46 ± 0.03

0.47 ± 0.04

Adrenals

14

18

18

17

(mg)

71.4 + 6.3

72.9 + 9.0

 74.4 ± 8.2

80.1 ± 13.8

(mg%)

24.2 + 2.6

 24.3 ± 3.8

24.9 ± 2.7

27.7 ± 5.9*

 

Table 2: Effect of test chemical administered within 8 — 20 days of gestation on pregnancy and development in rats

 

Control

0.14 g/kg

0.58 g/kg

1.15 g/kg

Females inseminated

17 (82.4)a

 19 (94.7)

18 (100)

19 (89.5)

Live fetuses per litter

11.8 ± 2.2 b

11.3 ± 2.2

11.1 ± 1.6

12.0 ± 2.0

Dead fetuses per litter

0

0

0.06 ± 0.24

0.12 ± 0.33

Litters with resorptions

3

10

9

7

Litters with late resorptions

2

6

4

4

Resorption per litter with resorptions

1.1 ± 0b

1.7 ± 1.1

1.2 ± 0.4

1.1 ± 0.4

Body weight gain of dams (g)

102.1 ± 13.5b

104.7 + 17.6

101.1 ± 11.8

 86.8 ±20.5d

Fetal crown-rump length (cm)

4.2 ± 0.1c

4.1 ±0.1

 4.1 ± 0.08

3.8 ±0.2d

Fetal body weight (g)

3.4 ± 0 .2c

3.3 ± 0.3

 3.4 ± 0.2

3.4 ± 0.2d

Weight of placenta (g)

0.48 ± 0.4c

 0.58 + 0.18d

0.53 ±0.04d

 0.51 ±0.0 4 d

a — Percentage of pregnant females given in parentheses,

b — Mean + SD.

c — Mean of litter means + SD.

d — Significantly different (p < 0.05) from control group.

Applicant's summary and conclusion

Conclusions:
Based on all the available data and under the given study conditions and observations, the developmental and maternal NOAEL were both judged to be 580 mg/kg/day.
Executive summary:

A study was performed to determine the effects of maternal exposure to the test chemical during prenatal development phase. Female rats were given by gavage every other day from days 8 —20 of gestation an aqueous solution of test chemical at daily doses equal to 0.025, 0.1 and 0.2 of median lethal dose of the test chemical which had been earlier observed to be 5.8 g/kg(5800 mg/kg). Females were mated overnight with 17-week-old male rats of the same strain. The morning when copulation plugs or spermatozoa appeared in vaginal smears was regarded as day 1 of gestation. The control animals were given, by gavage, an equivalent volume of distilled water. The maternal weight gain, daily food and water consumption intake were monitored throughout the gestation period. The female rats were sacrificed on day 21 of gestation under ethyl ether anesthesia. The uterus was opened and the number of live fetuses, dead fetuses, early and late resorption sites were recorded. A site was judged as a late resorption when macroscopic discrimination between fetal residues and placental material was possible. When this discrimination could not be made, the site was judged as an early resorption. Total implantation was calculated as the sum of the number of fetuses and resorption sites in each female. Live fetuses were measured for body weight, crown-rump length and examined for external malformations. Approximately half of the live fetuses from each litter were preserved in 95% ethanol for subsequent skeletal examination after staining with Alizarin S. The remaining fetuses were fixed in Bouin’s fluid for visceral examination. The test chemical administration was not associated with increased embryo or fetus intrauterine death rates or congenital defects at any dose level. The mid (0.58 g/kg) and high dose (1.15 g/kg) were reported to be associated with dose-related delays in fetal development and the high dose showed clear maternal toxicity. The test chemical does not cause impairment of physical development or behavioral disturbances. Therefore, based on all the available data and under the given study conditions and observations, the developmental and maternal NOAEL were both judged to be 580 mg/kg/day.