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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term 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:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, acceptable study according to GLP principles.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
Potassium Sulphate
IUPAC Name:
Potassium Sulphate
Details on test material:
Potassium Sulphate (K2SO4)
No details about test substance purity.
Due to a shortage of test substance, additional substance with equivalent composition was obtained and used in the latter phase of the study.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
Animals in the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Animals in the study were divided between two subgroups (toxicity and reproductive subgroups). The exposure period for males and females in the toxicity subgroup was 28 days. The exposure period for reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days pre-mating, 14 days mating, and gestational and lactational periods up to lactation day 4).
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 750, and 1,500 mg/kg/day (Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1,000 mg/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
Toxicity subgroup: Animals comprising the toxicity subgroup (5 males and 5 females per dose group) were administered K2SO4 for 28 days (7 days/week) via gavage administration. Among toxicity subgroup animals, functional observations (sensory reactivity, grip strength, motor activity) were conducted during the final days of treatment. Bleeds for hematology and blood chemistry were conducted on Day 28 of treatment. Organ weights were recorded at termination and major organs and tissues (and any other abnormalities observed at necropsy) were processed for microscopic examination.
Reproductive subgroup: Male rats (5 males) in the reproductive subgroup were administered K2SO4 for 28 days via oral gavage. Female rats (10 females) in the reproductive subgroup were administered K2SO4 for a period encompassing approximately 53 continuous days via oral gavage: 14 days of initial treatment, plus a maximum of 14 days of cohabitation to ensure mating, and 25 days to litter and rear their young until Day 4 of age. Histology for reproductive subgroup animals was restricted to retained reproductive organs (and any other abnormalities observed at necropsy).
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
Among toxicity subgroup animals, functional observations (sensory reactivity, grip strength, motor activity) were conducted during the final days of treatment. Bleeds for hematology and blood chemistry were conducted on Day 28 of treatment.
Sacrifice and pathology:
Organ weights were recorded at termination and major organs and tissues (and any other abnormalities observed at necropsy) were processed for microscopic examination.
Other examinations:
Reproductive subgroup: Male rats (5 males) in the reproductive subgroup were administered K2SO4 for 28 days via oral gavage. Female rats (10 females) in the reproductive subgroup were administered K2SO4 for a period encompassing approximately 53 continuous days via oral gavage: 14 days of initial treatment, plus a maximum of 14 days of cohabitation to ensure mating, and 25 days to litter and rear their young until Day 4 of age. Histology for reproductive subgroup animals was restricted to retained reproductive organs (and any other abnormalities observed at necropsy).
Statistics:
no data

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:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
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:
no effects observed
Details on results:
Toxicity subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Functional observational battery (FOB) and motor activity tests identified no treatment-related changes in behavior, function, or motor activity. Dams at 1,500 mg/kg/day experienced slightly lower food consumption and body weight than the controls during the gestation period only. Because of their moderate and transient nature, these observable effects were considered a LOEL rather than a LOAEL. No treatment-related histopathological changes were reported.

Reproductive subgroup: There were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weight, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days. There were no treatment-related effects on gestation length, gestation index, litter size, offspring survival indices, sex ratio, offspring bodyweight, or macropathology for offspring.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: General toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reproduction/developmental toxicity
Dose descriptor:
LOAEL
Effect level:
> 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No adverse effects were seen on general toxicity endpoints. No adverse effects were seen on reproduction/developmental toxicity endpoints

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:
NOAEL: 1,500 mg/kg/day (general toxicity)
               1,500 mg/kg/day (reproduction/developmental toxicity)
LOAEL: No adverse effects were seen on general toxicity endpoints. No adverse effects were seen on reproduction/developmental toxicity endpoints.