Sodium 2-biphenylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

96.27 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation starting from an oral OECD 453 combined chronic toxicity/carcinogenicity study in rats (Wahle, B.S. and Christenson, W.R., 1996; Wahle, B.S. and Christenson, W.R., 1999; Wahle, B.S. et al., 1997 and Bomhard, E. M. et al., 2002). Despite of the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalation route for animals and humans) was considered for the extrapolation from oral to inhalation absorption based on the available data. This was based on the available experimental ADME data on sodium 2-phenylphenolate (CAS 132-27-4) and its analogue compound 2-phenylphenol (CAS 90-43-7), which indicate rapid and complete absorption and bioavailabilty.

A NOAEL of 39 mg/kg bw/day was used as starting point, which was obtained from the combined chronic toxicity/carcinogenicity study (according to OECD 453 and in compliance with GLP) conducted with the analogue substance 2-phenylphenol (Wahle, B.S. and Christenson, W.R., 1996; Wahle, B.S. and Christenson, W.R., 1999; Wahle, B.S. et al., 1997 and Bomhard, E. M. et al., 2002).

The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document.

The following corrections were made to the NOAEL:

No correction for relative absorption oral vs. inhalation.

Correction for number of exposures per week: 7 days/week in animal study versus 5 days/week for workers

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

Therefore, the corrected NOAEC for repeated-dose systemic effects via inhalation is:

39 mg/kg bw/day×(7d/5d) ×1/(0.38 m³/kg bw)×(6.7 m³/10 m³) = 96.27 mg/m³/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for the inhalation route.

AF for other interspecies differences:

1

Justification:

Please refer to "additional information - workers".

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21.84 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

39 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

109.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects via dermal route can be determined following two different approaches: either by using the available data with the source substance 2-phenylphenol from a subacute repeated dose toxicity study via the dermal route or by means of route-to-route extrapolation using the available data with the source substance 2-phenylphenol from a chronic repeated dose toxicity study via the oral route.

1. The DNEL for systemic effects via dermal route is determined on the basis of the subacute dermal OECD 410 repeated dose toxicity study in rats:

No corrections were made to the NOAEL of ≥1000 mg/kg bw/day.

2. The DNEL for systemic effects via dermal route is determined by means of route-to-route extrapolation using the available data from a chronic oral OECD 453 combined repeated dose toxicity / carcinogenicity study in rats. The NOAEL derived from this study is 39 mg/kg bw/day.

Data are available on dermal absorption in man, indicating that approximately 50% of the applied dose is rapidly absorbed via human skin.

The following correction was made to the NOAEL:

Correction of absorption rates: dermal absorption ≈ 50%, oral absorption ≈ 100%

Correction for number of exposures per week: 7 days/week in animal study versus 5 days/week for workers

Therefore, the corrected NOAEL for repeated-dose systemic effects via dermal exposure is:

39 mg/kg bw/day×(7d/5d)×(100%/50%) = 109.2 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Please refer to "additional information - workers".

AF for other interspecies differences:

1

Justification:

Please refer to "additional information - workers".

AF for intraspecies differences:

5

Justification:

Default AF for workers.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Justification for application of specific assessment factors (AFs):

An assessment factor of 1 for interspecies differences (toxicokinetics, rat/human) was applied, because there are high quality data available investigating the toxicokinetic behaviour of the source substance 2-phenylphenol in both rodents and man (Bartels, M. J. et al., 1997; Selim, S., 1996 and Bomhard, E. M. et al., 2002; McNett et al., 1997). These data indicate that toxicokinetics of the source substance 2-phenylphenol are comparable in rats, mice and human volunteers: independent on the species tested, 2-phenylphenol was rapidly taken up, metabolised, and eliminated via the renal pathway. Metabolism of 2-phenylphenol at concentrations relevant for human exposure followed the same principles in both rodents and man, comprising above all of sulfation, followed by glucoronidation, conjugation of phenylhydroquinone (PHQ), and sulphate conjugation of 2,4`-dihydroxy biphenyl (DHB). Thus, due to comparable metabolism and formation of the same breakdown products, elimination of these metabolites is comparable in rats, mice, and humans, too. Renal elimination was rapid in all species tested, and the bioaccumulation potential of 2-phenylphenol is even less in man as compared to rodents. Thus, it can be concluded that application of an assessment factor of 1 for interspecies differences (toxicokinetics, rat/human) is appropriate, as there is a comparable toxicokinetic behaviour of 2-phenylphenol in rats, mice and man. Based on the read across approach, the same consideration can be applied for the target substance sodium 2-phenylphenolate.

An assessment factor of 1 for interspecies differences (toxicodynamics) was further applied, because there are high quality data available for three different species, including two rodent species (rat, mouse) and one non-rodent species (dog). Out of all these data, the effect level deduced from the study with the most severe outcome and, thus, the species with the highest sensitivity was used to derive the DNELs. Thus, interspecies differences were already taken into account when selecting the starting point for DNEL derivation.

There is further evidence that association between intra- and interspecies assessment factors is conservative and that the inclusion of a remaining difference factor is only necessary under rare circumstances. ECETOC (2003) analyzed the available data of Freireich, E. et al. (1966), Schein, P. et al. (1979), and Watanabe, K. et al. (1992) and concluded that apart from allometric scaling there is the likelihood of additional variability around the extrapolated dose or predicted NOAEL in humans. However, this additional variability is probably due not only to possible differences in biological sensitivity between species, but also to intraspecies differences. Apart from these aspects, one also has to consider the different endpoints (maximum tolerated dose – MTD - versus toxic dose low - TDL) used for the evaluation of human and animal data. Thus, it is evident that the comparison of ‘toxic doses’ across species is actually a comparison between doses that cause ‘dose-limiting’ toxicity (MTDH) in a sensitive subpopulation of humans (health-compromised, cancer patients) at one extreme and lethality in 10% of the population of otherwise assumed healthy animals (lethal dose - LD10) at the other. This will overestimate the sensitivity of humans in relation to other species, but to an extent which is unquantifiable. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is scientifically questionable. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, E.J., 1985; Hattis, D. et al, 1987).

The assumption is further supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with BASF Personal Care and Nutrition GmbH. Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for interspecies extrapolation. It was shown that, despite the factor for allometric scaling, no additional factor for interspecies differences is required (Escher, S.E. et al., 2013). Based on this newly available scientific evaluation of repeated dose toxicity studies the used interspecies factor of 1 is further supported.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

1.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Based on the chronic oral OECD 453 study with the source substance 2-phenylphenol various regulatory bodies [e.g. FAO/WHO (1999), EFSA (2008) and US EPA (2006)] have proposed an acceptable daily intake (ADI) of 0.4 mg/kg bw/day. This ADI is taken forward as a "toxicological threshold” for system long-term oral exposure for the general population.

The oral ADI of 0.4 mg/kg bw/day is also taken forward as a conservative toxicological threshold for system long-term dermal exposure for the general population. This toxicological threshold is considered conservative, because compound specific data discussed in the worker section for DNEL derivation are not taken into account (e.g. dermal/oral absorption; toxicokinetic aspects, ...).

A conservative toxicological threshold for systemic long-term inhalation exposure for the general population can be derived taking into account the oral ADI of 0.4 mg/kg bw/day as a starting point, a body weight of 60 kg and a respiratory volume of 20 m3/day. The calculated toxicological threshold for system long-term inhalation exposure is: 0.4 mg/kg bw/day × 60 kg bw / 20 m3/day = 1.2 mg/m3.

Overall:

The available oral ADI for the source substance 2-phenylphenol (OPP) is taken as a conservative starting point for the derivation of a toxicological threshold for system long-term dermal and inhalation exposure for the general population. Compound specific data discussed in the worker section are not taken into account (e.g. dermal/oral absorption; toxicokinetic aspects, …) leading to very conservative toxicological thresholds.