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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: Reproduction / Developmental Toxicity Screening Test
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): potassium tetrafluoroborate
- Physical state: white powder
- Analytical purity: 98.9%
- Lot/batch No.: BWF41213
- Expiration date of the lot/batch: 13 December 2009
- Storage condition of test material: ambient temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany, SPF-bred colony
- Age at study initiation: (P) 8-9 wks
- Weight at study initiation: (P) within 20% of the mean weight for each sex
- Housing: in macrolon cages with wood shavings (Lignocel, Type 3/4) as bedding material and strips of paper (Enviro-dri) as environmental enrichment. During the premating period, the animals were housed in groups of 4/sex. For mating, 1 male and 1 female were housed together. Mated femaleswere housed individually in macrolon cages, which were then placed in another cage rack. After delivery, the cage containing the dam with litter were transferred to another cage rack
- Diet: cereal-based (closed formula) rodent diet (Rat & Mouse No. 3 Breeding Diet, RM3) from a commercial supplier (SDS Special Diets Services, Witham, England), ad libitum
- Water: tap water in polypropylene bottles, cleaned weekly and filled as needed, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% solution in water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was suspended in 1% CMC. The dosing solutions were prepared weekly and stored at 2-10 ºC. The miscibility of the test substance in vehicle were checked by visual inspection before the start of the study.

VEHICLE
- Concentration in vehicle: 0, 20, 58.2, 175 and 500 mg/mL
- Amount of vehicle: 2 mL/kg bw
- Lot/batch no.: 101K0185
- Purity: 1% solution in water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses to determine the stability, homogeneity and content of the test substance in the vehicle was conducted, by quantitative determination of the level of potassium tetrafluoroborate by determination of boron using ICP-AES and determination of fluoride using GC-FID with headspace.
Duration of treatment / exposure:
Males: during 4 weeks premating period and during the mating period for at least 5 weeks until sacrifice. Females: during a 2-week premating period, during the mating, gestation and lactation period until sacrifice. Animals were not dosed on the day of necropsy.
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
40, 116.5 and 350 mg/kg bw/day (adjusted from 116.5, 350 and 1000 mg/kg bw/day due to body weight loss in high-dose animals)
Basis:
actual ingested
No. of animals per sex per dose:
12/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: computer randomization proportionally to body weight.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily in the morning hours by cage-side observations. On working days, all cages were checked again in the afternoon for dead or moribund animals to minimise loss of animals from the study. On Saturdays and Sundays only one check per day was carried out.

BODY WEIGHT: Yes
- Time schedule for examinations: shortly before the time of dosing (randomization) and on the first day of dosing and weekly thereafter during the premating period. In addition, body weights of the male animals were measured on day 3 and 5 of the study. Males were weighed approximately weekly during the mating period until sacrifice. Females were weighed approximately weekly during mating and mated females were weighed on days 0, 7, 14 and 21 during presumed gestation and on day 1 and 4 of lactation. All animals were weighed on the day of sacrifice.

FOOD CONSUMPTION: Yes
Food consumption of male rats was measured approx. weekly, except during the mating period. In addition, food consumption of the male animals was measured on day 3 and 5 of the study, except for male animals of lowest dose group.
Food consumption of female rats was measured weekly during the premating period and during the gestation period from gestation days 0-7, 7-14 and 14-21, and once during the lacation period from day 1 to 4.

WATER CONSUMPTION: Yes
During daily observations, until day 5 of gestation.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
SACRIFICE
- Male animals: all male animals of the 1000 mg/kg bw/day group were sacrified on day 7 of the study after 3 daily dosages and 5 days of recovery. Males from other groups were euthanised after approximately 5 weeks of exposure.
- Maternal animals: sperm-positive females that turned out to be non-pregnant were killed 24-26 days after copulation. Females that became pregnant were sacrificed at day 4 of lactation.

GROSS NECROPSY
Animals were examined grossly for macroscopic changes.

HISTOPATHOLOGY / ORGAN WEIGHTS
Samples of the following organs were preserved: ovaries (after counting of the corpora lutea), uterus (after counting of the implantation sites), testes, epididymides, seminal vehicles, prostate, organs and tissues showing macroscopic abnormalities.
Statistics:
Clinical findings were evaluated by Fisher's probability test. Body weight, body weight gain, organ weights and food consumption data were subjected to one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison tests. Histopathological changes were evaluated by Fisher's exact probability test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Two female animals of the 350 mg/kg bw/day died during lactation period. Daily clinical observations during the study did not reveal any remarkable findings in animal appearance, general condition or behaviour among the dosing and control groups.

BODY WEIGHT (PARENTAL ANIMALS)
Twelve male animals of the 1000 mg/kg bw/day group lost ca. 10% (30 g) of their initial body weight on day 0 after 3 daily dosages. It was decided, after the consultation with the sponsor, to stop dosing these male animals and to keep these animals in the study without treatment up to day 7, to study the reversibility of this effect. Mean body weight of the animals of day 7 was comparable to their body weight on day 0.
Mean body weight and/or body weight change of the male and female animals of 350 mg/kg bw/day group were statistically significantly decreased during several periods of the study. Mean body weight of the male animals of the 350 mg/kg bw/day group was statistically significantly decreased from day 3 until sacrifice. Mean body weight change of the male animals of this group was statistically significantly decreased between days 0-3, 3-5, 7-14 and 21-28. Mean body weight of the male animals of the 116.5 mg/kg bw/day group was statistically significantly decreased from day 28 until sacrifice. Mean body weight change of the male animals of this group was statistically significantly decreased between days 21-28. No decreased in body weight and body weight change was observed in the male animals of the 40 mg/kg bw/day group. During the premating period, no effect on body weight or body weight change was observed in female animals treated with KBF4. Mean body weight of the female animals of the 350 mg/kg bw/day group was statistically significantly decreased from gestation day 7-21. Mean body weight change of the female animals of this group was statistically significantly decreased from gestation days 7-14. Mean body weight of the female animals of this group was statisitcally significantly decreased on lactation day 1. During the lactation period no effect was observed on mean body weight change of the KBF4-treated females.

FOOD CONSUMPTION (PARENTAL ANIMALS)
Food consumption of the male animals of the 1000 mg KBF4/kg body weight group was statistically significantly decreased (5.45 g/animal/day versus 19.65 g/animal in the control group) from day 0-3. Animals of this group were not longer dosed from day 3 to 7; food consumption of the animals was back to normal or even higher from day 5 to 7. Food consumption of the male animals of the 350 mg KBF4/kg body weight group was statistically significantly decreased during the premating period. Food consumption of the animals of the 116.5 mg KBF4/kg body weight group was comparable to the control group except for the statistical significant difference between dat 7 and 14. Food consumption of the female animals of the 350 mg KBF4/kg body weight group was statistically significantly decreased from day 14-21 of the premating period, during GD 0-14 (g/animal/day) and GD 0-7 (g/kg/day) and day 1-4 of lactation (g/animal/day). One animal of this group did not eat any food from lactation day 1-4. Furthermore, no remarkable differences were observed in the KBF4-treated groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute and relative testes and epididymides weights were comparable in all groups.

GROSS PATHOLOGY (PARENTAL ANIMALS)
At scheduled necropsy no treatment-related gross changes were observed.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Microscopic examination did not reveal treatment related histopathological changes in any of the sampled organs and tissues (epididymides, testes, uterus and ovaria).

OTHER FINDINGS (PARENTAL ANIMALS):
Effects on water consumption were observed (not exactly measured) in the male and female animals of the 350 mg/kg bw/day group from week 3 onwards. In consultation with the study director it was decided to stop registration of water consumption after day 5 of gestation.

Effect levels

Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the effects on mortality in the 350 mg/kg bw/day group and body weight and food consumption in the 116.5 and 350 mg/kg bw/day group.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A NOAEL of 40 mg/kg bw/day was established in a reproduction/developmental toxicity screening test.
Executive summary:

In a GLP compliant reproduction/developmental toxicity screening test, performed according to OECD Guideline 421, Wistar rats of both sexes were orally exposed to potassium tetrafluoroborate. 1% carboxymethylcellulose solution in water (CMC) was used as vehicle. Groups of 12 rats per sex were dosed daily with 0, 40, 116.5 and 350 mg KBF4/kg body weight for up to approx. 35 days (males) or during 4 weeks premating, mating, gestation and up to day 4 of lactation (females). Initially a group of male rats was dosed with 1000 mg KBF4/kg body weight. These animals showed a weight loss of approx. 10% after 3 daily dosages. For that reason this group was replaced by the 40 mg KBF4/kg body weight. Two female animals of the 350 mg KBF4/kg body weight died during the lactation period. Daily clinical observations during the study did not reveal any remarkable findings in animals' appearance, general condition or behavior among the dosing and control groups. Effects on water consumption were observed (not exactly measured) in the male and female animals of the 350 mg KBF4/kg body weight group from week 3 onwards. Mean body weight and or body weight change of the male and female animals of the 350 mg KBF4/kg body weight were statistically significantly decreased during several periods of the study. Mean bodyweight or bodyweight change of the 116.5 mg KBF4/kg body weight group was only statistically significantly decreased in the male animals from day 21 onwards. Food consumption of the 350 mg KBF4/kg body weight group was statistically significantly decreased in male and female animals during several periods of the study. Food consumption of the male animals of the 116.5 mg KBF4/kg body weight group was statistically significantly decreased from day 7 to 14. Terminal body weight of the male animals of the 40 and 116.5 mg KBF4/kg body weight groups was statistically significantly decreased. At scheduled necropsy no treatment related gross changes were observed. Microscopic examination did not reveal treatment related histopathological changes in any of the sampled organs and tissues (epididymides, testes, uterus and ovaries). Based on the effects on mortality in the 350 mg KBF4 group/ kg body weight group, (terminal) body weight and food consumption in the 116.5 and 350 mg KBF4/kg body weight groups, the NOAEL for parental toxicity is 40 mg KBF4/kg body weight/day.