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Toxicity to reproduction

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Administrative data

one-generation reproductive toxicity
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
Study period:
no data
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Sodium sulfate was tested, Limited documentation, low numbers of animals per dose group, only females were treated, no fertility indices were measured.

Data source

Reference Type:
Influence of sulfate in drinking water on mouse reproduction during two parities.
Andres CJ and Cline TR
Bibliographic source:
J Anim Sci 67: 1313-1317.

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
see principels
Principles of method if other than guideline:
10 females were treated with sodium sulfate, the males were untreated.
Sixty random-bred ICR female virgin mice were used. Mice were assigned randomly to one of six water treatments (control, Na control, 4 dose levels of sodium sulfate). All groups contained equal levels of Na, which was maintained by varying the amount of sodium bicarbonate added. The treated water was available ad libitum beginning 1 wk prior to breeding and was continued throughout the experiment. After 1 wk of acclimation to the treatments, a male mouse that had received tap water was paired randomly with each female mouse. The females were checked every 24 hours in the morning for  the presence of a vaginal plug. After a vaginal plug was observed, the  male mouse was removed and the female was weighed. Water consumption was measured daily during the 2nd and 3rd wk of gestation, and the 1st and 2nd wk of lactation. At parturition, the dams were weighed and litter size was recorded. The litters then were standardized to eight pups per litter. At 21 days postpartum, the pups were weaned and the litters and dams were weighed individually. The dams were then rebred at first estrus immediately following weaning. This procedure was carried out over two parities. Only animals that whelped during each parity were used in the analysis. Thus, the number of dams per dose group in the first parity  was 4-9, in the second parity it was only 4. Fertility indices were not  measured.
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Reference substance name:
Sodium sulfate
Sodium sulfate
Constituent 2
Reference substance name:
EC Number:
Cas Number:
Details on test material:
Analogous compound

Sodium sulfate; no further data

The doses 625, 1250, 250 and 5000 mg sulfate/ litre correspond to the following dose levels:

1) 625 mg sulfate/l:
first parity
gestation: ca. 250-300 mg sulfate/kg bw
lactation: ca. 450-710 mg sulfate/kg bw
second parity
gestation: ca. 270-360 mg sulfate/kg bw
lactation: ca. 470-840 mg sulfate/kg bw

2) 1250 mg sulfate/l:
first parity
gestation: ca. 480-570 mg sulfate/kg bw
lactation: ca. 930-1450 mg sulfate/kg bw
second parity
gestation: ca. 595-920 mg sulfate/kg bw
lactation: ca. 1390-2040 mg sulfate/kg bw

3) 2500 mg/kg sulfate/l:
first parity
gestation: ca. 1270-1660 mg sulfate/kg bw
lactation: ca. 2290-3180 mg sulfate/kg bw
second parity
gestation: ca. 1500-1875 mg sulfate/kg bw
lactation: ca. 2560-4320 mg sulfate/kg bw

4) 5000 mg sulfate/l
first parity
gestation: ca. 1790-2190 mg sulfate/kg bw
lactation: ca. 3680-5360 mg sulfate/kg bw
second parity
gestation: ca. 2025-2610 mg sulfate/kg bw
lactation: ca. 3910-6560 mg sulfate/kg bw

Test animals

Details on test animals or test system and environmental conditions:
random-bred virgin female ICR mice
- Housing: individually in stainless steel cages
- Diet (ad libitum): commercially prepared breeder block
- Water (ad libitum): dosing solution or control water
- Acclimation period: 1 week

- Temperature (°C): 23.6 °C
- Humidity (%): 55%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Details on mating procedure:
cohabitation with untreated males
- M/F ratio per cage: 1/1
- Length of cohabitation: 24 h
- Proof of pregnancy: vaginal plug
Duration of treatment / exposure:
Exposure period: from one week prior to breeding until study end (day 21 of second parity)
Premating exposure period (males): no treatment (tap water ad lib)
Premating exposure period (females): 1 week
Frequency of treatment:
continuously in the drinking water
Doses / concentrations
Doses / Concentrations:
625, 1250, 2500 or 5000 mg sulfate/l in drinking water
nominal in water
No. of animals per sex per dose:
10 females per group
Control animals:
yes, concurrent vehicle


Least squares mean analysis of variance (SAS, 1982).
Student's t-test was used to determine the difference in water consumption.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
Effect level:
5 000 mg/L drinking water

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Control mice, receiving only distilled water, consumed significantly less than mice receiving sulfate treatments, and sodium-control mice drank significantly more water than mice treated with sulfate.

No differences were found in litter size, litter weaning weights, or gestational or lactational weight gain of the dams among sulfate treatments.

For further details, see attached files.

Applicant's summary and conclusion

Executive summary:

Sixty random-bred albino mice were randomly assigned to six sulfate treatments. Sodium sulfate was added to deionized distilled water to give sulfate levels in ppm as follows:

(1) 0 (control);

(2) 0 (Na control);

(3) 625;

(4) 1250;

(5) 2500 and

(6) 5000.

Treatments 2 to 6 contained the same Na content (2392 ppm) by varying Na bicarbonate content. Mice receiving only the deionized distilled water drank less (P <0.05) than mice receiving the other treatments at all times measured. Animals offered the 0 (Na control) water drank more (P < 0.05) water than mice on the other sulfate treatments. There was no difference (P> 0.10) in litter size, litter weaning weight, or gestational and lactational weight gain of the dams among water treatments. Although levels of sulfate up to 5000 ppm and 2392 ppm Na in the thinking water cubicly altered water consumption, they did not affect litter size, litter weaning weight, or gestational and lactational weight gain of the dam when sulfate ingestion was continued over two parities.