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EC number: 202-163-5
CAS number: 92-52-4
Oral (dietary) exposure route:Five Klimisch 2 studies are available. The NOAEL was based on the 2-year study in male/female rats of Umeda et al. (2002) as this study shows the lowest NOAEL, which is 38 mg/kg bw/d (recalculated from the dietary concentration of 500 ppm). The study was performed according to OECD Guideline 453.Dermal exposure route:Only two Klimisch 4 studies were available. Based on these studies, no key NOAEL could be defined.Inhalation exposure route:Only one Klimisch 4 study was available. Based on this study, no key NOAEC could be defined.
Oral (dietary) exposure route:
In the 2-year study conducted by Umeda et al. (2002), adverse effects
were mainly observed in the kidney, both in male and female rats, and in
the male urinary bladder where neoplastic lesions (tumours) were
observed. The NOAEC was 500 ppm in female rats and 1500 ppm in male rats
(concentrations of biphenyl in the diet). It was suggested that bladder
tumours in male rats are induced by calculi formation triggered by a
different metabolic pathway compared to female rats. In a 2-year study
with mice (Umeda et al., 2005), liver tumours were observed in female
mice, rather than in male mice. Non-neoplastic kidney lesions were
observed in both males and females. The NOAEC was 667 ppm biphenyl in
the diet in female mice and 2000 ppm in male mice. Recent Zhang, Clark
et al., (2013) absorption, metabolism and elimination (AME) study
indicated clear gender differences in the elimination rates of the
biphenyl-derived radioactivity in the BDF1 mice and not in the
proportion of biphenyl metabolites formed in males and females. Liver
injury would thus be attributed to gender-specific elimination
differences in the BDF1 mouse strain, but not in other strains or
species. MOA involving sustained regenerative and proliferative changes
in the livers of high-dose treated BDF1 females in response to
cytotoxicity from prolonged exposure to reactive metabolites of biphenyl
is consistent with the results of both Zhang et al., 2013 and Umeda et
al., 2005. As a result of cytotoxicity in the liver of biphenyl-treated
females, significant regenerative cellular proliferation has to occur to
compensate for the damaged tissue. Finally, no adverse effects have been
observed in a 90-day female rat study by Newell et al. (1953) up to
concentrations of 1000 ppm in the diet, nor in a 1-year monkey study
conducted by the same authors up to concentrations of 1% (i.e. 10000
ppm) in the diet. The lowest NOAEL was based on the lowest NOAEC of 500
ppm obtained for female rats by Umeda et al. (2002). The NOAEL was
recalculated using the NOAEC, the maximal final weight of female control
rats, which was 300 g, and a default food consumption of 22.5 g for rats
of 300 g, calculated using the formula mentioned in the TGD: Food
consumption (kg/d) = 0.040 x body weight (kg)^0.479. This way, the NOAEL
was calculated to be 38 mg/kg bw/day.
Dermal exposure route:
Only two Klimisch 4 studies were available (Deichmann et al., 1947;
Newell, 1953). Although based on these studies, no key NOAEL could be
defined, these studies indicate that no toxicologically adverse effects
occur up to concentrations of 2000 mg/kg bw/d in rabbits.
Inhalation exposure route:
Only one Klimisch 4 study was available (Deichmann et al., 1947). This
study indicates that lung effects and minor effects to kidney and liver
occur, however, details are lacking. Animals (rats, mice and rabbits)
had been exposed to 0.005, 0.04 and 0.3 mg/L air. The animals were
exposed to air contaminated with dust composed of 50% biphenyl on celite
(i.e. diatomaceous earth or kieselgur). It cannot be ruled out that the
celite (partly) induced the observed effects. No key NOAEC could be
defined based on the available information.
The substance does not need to be classified for long-term effects, as
adverse effects did not occur at a concentration of 50 mg/kg bw/d or
below after repeated oral exposure.
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