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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Inlife Februaty 12 - March 20, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, acceptable study according to GLP principles. No details about test substance purity.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 422 and OPPTS 870.3650
Deviations:
yes
Remarks:
But not which have a negative impact on the outcome of the study. 1) The protocol stated that the vehicle (distilled water) was to be analyzed with the prepared test mixture for the pressence of Potassium Sulfate. Although the test mixtures were analyzed,
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
Potassium sulphate
IUPAC Name:
Potassium sulphate
Constituent 2
Reference substance name:
Potassium sulfate
EC Number:
231-915-5
EC Name:
Potassium sulfate
Cas Number:
7778-80-5
IUPAC Name:
dipotassium sulfate
Details on test material:
Due to a storage of test substance, additional substance with equivalent composition was obtained and used in the latter phase of the study.
Potassium sulphate (K2-S-O4)
Physical Description: White crystals
Composition: > 97% Potassium Sulfate / < 3% impurities
Lot/batch No.: and (Due to shortage of test substance, both test substance batches (which both meet the above definition) were mixed together at a 2:1 ratio and used from day 4 till the end of the study.
- Expiration date of the lot/batch: Not applicable
- Stability under test conditions: stable
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: males: 64 days old on arrival and females 61 days old on arrival
- Weight at study initiation: males: 239 – 375 grams on arrival; females: 162 – 220 grams on arrival
- Fasting period before study:
- Housing:

- Diet (e.g. ad libitum): Purina Certified Rodent Diet #5002; ad libitum
- Water (e.g. ad libitum): filtered tap water; ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 23C
- Humidity (%): 45 – 69%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hr light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled water
Details on exposure:
Doses: 0, 50, 750, 1500 mg/kg/day
Doses were selected based on parameters assessed in a range-finding study at concentrations up to 1000 mg/kg/day
Frequency of treatment: daily
Details on oral exposure: gavage (oral intubation)
PREPARATION OF DOSING SOLUTIONS: Individual doses were calculated based on the most recent weekly body weights and were adjusted each week to maintain the targeted dose level for all rats in the general toxicity group (mg/kg/day). For female rats in the reproduction groups, individual doses were calculated based on the most recent body weights and were adjusted to maintain the targeted dose level (mg/kg/day). All doses were administered volumetrically after correcting for concentration of the test mixture. Control animals received the vehicle only at the same volume as the test groups.


DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): distilled water
- Concentration in vehicle:
- Amount of vehicle (if gavage):
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
See 7.6.1
Details on mating procedure:
no data
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 28days. The exposure period for the reproductive subgroup males was at most 28 days. The exposure period for reproductive subgroup females was at most 53 days (14 days mating and gestatioale and lactational periods up to lactation day 4)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 750, 1500 mg/kg bw/day
Basis:
nominal conc.
Control animals: Received the vehicle (distilled water) only at the same volume as the test groups.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Reproductive subgroup: male (5 males) in the reproductive subgroup were administrated K2SO4 for 28 days via oral gavage. Female rats (10 females) in the reproductive subgroup were administrated K2SO4 for a period encompassing approximately 53 continous 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).

Examinations

Maternal examinations:
no data
Ovaries and uterine content:
no data
Fetal examinations:
no data
Statistics:
Mean and standard deviations were calculated for all quantitative data. Except for clinical data where the contract laboratory, Huntingdon Life Sciences, elected to use statistics to aid in data interpretation; no further statistical treatment of the study data was conducted due generally to small group sizes.
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Reproductive subgoup: there were no treatment-related deaths and no signs of overt clinical toxicity. There were no effects on body weigth, food consumption, or food efficiency. Mating performance and fertility were unaffected by treatment. All animals mated within 4 days.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no treatment related effects on gestation length, gestation index, litter size, offspring survival indices, sex ratio, offspring bodyweight, or macropathology for offspring.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No adverse effects were seen on reproduction/developmental toxicity endpoints
NOAEL = 1500 mg/kg/day (reproduction and developmental)