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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
range-finding test
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
June 2014 - October 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Principles of method if other than guideline:
The objective of this study was to determine dose-levels of substance to be administered in the definitve study OECD guideleine 407
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 37060B
- Expiration date of the lot/batch: 01 March 2019
- Purity test date: >99%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
male and female Wistar Han™:RccHan™:WIST strain rats were obtained from Harlan Laboratories U.K. Ltd., Oxon.
The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:Harlan Laboratories U.K. Ltd., Oxon.
- Age at study initiation: approximately six to eight weeks old.
- Weight at study initiation: males weighed 202 to 226g, the females weighed 146 to 171g,
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

DETAILS OF FOOD AND WATER QUALITY:

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

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The test item was administered daily, for seven consecutive days, by gavage using a stainless steel cannula attached to a disposable plastic syringe.
Vehicle:
arachis oil
Remarks:
Control animals were treated in an identical manner with 4 mL/kg of Arachis oil BP.
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was prepared at the appropriate concentrations as a suspension in Arachis oil BP. The test item was administered within three hours of it being formulated. It is assumed that the
formulation was stable for this duration.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation.
Duration of treatment / exposure:
Seven consecutive days
Frequency of treatment:
The test item was administered daily
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (nominal)
Remarks:
Low concentration
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Medium concentration
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High concentration
No. of animals per sex per dose:
3 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels were chosen in consultation with the Sponsor. Based on available toxicity information, the acute oral lethal dose (LD50) of the test item in the rat was >2000 mg/kg and therefore, it was considered that there was no requirement to do any preliminary work. A high dose level of 1000 mg/kg bw/day was considered suitable for investigations with 250 and 500 mg/kg bw/day as the low and intermediate dose levels, respectively. The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item. The results of the study will aid dose level selection for subsequent studies.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- All animals were examined for overt signs of toxicity, ill health or behavioral change immediately before dosing, up to thirty minutes after dosing and one hour after dosing.

BODY WEIGHT: Yes
- Individual body weights were recorded on Days 1, 3, 5 and 8.

FOOD CONSUMPTION and FOOD EFFICIENCY: yes
- Food consumption was recorded for each cage group for Days 1 to 3, 3 to 5 and 5 to 8. Food conversion efficiency was calculated retrospectively.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Water intake was measured and recorded daily for each cage group

OPHTHALMOSCOPIC EXAMINATION: No :

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER: On completion of the dosing period, all animals were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination and subjected to an internal and external macroscopic examination.

Sacrifice and pathology:
GROSS PATHOLOGY: yes
On completion of the dosing period, all animals were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination and subjected to an internal and external
macroscopic examination. No tissues were retained.

HISTOPATHOLOGY: No

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs for any of the animals throughout the treatment period.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At the start of dosing period, males given the test item at 500 or 1000 mg/kg bw/day showed a slight reduction in group mean body weight gains when compared with controls. Subsequent recovery was apparent for males receiving 500 mg/kg bw/day such that body weight gains from Day 3 of dosing were similar to controls. Males given 1000 mg/kg bw/day also showed an improvement towards the end of dosing period with two out of three animals showing body weight gains comparable with controls over Days 5 to 8 of dosing. At 250 mg/kg bw/day, there was no effect of treatment on body weight development throughout the treatment period.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Males given the test item at 500 or 1000 mg/kg bw/day showed a slight reduction in food intake at the start of the dosing period when compared with controls. Thereafter, food intake for males receiving 500 mg/kg bw/day was similar to controls whereas for the high dose males it remained slightly lower than controls throughout the treatment period. At 250 mg/kg bw/day, food intake for males was similar to controls throughout the dosing period.
Food consumption for the treated females at all dose levels, in particular for the high dose animals, remained slightly lower than controls throughout the treatment period.
At all dose levels, food conversion efficiency for animals of either sex, in particular for the high dose animals, was generally lower than controls throughout the treatment period. It is worth noting that inter-group variation was high, reflecting high variation in body weight gain and/or food intake for these animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
At all dose levels, treatment with the test item was related to increased water consumption in animals of both sexes. Despite high variation, inter-group differences were occasionally doserelated.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no macroscopic findings for any of the animals at necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Any other information on results incl. tables

Administration of XA31 to rats by oral gavage for seven consecutive days at dose levels of 250, 500 and 1000 mg/kg bw/day was well tolerated. There were no clinical signs for any of the animals throughout the study. Males given the test item at 500 or 1000 mg/kg bw/day and females at all dose levels showed body weight impairment that was associated with a reduction in food intake at the start of the dosing period. Subsequent recovery in body weight gain was apparent, however weight gain and food consumption for males receiving the high dose and females at all dose levels were still lower than controls towards the end of the dosing period. In the absence of any clinical signs or macroscopic findings, it is likely that these animals would have attained full recovery over time. At all dose levels, animals of both sexes receiving the test item showed a persistent and occasionally dose-related increase in daily water intake in comparison with controls.

Applicant's summary and conclusion

Conclusions:
The oral administration of the Reaction mass of AminoPhosphonium salt and Bisphenol AF (XA 31) to rats by gavage, at dose levels of 250, 500 and 1000 mg/kg bw/day for seven consecutive days was well tolerated. Based on the results obtained, a high dose level of 1000 mg/kg bw/day together with 100 and 300 mg/kg bw/day as low and intermediate dose levels, respectively, are considered to be suitable for use in a 28 day repeat dose toxicity study in the rat.
Executive summary:

The objective of this study was to determine dose-levels of substance to be administered in the definitive study OECD guideline 407.

In this preliminary study of the repeated dose toxicity study 28 days, the Reaction mass of AminoPhosphonium salt and Bisphenol AF(XA 31) was administered by gavage to three groups, each of three male and three female han Wistar rats, for seven consecutive days, at dose levels of 250, 500 and 1000 mg/kg bw/day. A control group of three males and three females was dosed with vehicle alone.

During the study, clinical signs, body weight change, dietary intake, water consumption and macropathology investigations were undertaken.

As a result, there were no treatment-related unscheduled deaths during the study and no relevant clinical signs were observed. There were also no macroscopic changes at necropsy. However, the mean body weight gains and the food consumption for males receiving the high dose and females at all dose levels remained lower than the respective controls throughout the treatment period. Gravimetric measurement of water intake revealed increased water consumption for animals of both sexes at all dose levels.

In conclusion, the oral administration of the Reaction mass of AminoPhosphonium salt and Bisphenol AF (XA 31) to rats by gavage, at dose levels of 250, 500 and 1000 mg/kg bw/day for seven consecutive days was well tolerated. Based on the results obtained, a high dose level of 1000 mg/kg bw/day together with 100 and 300 mg/kg bw/day as low and intermediate dose levels, respectively, are considered to be suitable for use in a 28 day repeat dose toxicity study in the rat.