Biphenyl

Endpoint summary

Description of key information

Key study for dermal absorption was identified as Fasano, 2005;  and reliable Key study performed under GLP principles for basic oral toxicokinetics was identified as Zhang et al., 2013.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

100

Additional information

A recent AME study by Zhang, Clark et al., (2013) was done according to GLP principles, to investigate MOA of threshold liver tumors in female BDF1 mice at high doses. This study is considered as reliable, and as Key Study for Basic Toxicokinetics. Eleven supporting studies were considered suitably reliable (Klimisch 2) to provide relevant information with regard to toxicokinetics, metabolism and distribution of biphenyl in animals and/or humans. The study of Fasano (2005) was considered reliable, and as Key Study for dermal absorption. Collectively, these studies provide a full and detailed description of how biphenyl behaves in vertebrate organisms.

Absorption

Dermal:

Using female human skin samples, Fasano (2005) observed that less than 1% of dermal absorption occurred from short exposure and 3.28% of dermal absorption occurred after 48 h of exposure to 100 µL/cm2 of a 100 mg/µL solution of biphenyl under the applied test conditions. For the purposes of the risk assessment a conservative 5% dermal bioavailability in humans will be assumed.

Oral:

The recent study by Zhang et al.,(2013) demonstrated high biphenyl absorption from gastrointestinal tract in BDF1 mice of at least 81 -82% of the orally administered radioactive dose. Based on the available information, it is clear that biphenyl is taken up via the oral route, consequently circulates in the organism and is metabolized and excreted as described below. Also, the uptake from gastrointestinal tract is fast, as evidenced by a blood time-course analysis from males and females indicating that the maximum concentration of biphenyl in blood, C_maxoccurred within 2 hours post-dosing (Zhang et al., 2013). Available studies indicate that unmodified biphenyl accounts for 5 -18% of the total radioactive dose excreted in faeces (Meyer et al., 1976b; Meyer, 1977). For the purposes of risk characterisation, the oral bioavailability will be assumed to be 100%.

Inhalation:

No information was identified regarding respiratory absorption. However, as biphenyl has low water solubility and low vapour pressure at room temperature with log Kow of 4, inhalation is not considered to be significant route of exposure. For the purposes of risk characterisation, the worst case of equivalent absorption to oral route is assumed (i.e. 100%).

Excretion and retention

Seven studies were identified reporting relevant information on excretion and/or retention of biphenyl in animals (Meyer and Scheline, 1976; Meyer et al., 1976a,b; Meyer, 1977; Freitag et al., 1982; Halpaap et al., 1978; Zhang et al., 2013). The major pathway for excretion of biphenyl appears to be the urinary pathway. Zhang et al., (2013) study indicated that mean of 81 and 69% of the administered dose was recovered in urine of male and female mice, respectively. Radioactivity was rapidly excreted, most occurring within 24 hours post-dosing with 91% of total urinary elimination observed for males and 56% for females, indicating that biphenyl was eliminated much faster in male mice than in female BDF1 mice. Excretion via the faeces also occurs, be it dominated by unmodified (and likely unabsorbed) parent biphenyl, representing 5 -18% of total administered dose. Zhang et al., (2013) study indicated that 8 to 10% of radioactive dose is excreted in faeces. Biliary excretion patterns are in agreement with the observations of metabolites in the faeces. Overall, excretion is fast and most of the excretion occurs within 24 h after dose administration both in urine and in feaces. Only a limited amount of biphenyl appears to be retained in the body of rats that were administered a single oral dose (0.43% reported by Freitag et al., 1982, 0.6% reported by Meyer et al., 1976a, and 0.06-0.09% reported by Zhang et al., 2013).

Metabolism

Eight studies investigated the identity of biphenyl metabolites in experimental animals or human tissue (Meyer and Scheline, 1976; Meyer et al., 1976b; Meyer, 1977; Halpaap et al., 1978; Wiebkin et al., 1976; 1978; Pacifici et al., 1991; Zhang et al., 2013). Some of these studies were in-vivo studies, the other studies investigated biotransformation in isolated hepatocytes or cytosolic fractions of tissues. Recent study by Zhang et al., (2013) confirmed that biphenyl is highly metabolized. In urine samples, approximately 35-50% of the radioactive dose was identified as the glucuronide conjugates of mono-hydroxylated biphenyl, various sulphate and glucuronide conjugates of di-hydroxy biphenyls and tri-hydroxy biphenyls represented half of the urinary activity, sulphate conjugates of mono-hydroxy biphenyl totaled about 5% of the dose, N-acetyl cysteine conjugates of mono-hydroxy biphenyl represented <1% of the dose. Overall, up to 20 other metabolites were identified by Zhang et al., (2013), each representing <1% to approximately 3% of the dose and the study did not show sex differences in metabolite profile produced. Overall, biphenyl appears to be hydroxylated to 4-hydroxybiphenyl and to a much lesser extent to 3- and/or 2-hydroxybiphenyl (relative abundance depending on the species). 4-hydroxybiphenyl is further oxidized to 4,4'-dihydroxybiphenyl, which is the most important metabolite observed in rats. The other primary hydroxybiphenyls can also be further oxidized to several dihydroxybiphenyls. In several cases, also trihydroxybiphenyls and hydroxymethoxylated metabolites have been observed. Most of the formed metabolites are excreted in a conjugated form. Sulphate conjugation was observed to be relatively more important although glucuronidation also occurs. Three additional studies have been discussed under IUCLID endpoint 7.9.3. (specific investigations). These studies (Ohnishi et al., 2000a,b; 2001) investigated the formation and composition of urinary crystals and/or calculi in rats. Two of these studies also report on the relative abundance of sulphate conjugates in urine and/or blood plasma. A more detailed overview of the identified conjugates can be found under 'specific investigations' (CSR section 5.10.1.3.).

Urinary crystal and calculi formation

The studies of Ohnishi et al. (2000a,b; 2001) (see IUCLID endpoint 7.9.3. and CSR section 5.10.) investigated the formation and composition of urinary crystals and/or calculi in rats. In male rats, multilayered calculi have been observed consisting of alternating layers of 4-HBPOSK (the potassium salt of 4-hydroxybiphenyl-O-sulfate) and calcium phosphate. The formation of these calculi may involve a series of successive and irreversible reactions. In female rats, non-layered calculi have been observed (open holes in which needle-shaped crystals are present) consisting of mainly 4-HBP and KHSO4. The formation of these calculi most likely involves reversible reactions including hydrolysis of 4-HBPOSK. Overall, the predominant involvement of 4-HBPOSK is most likely related to the lower solubility of the potassium salt of 4-HBPOS as compared to other urinary sulphate conjugates. Especially the calculi in male rats have been related to cancer formation in the bladder. It must be noted that this mechanism of cancer formation may be less important in humans, which are upright organisms in which any urinary crystals formed will soon obstruct the urinary tract and cause severe pain leading to consultation of an urologist and removal of the crystals, whereas in horizontal organisms they may stay present for several years and therefore cancer formation is expected to occur rather in these organisms due to substantially longer periods of epithelial hyperplaesia (Cohen, 1995a,b; 1998).