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Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
Published 1979
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Justification for type of information:
No studies are proposed for scientific reasons or reasons of animal welfare given the corrosive nature of sulphuric acid. When added to water, sulphuric acid rapidly dissociates to the hydrogen and sulphate ions (pKa = 1.92), with the hydrogen ion responsible for localised irritation and corrosivity toxicity. As structurally sulphuric acid and sodium sulphate differ only by the cation this approach is considered acceptable. The data therefore adequately covers the reproductive toxicity endpoint following high exposure to sulphate in drinking water.
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
other: Journal publication
Adequacy of study:
weight of evidence
Study period:
Published 1979
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thirty-one sows and 27 gilts were each assigned to three treatments to study the effect of sulfate water quality during gestation and lactation. Sodium sulfate was added to local water to give sulfate at: 320 ppm, 1820 ppm and 3320 ppm. Water was offered ad libitum from about 30 days post breeding through to day 28 of lactation. Fifty-four weaned pigs (representing the three treatment groups) were given water with 0 ppm, 3000 ppm (sulfate from sodium sulfate) or 3000 ppm (1:1 sulfate from magnesium and sodium sulfate) for a 28-day period.
Parameters evaluated were gestation or lactation gains, number or weight of pigs at birth or at weaning, water consumption, fecal consistency, daily gain
or feed to gain ratio.
GLP compliance:
no
Limit test:
no
Justification for study design:
- Premating exposure duration for parental (P0) animals: Water was offered (ad libitum) from approximately 30 days post breeding through to lactation day 28.
- Basis for dose level selection: Three sulfate concentrations, 320 ppm, 1820 ppm and 3320 ppm
- Inclusion/exclusion of extension of Cohort 1B. No, non-standard study (1989) which does not meet current guideline requirements.
- Termination time: Not stated
- Route of administration: Ad libitum via drinking water
- Other considerations:
Low number of pigs per group which does not reflect current guidance requirements.
Limited reproductive parameters recorded which does not reflect current guidance requirements.
The pig is considered an applicable experimental model.

In addition, an evaluation of the effect of water quality on offspring after weaning was examined. 54 four week-old pigs averaging 7.5 to 8.0 kg were assigned into nine groups. Each group consisted of two pigs from each of the three sow treatments. These groups were randomly allotted to three replications of three treatments:
1: Control water
2: 3000 ppm of added sulfate from sodium sulfate
3: 3000 ppm of added sulfate supplied equally from magnesium and sodium sulfate.
Each 2.4 x 3 m pen contained six pigs. All pigs were offered water and an 18% protein, fortified corn-soybean meal diet ad libitum for the 28-day trial.
Specific details on test material used for the study:
Sulfate in the form of analytical grade sodium sulfate was added as appropriate to achieve the desired concentrations.
Species:
pig
Strain:
not specified
Details on species / strain selection:
31 sows and 27 gilts of Hampshire, Yorkshire and Duroc breeds.
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- The reproductive trial involved 31 sows and 27 gilts, grouped separately on the basis of ancestry and weight.
- Source: Not stated
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Not stated
- Weight at study initiation: Not stated
- Fasting period before study: Not stated
- Housing: Housed in unsulfated , wooden, colony type houses located in dry lots.
- Diet (ad libitum): No, each animal was restricted to 1.8 kg of feed/per day via individual feeding stalls. Fortified corn-soyabean meal diets with 10% alfalfa meals (gestation) and 10% beet pulp (lactation) included 0.5% trace mineralized salt. Crude protein content was 12.65% and 15.70% respectively.
- Water (ad libitum): yes, available from 227 litre circular tank waterers.
Self-feeders containing the lactation diet and the 227 waterers were located distant to their housing. Animals were allowed access for 2 hours in the morning and 1.5 hours in the evening.
- Acclimation period: Not stated
ENVIRONMENTAL CONDITIONS
- Temperature (°C), Humidity (%), Photoperiod (hrs dark / hrs light): Not stated
IN-LIFE DATES: From: To: Not stated
Route of administration:
oral: drinking water
Vehicle:
water
Remarks:
The local water supply was used both for the control and for making the experimental waters.
Details on exposure:
In sows and gilts water (containing sulfates at 320, 1820 and 3320 ppm) was offered (ad libitum) from approximately 30 days post breeding through to lactation day 28.

To examine the effects of high sulfate levels on offspring after weaning, 54 weaned pigs representing the above three sow treatments were given water with 0 sulfates (Control), or 3,000 ppm sulfate (from sodium sulfate ) or 3,000 ppm sulfate (from magnesium and sodium sulfate, 1:1 ratio) for a 28-day period.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Sulfate content was determined weekly by turbidimetric method. Averages with their standard deviations for the entire experimental period were: Control, 320 (±24) ppm; low sulfate: 1790 (±35) ppm and high sulfate, 3298 (±139) ppm.
Duration of treatment / exposure:
For 30 days post-breeding sows and gilts were randomly assigned to three groups, a control group (320 ppm sulfate), a low sulfate group (1820 ppm sulfate) and high sulfate group (3320 ppm sulfate). Water was available ad libitum from 30-days post-breeding through to 28-days post-lactation. During gestation, feed was restricted to a daily amount of 1.8 kg/per head with sows allowed access for 2 hrs (am) and 1.5 hrs (pm). After parturition, offspring at 4-weeks were placed into three treatment groups to evaluate sulfate administration to offspring. The groups were, 1: (Control water), 2: (3000 ppm sulfate from sodium sulfate) and 3: (3000 ppm sulfate, 1:1 magnesium and sodium sulfate) for an exposure period of 28-days.
Frequency of treatment:
Exposure period was daily (ad libitum in water) from 30-days post breeding to 28-days post-lactation.
Details on study schedule:
The trial involved 31 sows and 27 gilts (grouped separately) which were randomly assigned to three treatment groups ca. 30 days post breeding. Local water was used as the control and for treatment formulations. The three three treatment groups were 320 ppm (control), 1820 ppm (low sulphate) and 3320 ppm (high sulfate). Analysis used a turbidimetric method. During gestation, feed was restricted to 1.8 kg/animal daily with water available ad libitum. Sows were allowed access to feed and water each morning and evening for 2 hrs and 1.5 hrs respectively. Saline water was available to pigs from a creep area after 10 days of age.

At parturition, the number of live and stillborn, litter weight and average pig weight were recorded. Litter weight at 14 days, number of pigs at 28 days, litter weight and average pig weight at 28 days were recorded.

To determine the effect of water quality on offspring after weaning, 54 four-week-old pigs were allotted to three treatment groups: a control group (water), a sulfate group of 3000 ppm of added sulfate from sodium sulfate and a high sulfate group of 3000 ppm of added sulfate 1:1 from magnesium and sodium sulfate. All pigs were offered water and diet ad libitum for the 28-day trial.
Dose / conc.:
320 ppm (nominal)
Remarks:
Control
Dose / conc.:
1 820 ppm (nominal)
Remarks:
Sulfate (Low) treatment group
Dose / conc.:
3 320 ppm (nominal)
Remarks:
Sulfate (High) treatment group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Three sulphate groups,
1: Control: Local water - Sulfate 320ppm
2: Sulfate (Low) group - 1820 ppm
3: Sulfate (High) group - 3320 ppm
- Rationale for animal assignment (if not random): Random
- Fasting period before blood sampling for clinical biochemistry: Not stated
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Litter observations:
At parturition, the number of live and stillborn pigs as well as litter weight and average pig weight were obtained.
Litter weight at 14 days, number of pigs at 28 days, litter weight and average pig weight at 28 days were recorded.
Statistics:
Data were analyzed by least squares analysis of variance.
Reproductive indices:
Sulfates up to and including 3320 ppm in water have no significant effect on reproduction performance in the gilt or sow.
Offspring viability indices:
Sulfate content of water consumed during gestation had no significant effect on gestation gain, number of pigs per litter at birth (total and live) or average pig and litter birth weights.
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption did not differ during gestation but increased during lactation as salt level increased
Reproductive function: oestrous cycle:
not examined
Reproductive performance:
no effects observed
No significant differences in gestation or lactation gains and number
or weight of pigs at birth or at weaning were observed. Fecal consistency was normal in all treatments. Water consumption did not differ during gestation but
increased during lactation as salt level increased. Results suggest that sulfates up to 3320 ppm in water have no significant effect on reproduction in the gilt or sow.
Key result
Dose descriptor:
NOAEL
Effect level:
3 320 ppm
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable because of methodological limitations
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
After 28-days exposure to weaned pigs, no significant treatment differences in average daily gain
or feed to gain ratio were noted. Water consumption was greater among pigs that received water with added sulfates. No differences were observed in pigs that received water containing sodium sulfate or equal parts of sulfate from sodium and magnesium sulfate.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable because of methodological limitations
Key result
Critical effects observed:
not specified
Key result
Reproductive effects observed:
not specified
Effect Of Sulfate Content Of Water On Reproductive Performance





















































Parameter


0(Control)


3000 ppm
Na Sulfate


3000 ppm
Mg & Na Sulfate


No. of pigs a


16


18


17


Avg initial wt. (kg)


7.5


8.0


7.7


Avg final wt. (kg)


13.4


15.0


13.8


Avg daily gain (kg)


0.21


0.25


0.22


Feed to gain ratio


2.25


2.05


2.18


Avg daily water consumption (l)


1.25 b


1.89 c


1.63 d


Avg fecal condition e


1.7 f


3.3 g


3.6 g


a: Three replications of six pigs per treatment. Three pigs died, data not included.
b, c, d: Means on the same line with different superscripts are significantly different (P<.05).
e: Based on a score of 1 to 5, with 1 being firm.
f, g: Means on same line with different superscripts are significantly different (P<.01).
Conclusions:
Study results suggest that sulfates up to and including 3320 ppm in water have no significant
effect on reproduction either in the gilt or sow. Furthermore, no significant treatment differences occurred in average daily gain or feed and gain ratio in offspring after weaning administered high sulfate levels of 3000 ppm with sulfate (from sodium sulfate) or 3000 ppm sulphate (equally from sodium and magnesium sulfate).
Executive summary:

In this study, thirty-one sows and 27 gilts were each assigned to three treatments groups to study the effect of water quality during gestation and lactation. Sodium sulfate was added to the water to give sulfate at 320 ppm, 1820 ppm and 3320 ppm. Water was offered ad libitum from about 30 days postbreeding through 28 days lactation.  It was concluded that sulfate content of water consumed during
gestation had no significant effect on gestation gain, number of pigs per litter at birth (total and live) or average pig and litter birth weights. Sulfate in water during lactation also had no sigificant effect on lactation gain, number of pigs at 28 days and average pig and litter weights at 28 days. The ingestion of sulfates in water upto 3320 ppm had no effect of reproductive performance. When water quality was evaluated using the offspring after weaning, no significant differences occurred at 28 days in average daily gain or feed to gain ratio among weaned pigs that consumed 3000 ppm sulfate (from sodium sulfate) or 3000 ppm sulphate (equally from sodium and magnesium sulfate).


 

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Sulphuric acid
EC Number:
231-639-5
EC Name:
Sulphuric acid
Cas Number:
7664-93-9
Molecular formula:
H2O4S
IUPAC Name:
sulfuric acid
Details on test material:
Sodium sulphate

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption did not differ during gestation but increased during lactation as salt level increased

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

No significant differences in gestation or lactation gains and number
or weight of pigs at birth or at weaning were observed. Fecal consistency was normal in all treatments. Water consumption did not differ during gestation but
increased during lactation as salt level increased. Results suggest that sulfates up to 3320 ppm in water have no significant effect on reproduction in the gilt or sow.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
3 320 ppm
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable because of methodological limitations

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Details on results (F1)

After 28-days exposure to weaned pigs, no significant treatment differences in average daily gain
or feed to gain ratio were noted. Water consumption was greater among pigs that received water with added sulfates. No differences were observed in pigs that received water containing sodium sulfate or equal parts of sulfate from sodium and magnesium sulfate.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable because of methodological limitations

Target system / organ toxicity (F1)

Key result
Critical effects observed:
not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
not specified

Any other information on results incl. tables

Effect Of Sulfate Content Of Water On Reproductive Performance





















































Parameter


0(Control)


3000 ppm
Na Sulfate


3000 ppm
Mg & Na Sulfate


No. of pigs a


16


18


17


Avg initial wt. (kg)


7.5


8.0


7.7


Avg final wt. (kg)


13.4


15.0


13.8


Avg daily gain (kg)


0.21


0.25


0.22


Feed to gain ratio


2.25


2.05


2.18


Avg daily water consumption (l)


1.25 b


1.89 c


1.63 d


Avg fecal condition e


1.7 f


3.3 g


3.6 g


a: Three replications of six pigs per treatment. Three pigs died, data not included.
b, c, d: Means on the same line with different superscripts are significantly different (P<.05).
e: Based on a score of 1 to 5, with 1 being firm.
f, g: Means on same line with different superscripts are significantly different (P<.01).

Applicant's summary and conclusion

Conclusions:
Study results suggest that sulfates up to and including 3320 ppm in water have no significant
effect on reproduction either in the gilt or sow. Furthermore, no significant treatment differences occurred in average daily gain or feed and gain ratio in offspring after weaning administered high sulfate levels of 3000 ppm with sulfate (from sodium sulfate) or 3000 ppm sulphate (equally from sodium and magnesium sulfate).
Executive summary:

In this study, thirty-one sows and 27 gilts were each assigned to three treatments groups to study the effect of water quality during gestation and lactation. Sodium sulfate was added to the water to give sulfate at 320 ppm, 1820 ppm and 3320 ppm. Water was offered ad libitum from about 30 days postbreeding through 28 days lactation.  It was concluded that sulfate content of water consumed during
gestation had no significant effect on gestation gain, number of pigs per litter at birth (total and live) or average pig and litter birth weights. Sulfate in water during lactation also had no sigificant effect on lactation gain, number of pigs at 28 days and average pig and litter weights at 28 days. The ingestion of sulfates in water upto 3320 ppm had no effect of reproductive performance. When water quality was evaluated using the offspring after weaning, no significant differences occurred at 28 days in average daily gain or feed to gain ratio among weaned pigs that consumed 3000 ppm sulfate (from sodium sulfate) or 3000 ppm sulphate (equally from sodium and magnesium sulfate).