Sodium 2-biphenylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

excretion

metabolism

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Inc., Kanagawa, Japan
- Age at study initiation: 4 weeks old
- Diet: ad libitum except for the time in metabolism cages
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 - 26
- Humidity (%): 50 ± 5
- Air changes (per hr): 4
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

daily for 136 days

Dose / conc.:

2 other: % diet

Remarks:

The daily intake from the diet was estimated to be 280 mg for males and 180 mg for females according to the author

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent no treatment

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, liver and kidney
- Time and frequency of sampling: urine was collected every 2 h for 6 h every day; liver and kidney were immediately removed at necropsy
- Method type(s) for identification: GC, GC-MS and HPLC

TREATMENT FOR CLEAVAGE OF CONJUGATES:
For the extraction of metabolites from the liver and kidneys, the tissue homogenate was digested with pronase and thereafter with glucuronidase

Type:

excretion

Results:

54.97% (± 7.98) and 39.04% (± 4.74) of the daily intake in males and females were excreted during 24 h in urine.

Metabolites identified:

yes

Details on metabolites:

High concentrations of phenolic metabolites, o-phenylphenol and 2,5-dihydroxybiphenyl, were found in the urine of rats of both sexes. Glucuronic acid conjugation was identified as the major route of OPP metabolism in rats.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

distribution

excretion

metabolism

GLP compliance:

no

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Japan
- Weight at study initiation: Approximately 180 g
- Acclimation period: At least 7 days
- Water: Drinking water containing glucose and saline during the time in Bollman cages, ad libitum

Route of administration:

oral: unspecified

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
14C-OPP (1.57 mCi/mmol) was obtained from the Radiochemical Centre, England, and its sodium salt was prepared by neutralization of 14C-OPP with sodium hydroxide solution.

Duration and frequency of treatment / exposure:

single oral administration

Dose / conc.:

250 mg/kg bw/day (nominal)

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, bile , blood, adipose, kidney, liver, stomach, intestine, brain and bladder
- Time and frequency of sampling: urine and faeces were collected daily for 7 days. Organ and tissue distributions (blood, adipose, kidney, liver, stomach, intestine, brain and bladder) were examined on Days 1, 3 and 7 after dosing using the liquid scintillation counting. For whole body autoradiography, rats received radiolabeled test substance (32.1 µCi) and were sacrificed at 0.5, 2, 6, 12 and 24 h thereafter.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- From how many animals: samples pooled from 4 rats after receiving the test substance in the diet for 2 weeks
- Method type(s) for identification: GC-MS for analysis and HPLC for purification

Type:

excretion

Results:

24 h after a single oral administration of the radiolabeled test substance 85.1% (± 2.7) were excreted via urine.

Almost all the dose was excreted in 48 h (Table 1). Most of the radioactivity was recovered in the urine and fecal excretion was small. Urinary excretion was very rapid for OPP-Na. About 25% and 50% of the dose were excreted in the urine up to 3 and 6 h, respectively (Table 2). Regarding the biliary excretion about one quarter of the dose was found in the bile 72 h after 14C-OPP-Na administration (Table 3). No significant retention in any organ and tissue tested was apparent following ingestion (Table 4).

Table 1: Excretion (%) of radioactivity in the urine up to 7 days after a single oral administration of 14C-labeled test substance

Days	1	2	3	4-7	Total
Urine	83.3 ± 1.1	1.9 ± 0.5	0.6 ± 0.1	0.8 ± 0.3	93.1 ± 1.7
Faeces	2.1 ± 0.8	0.7 ± 0.5	0.2 ± 0.2	0.5 ± 0.2

Table 2: Excretion (%) of radioactivity in the urine up to 24 h after a single oral administration of 14C-labeled test substance

Time (hr)	0-3	3-6	6-9	9-13	13-24	Total
Rat #1	29.6	17.6	16.4	15.6	5.4	84.6
Rat #2	29.7	17.8	20.4	8.7	11.3	88.0
Rat #3	14.4	39.4	12.9	9.8	6.3	82.7
Mean±S.D.	24.6 ± 8.8	24.9 ± 12.5	16.6 ± 3.8	11.4 ± 3.7	7.6 ± 3.2	85.1 ± 2.7

Table 3: Excretion (%) of radioactivity in the bile after a single oral administration of 14C-labeled test substance

Time (hr)	0-1	1-2	2-3	3-4	4-5	5-6	6-8	8-24	24-72	Total
Rat #1	1.4	2.7	3.0	3.4	5.7	4.2	5.5	1.3	0.3	27.5
Rat #2	1.1	2.0	3.5	9.3	6.8	1.8	0.6	0.6	0.3	26.0

Table 4: Relative Concentration (% dose/g x 100) of Radioactivity in the Rats after Single Oral Doses of 14C-labeled test substance

Organs	Day 1 (n=3)	Day 3(n=3)	Day 7 (n=4)
Blood	0.43 ± 0.05	0.18 ± 0.05	0.06 ± 0.02
Adipose	0.05 ± 0.09	0.13 ± 0.18	0.01 ± 0.01
Kidney	0.67 ± 0.27	0.70 ± 0.22	0.25 ± 0.06
Liver	1.17 ± 0.15	1.01 ± 0.67	0.21 ± 0.06
Stomach	0.55 ± 0.24	0.39 ± 0.67	0.01 ± 0.01
Intestine	4.56 ± 2.75	0.88 ± 1.31	0.13 ± 0.10
Brain	0.09 ± 0.07	0.04 ± 0.08	0.08 ± 0.06
Bladder	0.24 ± 0.15	0.37 ± 0.34	0.03 ± 0.03

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

The follwing results were determined for the analogue substance 2-phenylphenol (OPP, CAS 90-43-7) in human:

OPP is rapidly absorbed via skin and excreted predominantly via urine. The vast majority of absorbed material is excreted within the first 24 h after application. The entire absorbed dose is recovered in excreta, thus leaving no potential for systemic or dermal accumulation.
The major metabolite identified in all urine samples analysed was the sulphate conjugate of OPP. This metabolite accounted for 68.33% of the absorbed dose. Conjugation of OPP with glucuronic acid was less significant, accounting for only 3.46% of the absorbed dose.

Hydroxylation of the phenol or phenyl ring, followed by conjugation was shown to be significant, with the glucuronide conjugate of phenylhydroquinone (PHQ-Gluc) and 2,4´-dihydroxy biphenyl-sulfate (2,4´-DHB-Sulf) representing 14.34% and 12.35% of the absorbed dose, respectively. No sulphate conjugates of PHQ was observed in any of the human urine samples analysed, contrary to metabolism of OPP in rat and mouse, in which comparable amounts of both PHQ-conjugates are found, independent from the applied dose.
Low levels of free OPP (0.5% of absorbed dose) and the glucuronide conjugate (OPP-Gluc) were found in the early time intervals. Free OPP was not observed in any of the analysed samples.

Conclusions:

No bioaccumulation potential was seen for the analogue substance based on study results. Applying the RA-approach similar results were expected for the target substance.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Objective of study:

metabolism

Metabolites identified:

yes

The following results were obtained for the analogue substance 2-phenylphenol (OPP; CAS 90-43-7):

Oral application in mice:
- 97 and 105% of the administered dose were recovered.
- The major excretory route was via the urine with 74 to 98% recovery of the applied radioactivity. The faeces represent a minor excretory route, with only 6-13 % recovery of the applied dose within 24 hours post-dosing.
- Less than 1% of the radioactivity was found in the tissues and carcass, suggesting a low potential for bioaccumulation.
- From the total of detected metabolites PHQ-glucuronide, PHQ-sulfate, OPP-sulfate and OPP-glucuronide were the main excretion products.
- Qualitative metabolite differences were not observed in mice, however, a dose-dependent quantitative difference in the extent of OPP sulfation and glucuronidation was observed.
- The percentage excretion was not dose- dependent.
Oral application in rats:
- The metabolic profile was similar to the one observed in mice.
- The percentage excretion was not dose- and sex-dependent.
- OPP-sulfate was the main urinary metabolite accounting for 91.4 % of the applied dose (for both dose groups)
- Two additional metabolite were found in urine of rats.

OPP was completely metabolised and rapid eliminated via the urine predominantly as a sulphate and glucuronide conjugate of OPP. Qualitatively the extent of metabolism was comparable between mice and rats, although quantitative differences in the extent of OPP sulfation and glucuronidation were seen between these species.

Conclusions:

A low bioaccumulation potential was determined for the analogue substance based on study results. Applying the RA-approach similar results were expected for the target substance.

Reference 5

Endpoint:

dermal absorption in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Time point:

8 h

Dose:

0.006 mg OPP/kg bw

Parameter:

percentage

Absorption:

43.15 %

Remarks on result:

other: human

Conclusions:

Following 8 h of exposure OPP is rapidly absorbed via human skin with an absorption rate of approximately 43%. Applying the RA-approach, similar results were expected for the target substance.

Description of key information

The target substance Na OPP was rapidly absorbed and excreted in the urine and faeces following oral administration. The source substance OPP is rapidly absorbed via skin and the gastrointestinal tract and widely distributed within the body. Thus, the bioavailability after oral intake is very high for both substances. Na OPP and OPP are completely metabolised and predominantly excreted via the urine and, to a minor degree, via faeces. There is only a low bioaccumulation potential noted in rodents, whereas for human, data indicate that there is no bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Experimental data regarding toxicokinetic behaviour are available for the target substance sodium 2-biphenylate (Na OPP, CAS 132-27-4) and for the source substance o-Phenylphenol (OPP, CAS 90-43-7) (McNett et al., 1997, Bartels, M. J. et al., 1997; Selim, S., 1996 and Bomhard, E. M. et al., 2002).

Sodium 2-biphenylate (Na OPP, CAS 132-27-4)

The metabolic profile of Na OPP was investigated in rats after sub-chronic oral administration (Nakao T. et al., 1983).

The elimination of various metabolites was investigated in 24 h urine samples over 136 days of five male and five female F344 rats administered 2% Na OPP in the feed (corresponding to at least 1000 mg/kg bw) (Bomhard, E. M. et al., 2002 and Nakao T. et al., 1983). Approximately 55% was eliminated in metabolized form by the males; approximately 40% by the females. Conjugates of glucuronic acid with OPP and phenylhydroquinone (PHQ) were identified as accounting for the major portion of the metabolites. Only 1% of the total phenolic metabolites eliminated was not conjugated with glucuronic acid. The concentration and distribution of the glucuronated metabolites were markedly different between males and females. Other metabolites were found neither in the urine, nor in the homogenized samples of liver and kidneys. The glucuronic acid content was reduced in the liver but not in the kidneys. The authors concluded that the two conjugates with glucuronic acid are the end products of the metabolic breakdown of SOPP in rats and that these metabolites are rapidly eliminated via the urine, because they were unable to detect either of these metabolites in the liver and kidney homogenates.

Excretion, organ distribution, and metabolic fate of 250 mg/kg bw 14C-Na OPP and 160 mg/kg bw 14C-OPP (specific activity: 1.6 mCi/mmol) were studied in four male F344 rats after a single oral administration (Bomhard, E. M. et al., 2002 and Sato M. et al., 1987). Another two male rats were cannulated to collect bile for 3 days after a single dose of 250 mg/kg 14C-Na OPP. Na OPP and OPP were rapidly excreted in the urine and faeces. About 83% of Na OPP and 88% of OPP appeared in the 24 h urine. Within 48 h about 93 and 98% were eliminated in the urine and feces, respectively. Biliary excretion amounted to about 25% of the dose within 3 days after Na OPP. Because the biliary excretion was larger than that in faeces, the authors presume intestinal reabsorption (enterohepatic circulation). No specific-organ affinity was apparent from the data of the tissue autoradiography. Thin layer chromatography (TLC) of the urine indicated the presence of conjugated metabolites only. No unchanged OPP or non-conjugated metabolites were detected. On the other band, in the urine of six male F344 rats fed 2% Na OPP-free OPP and PHQ were detected in addition. Furthermore, 2-phenyl-1,4-benzoquinone (PBQ) in a free state was detected as a minor metabolite.

O-Phenylphenol (OPP, CAS 90-43-7)

Oral absorption

In tests with rats and mice after oral dosing (McNett et al., 1997 and Bomhard, E. M. et al., 2002), 97 and 105% of the administered OPP (radiolabeled) were recovered after 24 and 48 h, respectively, indicating a fast and complete absorption of OPP via the gastrointestinal tract. Thus, OPP is rapidly bioavailable after oral dosing. Following oral uptake, OPP was shown to be completely metabolised and rapidly eliminated via the renal pathway, predominantly as a sulphate and glucuronide conjugate of OPP. Qualitatively the extent of metabolism was comparable between mice and rats, although quantitative differences in the extent of OPP sulfation and glucuronidation were seen between these species. Only 1% of the administered radioactivity was found in the tissues and carcass of rats, suggesting a low potential for bioaccumulation.

Dermal absorption

Following 8 h of exposure OPP is rapidly absorbed via human skin with an absorption rate of approximately 43% (Selim, S., 1996 and Bomhard, E. M. et al., 2002). The vast majority of absorbed material is excreted within the first 24 h after application via the renal pathway. The entire absorbed dose is recovered in excreta, thus leaving no potential for systemic or dermal accumulation (Bartels, M. J. et al., 1997; Selim, S., 1996 and Bomhard, E. M. et al., 2002). The major metabolite identified in all urine samples analysed was the sulphate conjugate of OPP. This metabolite accounted for 68.33% of the absorbed dose. Conjugation of OPP with glucuronic acid was less significant, accounting for only 3.46% of the absorbed dose. Hydroxylation of the phenol or phenyl ring, followed by conjugation was shown to be significant, with the glucuronide conjugate of phenyl-hydroquinone (PHQ-Gluc) and 2, 4´ dihydroxy biphenyl-sulfate (2,4´-DHB-Sulf) representing 14.34% and 12.35% of the absorbed dose, respectively. No sulphate conjugates of PHQ was observed in any of the urine samples analysed, contrary to metabolism of OPP in rat and mouse, in which comparable amounts of both PHQ-conjugates are found, independent from the applied dose. Low levels of free OPP (0.5% of absorbed dose) and the glucuronide conjugate (OPP-Gluc) were observed in the early time intervals. Free OPP was not observed in any of the analysed samples.

 

Conclusion

In summary, the target substance Na OPP was rapidly absorbed and excreted in the urine and faeces following oral administration. The source substance OPP is rapidly absorbed via skin and the gastrointestinal tract and widely distributed within the body. Thus, the bioavailability after oral intake is very high for both substances. Na OPP and OPP are completely metabolised and predominantly excreted via the urine and, to a minor degree, via faeces. There was only a low bioaccumulation potential noted in rodents, human data indicate that there is no bioaccumulation potential.