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EC number: 202-163-5
CAS number: 92-52-4
GENOTOXICITY IN VITRO
Mutagenicity in bacteria:
Brams et al. (1987), Chung and Adris (2003), Cline and McMahon (1977),
Glatt et al. (1992), Haworth et al. (1983), Ishidate et al. (1984), NTP
(1979), and Pagano et al. (1983) are the available Klimisch 2 studies.
These studies cover all relevant tester strains, with and without S9
mix, including negative and positive controls. All studies, including
those assigned a Klimisch 3 or Klimisch 4 score, demonstrate that
biphenyl is negative in the Ames test under all conditions. A weight of
evidence approach was presented using all Klimisch 2 studies.
Chromosome aberration tests with biphenyl were performed with Chinese
hamster lung cells (CHL), Syrian Hamster cell line and Hamster Lung
fibroblasts. In the Klimisch 2 studies (Ishidate and Odashima, 1977;
Ishidate et al., 1984), used in a weight of evidence approach, biphenyl
tested negative for chromosome aberration in the absence of metabolic
activation. No positive control substances were tested under similar
conditions. No data on cytotoxicity were reported. One Klimisch 3 study
(Abe and Sasaki, 1977) and one Klimisch 4 study (Kawachi et al., 1980)
reported negative results without metabolic activation. In another
Klimisch 4 study (Sofuni et al., 1985) biphenyl tested negative with and
without metabolic activation (at a dose range of 0-0.125 mg/mL), but
biphenyl tested positive when tested in the presence of metabolic
activation (at a dose range of 0-0.02 mg/mL).
Mouse lymphoma assay:
Biphenyl tested negative in the absence of metabolic activation and
positive with metabolic activation when tested in the mouse lymphoma
assay (Wangenheim and Bolcsfoldi, 1988). Cytotoxicity was observed at
the two highest concentrations tested. Positive and negative controls
were tested as well. The genotoxicity results were supported by the
Klimisch 4 study of Wangenheim and Bolcsfoldi (1986). The former study
was selected as a key study with the remark that not too much weight
should be given to the weak positive results observed in the presence of
Unscheduled DNA synthesis:
Unscheduled DNA synthesis was tested in primary cultures of rat
hepatocytes and human lung fibroblast cells. Biphenyl tested negative in
the Klimisch 2 study of Probst et al. (1981). No data on cytotoxicity
were reported. Four Klimisch 4 studies were available in which biphenyl
tested negative. All unscheduled DNA synthesis studies with biphenyl
were used as supporting evidence for the in vitro genotoxicity endpoint.
Biphenyl tested negative for DNA damage in a Nick Translation Assay
without metabolic activation (Klimisch 3 study of Snyder and Matheson,
1985). No cytotoxicity data were reported. Negative results for DNA
damage in bacteria (E. coli strains 343/636, 343/591, WP2, WP2
urv A, CM 571 and WP100) were also reported in two Klimisch 4 studies
(Hellmer and Bolcsfoldi, 1992; Nishioka and Ogasawara, 1978). No data on
cytotoxicity were reported in this study. All studies can be used as
supporting evidence for the in vitro genotoxicity endpoint.
Gene mutation assay:
One Klimisch 2 supporting gene mutation assay was identified (Glatt et
al., 1992). Biphenyl tested negative in absence of a metabolic
activation system and positive with metabolic activation in Chinese
Hamster Lung fibroblasts (V79). No cytotoxicity was reported, however
biphenyl was tested up to concentrations resulting in precipitation.
Biphenyl tested negative in a bioassay for genetic activity profiling
with and without metabolic activation (Klimisch 4 study of Garrett et
al., 1986). No data on cytotoxicity were reported. This study was used
as supporting information.
Conclusion on genetic toxicity in vitro:
Bacterial genotoxicity studies, unscheduled DNA synthesis as well as DNA
repair tests have been uniformly negative. These results were supported
in a bioassay for genetic activity profiling. Testing in mammalian cells
has produced mixed results with limited positive results for gene
mutation and clastogenicity reported only in the presence of metabolic
activation. Positive results were observed in the Klimisch 4 chromosome
aberration test of Sofuni et al. (1985) in the presence of metabolic
activation (at a dose range of 0-0.02 mg/mL). However, no positive or
negative controls were tested simultaneously and no data on cytotoxicity
were reported. As the reliability of this study is not assignable, these
positive results should be neglected in determining whether biphenyl is
a mutagenic substance. In the mouse lymphoma assay (Wangenheim and
Bolcsfoldi, 1988) a weakly positive response was only observed at a
single concentration that significantly inhibited cell growth (12% of
control values) only in the presence of S-9 following a 4-hour exposure.
However, it was not mentioned if the positive control was valid and
therefore, not too much weight should be given at these results as it is
not clear if the test system was valid. In the Chinese hamster V79 gene
mutation assay, although no appreciable toxicity was observed during the
treatment period, as determined from the number of cells harvested at
subcultivation during the expression period (> 80% of control value),
cloning efficiencies were not reported, hampering interpretation of the
GENOTOXICITY IN VIVO
Mouse micronucleus test:
Biphenyl tested negative in the (CD-1) mouse micronucleus test
(Klimisch1 key study of Gollapudi et al., 2007). Cytotoxicity was
reported at the highest dose level tested (800 mg/kg bw/day).
Biphenyl tested negative in male Sprague-Dawley rats in a Klimisch 2
supporting study (Johnston et al., 1976). No data on cytotoxicity were
reported. Similar results were observed in a Klimisch 4 chromosome
aberration test with rats (Kawachi et al., 1980).
A Klimisch 2 comet assay was performed with male CD-1 male mice (Sasaki
et al., 1997) at 2000 mg/kg. Biphenyl tested positive in this comet
assay. No toxic effects were observed in this study.
Conclusion on genetic toxicity in vivo:
Biphenyl tested negative in two chromosome
aberration tests in rats. These results were confirmed in a mouse
(CD-1 strain). A Comet Assay was performed in
CD-1 males where biphenyl tested positive. No toxicity was reported for
the animals used in the Comet Assay, although it was reported in the
micronucleus test at 800 mg/kg (Gollapudi
et al., 2007, Klimisch 1 study); both
studies were performed in CD-1 mice. Although Comet Assay is
many questions have been raised regarding the validity of the test
results in Sasaki et al., (1997) report: no data on controls was given,
only males were tested, only one very high concentration was tested
(2000 mg/kg). Since data from lower
doses are missing in the Comet Assay and there are significant
methodological insufficiencies found with the study, DNA fragmentation
secondary to cell death should be
considered as a source of DNA comets. Also,
weight of evidence from in vitro assays suggests that biphenyl is not
DNA reactive, including results from USD and DNA repair assays.
Furthermore, the substance was entered into the OECD QSAR application
toolbox (v.1.1.02). After profiling the substance did not answer any of
the categorization criteria for DNA binding and protein binding. This
implies that the substance does not bind to DNA nor to associated
proteins. In order to exert a genotoxic effect, a substance should be
able to bind to DNA and/or to proteins, which biphenyl seems not to be
capable of. Finally, in the available carcinogenicity studies,
non-genotoxic mechanisms seem to underlie the
observed carcinogenic effects. In conclusion, it can be assumed that
biphenyl is not genotoxic in vivo.
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