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EC number: 231-665-7 | CAS number: 7681-38-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- from 2010-04-22 to 2010-08-31
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- This study has been performed in compliance with the: Swiss Ordinance relating to Good Laboratory Practice adopted May 18th, 2005 [SR 813.112.1]. This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted on November 26th, 1997 by decision of the OECD Council [C (97)186/Final]. These principles are compatible with Good Laboratory Practice regulations specified by regulatory authorities throughout the European Community, the United States (EPA and FDA), and Japan (MHLW, MAFF and METI). There were no circumstances that may have affected the quality or integrity of the data.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- TYPES OF QA INSPECTIONS: study plan; study based: test system, test item, dose preparation, raw data, body weight, treatment; process based: work up formulations analysis, histotechnique, appendix formulations analysis, appendix histopathology, report
- Limit test:
- no
Test material
- Reference substance name:
- Sodium sulphate
- EC Number:
- 231-820-9
- EC Name:
- Sodium sulphate
- Cas Number:
- 7757-82-6
- Molecular formula:
- H2O4S.2Na
- IUPAC Name:
- disodium sulfate
- Details on test material:
- Description: White Powder
Batch Number: 20091001
Molecular Weight: 142.04 g/mol
Purity: 99.5%
Expiry Date (Retest Date): 30-Sep-2010
Storage Conditions: Room Temperature (20 ± 5 °C)
Safety Precautions: Routine hygienic procedures (gloves, goggles, face mask).
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
Animals: Rat, RccHan: WIST(SPF)
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Harlan Laboratories, B.V.
Kreuzelweg 53
5961 NM Horst / Netherlands
Number of Animals: 40 males: 10 per group
40 females: 10 per group
Age (at Start of Treatment): 11 weeks
Body Weight Range
(at Start of Treatment): Males: 292 to 329 g
Females: 182 to 223 g
Identification: Cage card and individual animal number (ear tattoo).
Randomization: Computer-generated random algorithm. In addition body weights (recorded on the day of allocation) were taken into consideration in order to ensure similar mean body weights in all groups.
Acclimatization: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
ENVIRONMENTAL CONDITIONS
Conditions: Standard laboratory conditions. Air-conditioned with 10 - 15 air changes per hour, continuously monitored environmental conditions (temp. range: 22 ± 3 °C; relative humidity range: 30 – 73.5%). There was 12 hour fluorescent light / 12-hour dark cycle with music during the light period.
Accommodation: Individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding (‘Lignocel’ J.Rettenmaier & Söhne GmbH & CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba SA, 4303 Kaiseraugst / Switzerland). During the pre-pairing period, cages with males were interspersed amongst those holding females to promote the development of regular estrus cycles.
Diet: Pelleted standard Kliba Nafag 3433 rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) was available ad libitum (batch nos. 83/09 and 22/10).
Water: Community tap-water from Füllinsdorf was available ad libitum in water bottles.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- DOSE FORMULATIONS
The dose formulations were prepared weekly using the test item as supplied by the Sponsor.
Sodium Sulphate was weighed into a glass beaker on a tared precision balance and approximately 80% of the vehicle was added (w/v). Using a magnetic stirrer, a homogeneous suspension was prepared. Having obtained a homogeneous mixture, the remaining vehicle was added. Separate formulations were prepared for each concentration.
STORAGE OF DOSE FORMULATIONS
Dose formulations were stored at room temperature (20 ± 5 °C) in brown glass beakers.
TREATMENT
Method: Oral, by gavage
Rationale for Method: Administration by gavage is a common and accepted route of exposure for this type of studies.
Frequency of Administration: Once daily
Target Dose Levels: Group 1: 0 mg/kg/day (control group); Group 2: 100 mg/kg/day; Group 3: 300 mg/kg/day; Group 4: 1000 mg/kg/day
Rationale for Dose Level Selection: The dose levels were selected based on a previous dose range-finding toxicity study in Han Wistar rats, Harlan Laboratories Study C79092 (non-GLP), using dose levels of 100, 300 and 1000 mg/kg/day, resulting in a NOEL of 300 mg/kg/day.
Dose Volume: 10 mL/kg body weight
Duration of Acclimatization Period: 7 days
Duration of Treatment Period: Males (4 weeks); females (approximately 7 weeks) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- ANALYSIS OF DOSE FORMULATIONS
On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 2 g of each concentration were taken from the middle only to confirm stability (4 hrs and 7 days). During the second last week of the treatment, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to Analytic Department (Harlan Laboratories Ltd., Itingen / Switzerland) and stored there at -20 ± 5 °C until analysis.
The samples were analyzed by HPLC coupled to a conductivity detector following an analytical procedure developed at Harlan Laboratories. The test item was used as the analytical standard. Analyzed samples were not discarded without written consent from the study director.
Duplicates were taken of all samples and were stored at Harlan Laboratories Ltd., Füllinsdorf / Switzerland. The samples were not discarded without written consent from the study director.
The test item recoveries were found to be in the range of 86.7% to 97.4% with reference to the nominal concentration. The maximum variation from the mean of homogeneity samples which were taken from the top, middle and bottom of the samples, ranged from 0.5% to 4.7%. The stability of the application formulations was tested in samples taken four hours and seven days after preparation and stored at room temperature. The variation values ranged from 0.2% to 3.2% from the time-zero value. - Duration of treatment / exposure:
- Males: 4 weeks
Females: Approximately 7 weeks - Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Acclimatization: 7 days (males and females)
First Test Item Administration: Day 1 of pre-pairing (males and females)
Pre-Pairing: 14 days (males and females)
Pairing: 11 days (males); 11 days maximum (females)
Gestation: Approximately 21 days (females)
Treatment Ends: On day before sacrifice (males); on day 3 post partum (females)
Necropsy: After a minimum of 28 days treatment (males); on day 4 post partum (females)
Examinations
- Observations and examinations performed and frequency:
- Viability / Mortality: Twice daily
Clinical Signs: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy). Additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing.
Food Consumption: Males (weekly during pre-pairing and after pairing periods.); females (pre-pairing period days 1 - 8 and 8 - 14, gestation period days 0 - 7, 7 - 14 and 14 - 21 post coitum and lactation period days 1 - 4 post partum). No food consumption was recorded during the pairing period.
Body Weights: Recorded daily from treatment start to day of necropsy. - Sacrifice and pathology:
- TERMINATION OF THE STUDY
Males were sacrificed after they had been treated for at least 28 days. Dams were sacrificed on day 4 post partum.
When birth did not occur on the expected date (day 21 post coitum), the dam was sacrificed on day 25 post coitum.
NECROPSY
At the scheduled sacrifice, all parent animals were killed by an injection of sodium pentobarbital. All P generation animals were exsanguinated.
All parent animals were examined macroscopically for any structural changes at the scheduled necropsy.
For the parent animals, special attention was directed at the organs of the reproductive system.
The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites.
ORGAN WEIGHTS
At the scheduled sacrifice, the testes and epididymides of all parental males were weighed separately.
TISSUE PRESERVATION
The ovaries from all parental females were preserved in neutral phosphate buffered 4% formaldehyde solution.
The testes and epididymides from all parental males were preserved in Bouin’s fixative. The prostate and seminal vesicles from all males were fixed in neutral phosphate buffered 4% formaldehyde solution.
HISTOTECHNIQUE
All organ and tissue samples to be examined by the study pathologist were processed, embedded and cut at an approximate thickness of 2 - 4 micrometers and stained with hematoxylin and eosin. Additionally, the testes were stained by PAS-hematoxylin.
HISTOPATHOLOGY
Slides of all organs and tissues collected at terminal sacrifice from the animals of the control and high-dose groups were examined by the study pathologist. The same applied to all occurring gross lesions.
Special emphasis was made on the stages of spermatogenesis and histopathology of interstitial cell structure.
Histological examination of ovaries was carried out on any females (nos. 48, 49, 56 and 59) that did not give birth. Microscopic examination of the reproductive organs of all infertile males (nos. 8, 9, 16 and 19) was made.
A histopathology peer review was performed by the Pathology Department (Harlan Laboratories Ltd., Itingen / Switzerland) - Other examinations:
- LITTER OBSERVATIONS
The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 1 and 4 post partum.
TERMINATION AND NECROPSY OF OFFSPRING
Pups were sacrificed on day 4 post partum.
At the scheduled sacrifice, all pups were killed by an injection of sodium pentobarbital.
All pups were examined macroscopically for any structural changes at the scheduled necropsy. - Statistics:
- The following statistical methods were used to analyze food consumption, body weights, reproduction data, macroscopical findings and organ weight:
- Means and standard deviations of various data were calculated.
- The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Fisher's exact-test were applied if the variables could be dichotomized without loss of information.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- 1 IN-LIVE DATA - PARENTAL ANIMALS
1.1 CLINICAL SIGNS OR OBSERVATIONS
All animals survived until the scheduled necropsy and no clinical signs were noted during the entire duration of the study.
1.2 FOOD CONSUMPTION OF MALES
Pre-pairing and After Pairing Periods
Mean food consumption was not affected by the treatment with the test item at any dose level.
In order of ascending dose levels, the overall differences in food consumption were: ±0.0%, +2.4% and -0.8% during pre-pairing period and -1.7%, -7.4% and -2.9% during the after pairing period (percentages refer to the respective values of the control group).
1.3 FOOD CONSUMPTION OF FEMALES
Pre-pairing, Gestation and Lactation Periods
No statistically significant alterations of mean food consumption were observed at any dose level when compared to the respective values in the control group.
In order of ascending dose levels, the overall differences in food consumption were: +6.0%, ±0.0% and -3.3% during the pre-pairing period, +1.6%, +2.0% and -3.6% during the gestation period and -3.7%, +4.0% and -5.6% during the lactation period (percentages refer to the respective values of the control group).
1.4 BODY WEIGHTS OF MALES
Pre-pairing, Pairing and After Pairing Periods
No significant changes were observed in mean body weight and mean body weight gain.
In the order of ascending dose levels, the overall mean body weight gains were: +11%, +9%, +13% and +11% during the pre-pairing period, +6%, +5%, +5% and +4% during the pairing period and +4%, +4%, +4% and +3% during the after pairing period (percentages refer to the respective time intervals).
1.5 BODY WEIGHTS OF FEMALES
Pre-pairing, Gestation and Lactation Periods
No significant alterations of mean body weights and mean body weight gain were observed at any dose level when compared to the respective values in the control group.
In the order of ascending dose levels, the overall mean body weight gain was +10%, +11%, +12% and +9% during the pre-pairing period and +57%, +59%, +57% and +57% during the gestation period and +5%, +4%, +6% and +6% during the lactation (percentages refer to the respective time intervals).
2 REPRODUCTION AND BREEDING DATA
2.1 MATING PERFORMANCE AND FERTILITY
The median and mean precoital times were unaffected by treatment with the test item. Mean precoital times were 3.3, 4.3, 3.3 and 3.1 days in order of ascending dose level. The median precoital time was 3, 4, 3 and 3 days in order of ascending dose level.
Two females each in groups 1 and 2 were not pregnant. Thus the fertility indices were 80.0%, 80.0%, 100.0% and 100.0% in groups 1, 2, 3 and 4.
2.2 DURATION OF GESTATION
The mean duration of gestation was unaffected by treatment with the test item. Mean duration of gestation was 21.4, 21.5, 21.7 and 21.5 days, in order of ascending dose level.
2.3 CORPORA LUTEA COUNT
The mean number of corpora lutea per dam (determined at necropsy) was similar in all groups (14.6, 14.1, 14.2 and 14.1 in order of ascending dose level) and gave no indication of a test item-related effect.
2.4 IMPLANTATION RATE AND POST-IMPLANTATION LOSS
The mean number of implantations per dam and the post-implantation losses were unaffected by treatment with the test item.
The mean numbers of implantations per litter were 13.3, 13.5, 14.0 and 13.3 in order of ascending dose level. The mean incidence of post-implantation loss as a percentage of total implantations was 10.4, 5.6, 10.0 and 3.8% in order of ascending dose level.
2.5 LITTER SIZE AT FIRST LITTER CHECK
The number of live pups at first litter check was unaffected by treatment with the test item. The mean number of live pups per litter was 11.9, 12.8, 12.6 and 12.8 in order of ascending dose level. The number of pups found dead at first litter check was two pups each in the control group and in group 2.
2.6 POSTNATAL LOSS DAYS 0 - 4 POST PARTUM
The total number of pup loss during the first four days was only one pup in the control group on day 3. Therefore the viability indices were 98.9% in the control group and 100.0%, in groups 2, 3 and 4.
3 TERMINAL FINDINGS - PARENTAL ANIMALS
3.1 ORGAN WEIGHTS
In males, weights (absolute and relative to body weight) of testes and epididymides were not affected by the treatment with the test item in any groups.
3.2 MACROSCOPICAL FINDINGS
Males
In group 4, three males were noted to have the pelvis of right kidney dilated.
In group 3, no abnormal findings were noted.
In group 2, one male was noted to have both testes and epididymides reduced in size.
In control group, one male was noted to have a pelvic dilation and enlargement of left kidney and another male to have both testes and epididymides reduced in size.
Type and frequencies of these findings did not give an indication of a test item-related effect.
Females
No abnormal findings were noted in females.
3.3 HISTOPATHOLOGY FINDINGS
All findings recorded were within the range of normal background lesions which may be recorded in rats of this strain and age.
In testes of animal no. 9 in group 1 and no. 19 in group 2, marked to severe tubular atrophy was found bilaterally and this finding was considered to be associated with their infertility. In the above 2 animals, aspermia and cellular debris in epididymides which were considered to be associated with the tubular atrophy of testes were also observed. No microscopic findings were found in other reproductive organs of these animals, reproductive organs of other infertile males (nos. 8 and 16) and ovaries of females (nos. 48, 49, 56 and 59) that did not give birth.
Treatment with the test item did not reaveal effects on the completeness of stages or cell populations. There was no indication for maturation arrest or any other degenerative type.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: NOEL = highest dose tested
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
SUMMARY OF PERFORMANCE
P Animals Breeding for F1 Litters
Group |
1 |
2 |
3 |
4 |
Female numbers |
41-50 |
51-60 |
61-70 |
71-80 |
Number of females paired |
10 |
10 |
10 |
10 |
Number of females mated |
10 |
10 |
10 |
10 |
Number of pregnant females (A) |
8 |
8 |
10 |
10 |
Number of females which reared their pups until day 4 post partum |
8 |
8 |
10 |
10 |
(A) Female Nos. 48 and 49 in group 1 and nos. 56 and 59 in group 2 were not pregnant.
Applicant's summary and conclusion
- Conclusions:
- This study is a valid investigation of the toxicological effects resulting from repeated oral-gavage administration of the test item Sodium Sulphate to rats. Sodium Sulphate was administered in highly purified water as vehicle at dosages of 100, 300, and 1000 mg/kg body weight/day, and controls received the vehicle only. Sodium Sulphate was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.
In absence of any effect the general NOEL (No Observed Effect Level) was established at 1000 mg/kg/day. - Executive summary:
The purpose of this study was to generate preliminary information concerning the effects of Sodium Sulphate on male and female reproductive performance such as gonadal function, mating behavior, conception and parturition.
Four groups of 10 males and 10 females were treated by gavage with Sodium Sulphate once daily. Males were treated over a 14-day pre-pairing period and during the pairing period up to one day before necropsy. Females were treated throughout the pre-pairing, pairing, gestation and lactation period up to day 4 post partum.The following dose levels were used:
Group 1: 0 mg/kg body weight/day (control group)
Group 2 100 mg/kg body weight/day
Group 3: 300 mg/kg body weight/day
Group 4 1000 mg/kg body weight/day
A standard dose volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (highly purified water).
The following results were obtained:
PARENTAL ANIMAL
All animals survived until the scheduled necropsy and no clinical sign was observed during the study.
Food Consumption
Mean food consumption was not affected by treatment with the test item in males and females.
Body Weights
No test item-related effects were observed in mean body weight and mean body weight gain of males and females.
Reproductive Data
Mating performance, fertility index and conception rate were not affected by treatment with the test item.
The mean number of corpora lutea, the mean number of implantations per dam, and the post-implantation losses were unaffected by treatment with the test item. The mean duration of gestation was also unaffected by treatment with the test item.
Organ Weights
Mean weight of testes and epididymides were not affected by the treatment with the test item.
Macroscopical Findings and Histopathological Examinations
All organs and tissues examined did not reveal any macroscopic nor microscopic changes related to the treatment with the test item.
LITTER DATA - F1 PUPS
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