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EC number: 202-200-5 | CAS number: 92-88-6
Table 1: Summary table – Induction of micronuclei in bone marrow cells
Micronuclei in PCE
500 mg/kg bw
1000 mg/kg bw
2000 mg/kg bw
20 mg/kg bw
PCE = polychromatic erythrocytes
NCE = normochromatic erythrocytes
bw = body weight
a = sum of small and large micronuclei
b = large micronuclei (indication for spindle poison effect)
c = calculated number of PCEs per 2000 erythrocytes (PCE + NCE) when scoring a sample of 10000 PCE per test group
* = p ≤ 0.05
** = p ≤ 0.01
The test substance was assessed for its potential to induce chromosomal damage (clastogenicity) or spindle poison effects (aneugenic activity) in NMRI mice using the micronucleus test method, according to OECD guideline 474 and in compliance with GLP.
The test substance, dissolved or suspended in DMSO and subsequently emulsified or suspended in corn oil, was administered once orally to male animals at dose levels of 500 mg/kg, 1000 mg/kg and 2000 mg/kg body weight (bw) in a volume of 10 mL/kg body weight in each case. The animals were sacrificed and the bone marrow of the two femora was prepared 24 and 48 hours after administration in the highest dose group of 2000 mg/kg body weight and in the vehicle controls. In the test groups of 1000 mg/kg and 500 mg/kg body weight and in the positive control group, the 24-hour sacrifice interval was investigated only. After staining of the preparations, 2000 polychromatic erythrocytes were evaluated per animal and investigated for micronuclei. The normocytes with and without micronuclei occurring per 2000 polychromatic erythrocytes were also recorded.
As vehicle control, male mice were administered merely the vehicle, DMSO/corn oil (ratio 2:3), by the same route and in the same volume as the animals of the dose groups, which gave frequencies of micronucleated polychromatic erythrocytes within the historical vehicle control data range. The positive control substance cyclophosphamide led to the expected increase in the rate of polychromatic erythrocytes containing only small micronuclei.
A slight inhibition of erythropoiesis determined from the ratio of polychromatic to normochromatic erythrocytes (slightly below 90% of control, each) was detected after test substance administration at all doses at 24-hour sacrifice interval. According to the results of the present study, the single oral administration of the test item did not lead to any biologically relevant increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of micronuclei was close to the range of the concurrent vehicle controls in all dose groups and at all sacrifice intervals and within the range of the historical vehicle control data.
In an additional study, the exposure of the bone marrow was confirmed by the analysis of the test substance in plasma after oral dosing of animals (see study described in the section "Toxicokinetics", from BASF, study number 99M0276/13M370, author: Dr. M. Schulz).
Thus, under the experimental conditions of this study, the test substance did not induce cytogenetic damage in bone marrow cells of NMRI mice in vivo.
Results of clinical examinations:
The single oral administration of the test substance did not lead to clinical signs of toxicity which was in accordance with the observations in the previous Micronucleus study.
Results of the analytical investigation of dosing preparations:
The concentration control analyses of all concentrations revealed that the values were in the expected range of the target concentrations, i.e. were always in a range of 90% - 110% of the nominal concentration.
Based on the recovery rates it has to be considered that the test substance was stable at room temperature in the vehicle DMSO/corn oil at least over a period of 40 minutes.
The bioavailability of the test substance Biphenyl-4,4’-diol in mouse plasma samples was clearly demonstrated 2 and 4 hours after oral administration of 2000 mg/kg body weight in either male and female NMRI mice. The plasma level was in a concentration range of 293.67 to 1113.34 ng/mL depending on the animal and time point. The blank plasma samples taken from the same animals about 24 hours before test substance administration confirmed the absence of test substance as expected.
2 hours after
4 hours after
< 99.6 ng/mL: not detected, = Limit Of Quantification (LOQ)
In a previously performed Micronucleus study in NMRI mice (BASF Project No. 26M0276/13M335) the absence of a clastogenic and aneugenic potential of the test substance Biphenyl-4,4’-diol after oral administration was demonstrated. To fulfill the recommendations of the current OECD Guideline No. 474 an additional bioavailability study was performed which demonstrates the occurrence of the test substance in the plasma samples. Definite test substance concentrations in the samples were determined.
NMRI mice of both sexes, two animals per sex, were given 2000 mg/kg body weight once orally (gavage) with a volume of 10 mL/kg body weight of the test substance. The animals were sacrificed 4 hours after the treatment.
At the beginning of the study, the animals were weighed and the substance to be administered was related to the specific weight of the individual animals.
Blood was taken from vena facialis 2 hours after administration (about 100 μL per animal). Four hours after administration, the animals were sacrificed by decapitation under isoflurane anesthesia. Again, blood samples were taken, i.e. 4 hours after administration (about 500 μL per animal). In order to have plasma control samples of untreated animals (blank samples), from all animals blood was taken from vena facialis the day before test substance administration (about 100 μL per animal) under isoflurane anesthesia. These samples were processed as those from treated animals.
Blood was collected with EDTA as anticoagulant. The samples were centrifuged for 2 minutes at 20000 x g at 4°C. The supernatant, plasma, was transferred to the Analytical Chemistry Laboratory of the test facility and was kept frozen at about -80°C prior to analysis.
The single oral administration of the test substance did not lead to clinical signs of toxicity which was in accordance with the observations in the previous Micronucleus study
The plasma level was in a concentration range of 293.67 to 1113.34 ng/mL depending on the animal and time point.
The blank plasma samples taken from the same animals about 24 hours before test substance administration confirmed the absence of test substance as expected.
These additional data confirm the exposure of the bone marrow of the animals in the above mentioned Micronucleus study.
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