Sodium hydrogensulphate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1976-07-14 to 1976-10-13

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Sodium sulfate was used as the positive control in this study. Study was conducted in methods comparable to OECD guideline 411 "Subchronic Dermal Toxicity: 90-day study". However, only one dose level was tested. There were only 10 animals in each group. Not GLP.

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1977

Report date:

1976

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Version / remarks:

N/A

Deviations:

yes

Remarks:

see above rationale

Principles of method if other than guideline:

N/A

GLP compliance:

no

Remarks:

N/A

Limit test:

no

Test material

Test material information

Constituent 1

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:

- Name of test material (as cited in study report): Sodium sulfate (positive control)
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): N/A
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): N/A
- Substance type: Positive control
- Physical state:N/A

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sweetwater Farms
- Age at study initiation: N/A
- Weight at study initiation: 2160-2820 g
- Fasting period before study: N/A
- Housing: N/A
- Diet (e.g. ad libitum): N/A
- Water (e.g. ad libitum): N/A
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light): N/A


IN-LIFE DATES: From: N/A To: N/A

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: N/A
- % coverage: N/A
- Type of wrap if used: N/A
- Time intervals for shavings or clipplings: N/A


REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
- Time after start of exposure: N/A


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg/day
- Concentration (if solution): Sodium sulfate-16 % w/w aq.; BH-Base-20 % w/w aq.
- Constant volume or concentration used: yes
- For solids, paste formed: N/A


VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit): 2 ml/kg/day
- Concentration (if solution): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A


USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

N/A

Duration of treatment / exposure:

65 treatments in 91 days

Frequency of treatment:

65 treatments in 91 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2 ml/kg/day-16 % w/w aq.- Sodium sulfate
Basis:
nominal per unit body weight

Doses / concentrations 2

Remarks:

Doses / Concentrations:

Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: N/A
- Rationale for animal assignment (if not random): N/A
- Rationale for selecting satellite groups: N/A
- Post-exposure recovery period in satellite groups: N/A
- Section schedule rationale (if not random): N/A

Positive control:

Sodium sulfate, the test substance of interest, was used as the positive control in the study.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: N/A
- Cage side observations included: Mortality; no further data given


DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: N/A


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: N/A


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data
- Time schedule for examinations: N/A


OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: N/A
- Dose groups that were examined: N/A


HAEMATOLOGY: Yes
- Time schedule for collection of blood: N/A
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: WBC, RBC, HGB, HCT, MCV, MCH, MCHC, POLY, STAB, LYMPH, MONO, EOS, BASO, NRBC


CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: N/A
- Animals fasted: N/A
- How many animals: N/A
- Parameters examined: N/A


URINALYSIS: No data
- Time schedule for collection of urine: N/A
- Metabolism cages used for collection of urine: N/A
- Animals fasted: N/A
- Parameters examined: N/A


NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: N/A
- Dose groups that were examined: N/A
- Battery of functions tested: N/A


OTHER: N/A

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; complete necropsy
HISTOPATHOLOGY: Yes: skin- dermatitis, acanthosis, hyperkeratosis; thyroid- vascular congestion, atrophy; adrenal- nodular hyperplasia; spleen- hemosiderosis, erythrophagocytosis, amyloidosis; bone marrow- hypocellular; spinal cord- perivascular cuffing; brain- perivascular cuffing, gliosis, granulomas, meningitis, status spongiosis; heart- myocarditis; lung- interstitial pneumonitis, perivascular lymphoid hyperplasia, peribronchial lymphoid hyperplasia, pneumonia, aspirated blood; trachea- tracheitis, aspirated blood, laryngitis; lymph node- lymphadenitis, abscess, lymphoid hyperplasia; liver- pericholangitis, nonsuppurative, hepatitis, necrosis; gall bladder- cholecystitis, mineralization; tongue- glossitis; esophagus- parasites; stomach- gastritis, parasites; pancreas- ectopic spleen; small intestin- parasites, enteritis, myositis, serositis; large intestine- parasites, enteritis, mineralization; kidney- interstitial nephritis, regenerative epithelium, mineralization, fibrosis, dilated tubules; urinary bladder- mineralization; uterus- endometritis, hyperplasia; testis- giant cells, degeneration/atrophy

Other examinations:

Liver and kidney weights were measured.

Statistics:

Hematology- Males and females in the test substance group and the BH-Base group were compared to those from the respective sexes in the vehicle control group by the Student's t-test. Significant differences were determined at a 5 % risk.
Gross Pathology- Data on body weights, selected organ weights, and ratios were analyzed using analysis of variance on computer program B8944.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

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:

effects observed, treatment-related

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY- N/A


BODY WEIGHT AND WEIGHT GAIN- An overall weight gain was seen for all groups in the study.


FOOD CONSUMPTION- N/A


FOOD EFFICIENCY- N/A


WATER CONSUMPTION- N/A


OPHTHALMOSCOPIC EXAMINATION- N/A


HAEMATOLOGY-One animal in the test substance group and one animal in BH-Base group had slightly increased total white blood cell counts and an absolute neutrophilia. These increases were not considered biologically significant. One animal in the BH-Base group had moderately increased total white blood cell count with an absolute neutrophilia. This increase was indicative of a response to inflammation, but it was not likely treatment related since such an increase was observed only for this one animal. One animal in the test substance group, 3 animals in the BH-Base group, and 2 animals in the vehicle control group had RBC, HGB and HCT values below the normal range for rabbits. The decreases in these parameters were not considered treatment related since similar decreases were observed in the two control animals. Also, the group mean values for these parameters did not differ significantly (P<0.05) between treated animals and control. A statistically significant (P<0.05) increase in MCV and MCH values was noted for the females in the test substance group as compared to the vehicle control females. This increase did not appear to be biologically significant since all individual values were within a normal range for rabbits.


CLINICAL CHEMISTRY-N/A


URINALYSIS-N/A


NEUROBEHAVIOUR-N/A


ORGAN WEIGHTS- N/A


GROSS PATHOLOGY- N/A


HISTOPATHOLOGY: NON-NEOPLASTIC-The only test-related lesion observed was a subacute dermatitis. 3 animals in the vehicle control group had mild subacute dermatitis. 8 animals in the test substance group and BH-Base group had subacute dermatitis that varied from mild to moderate in nature. All other findings were normal or related to spontaneous disease. Some lesions were incidental in nature.


HISTOPATHOLOGY: NEOPLASTIC (if applicable)


HISTORICAL CONTROL DATA (if applicable)


OTHER FINDINGS- The skin from the vehicle control, BH-Base group, and the test substance group appeared normal, except that the BH-Base group was discolored from the BH-Base.

Effect levels

Dose descriptor:

LOAEL

Effect level:

2 other: ml/kg/day (16 % w/w)- Sodium sulfate

Sex:

male/female

Basis for effect level:

other: Histopathological examination showed that all treated animals had subacute dermatitis compared to solvent control group.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

N/A

Applicant's summary and conclusion

Conclusions:

Male and female New Zealand White Rabbits were treated with the test substance (2 ml/kg/day; 16 % w/w), BH-Base (2 ml/kg/day; 20 % w/w) or the vehicle control (water; 2 ml/kg/day) percutaneously 65 times in 91 days. The only test related effect, which was observed for all groups, was subacute dermatitis. LOAEL for the test substance was 2 ml/kg/day (16 % w/w).

Executive summary:

Male and female New Zealand White Rabbits were treated with the test substance (2 ml/kg/day; 16 % w/w), BH-Base (2 ml/kg/day; 20 % w/w) or the vehicle control (water; 2 ml/kg/day) percutaneously 65 times in 91 days. Five males and five females were assigned to each group. Body weights were measured weekly. In addition, the animals were analyzed for adverse effects on skin, hematology, gross pathology, and histopathology.

The skin appeared normal in all groups. A statistically significant (P0.05) increase in MCV and MCH values was noted for the females in the test substance group as compared to the vehicle control females.  This increase did not appear to be biologically significant since all individual values were within a normal range for rabbits. The only test-related lesion observed was a subacute dermatitis.  3 animals in the vehicle control group had mild subacute dermatitis. 8 animals in the test substance group had subacute dermatitis that varied from mild to moderate in nature.  All other findings were normal or related to spontaneous disease.  Some lesions were incidental in nature.

Based on the results of the study, the LOAEL for the test substance was 2 ml/kg/day (16 % w/w)