Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

No specific study on toxicokinetics is available. therefore an assessment based on the available inforamtion on the susbtance is done. See below.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of the registered substance, the results obtained from acute and repeated-dose toxicity studies as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

 

Physical-chemical properties

 

The substance is a mono-constituent, white crystalline solid at room temperature, having a relatively low molecular weight of 186.21 g/mol and a median particle size of 158 µm (laser diffraction measurement). The substance is a slightly water-soluble solid/powder (33.7 mg/L) and is moderately lipophilic based on the octanol/water partition coefficient (Log Kow = 2.7). The substance has very low volatility according to its estimated vapour pressure (0.000105 Pa at 20°C).

 

Absorption

 

Oral/GI absorption

 

Biphenyl-4,4'-diol is considered not to be prone to hydrolysis by the absence of hydrolysable groups within its structure. This means that parent compound is only present in the GI tract and therefore predictions based upon the physico-chemical characteristics of the parent substance may be applied.

The physical chemical characteristics described above suggest that the registered substance is of adequate molecular size to participate in endogenous absorption mechanisms (active transport) within the mammalian gastrointestinal tract. Being moderately lipophilic, absorption by diffusion across the gastrointestinal epithelial barriers cannot be excluded. In additions, the absorption may be potentiated by the ability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. However, the water solubility of the registered substance (33.7 mg/L) ) and a pHs of GI tract below the substance’s pKa (= 9.42) do not favour the absorption.

Evidence of oral absorption was demonstrated after oral administration of the test substance to mice in the Micronucleus study (Schulz, 2017). The bioavailability of biphenyl-4,4’-diol in blood after oral exposure was clearly demonstrated by analysis of plasma samples taken 2 and 4 hours after administration.

Furthermore, adverse effects to kidneys associated with changes in clinical haematology, serum chemistry and urine parameters were observed in the 90-days toxicity study via oral route and also to liver in the combined repeat dose and reproductive/developmental toxicity screening test. These systemic oral effects support the hypothesis of an oral absorption.

 

Based on all above mentioned considerations it was conservatively assumed arate of oral absorption of 100%after oral exposure for the purposes of human health risk assessment. 

 

Dermal absorption

 

Regarding dermal absorption, the log Kow value (= 2.7) favours dermal absorption. However it is assumed that the dermal uptake is limited by the low water solubility of the substance. This is supported by the absence of signs of systemic toxicity in the dermal toxicity study performed in accordance with OECD Guideline 402 at the limit dose of 2000 mg/kg bw. 

In light of these data, adermal absorption of 50%was assumed for the purposes of human health risk assessment.

 

Respiratory tract absorption

 

The potential for inhalation toxicity was not evaluated in vivo.

The vapour pressure of the substance (0.000105 Pa at 20°C) indicated an absence of volatility. Although the substance is a crystalline solid, data on its particle size distribution showed a median particle size of 158 µm (D10= 48.5 µm, D50= 158 µm and D90= 309 µm) that indicates a low potential to be inhaled. Based on the vapor pressure and particle size of biphenyl-4,4’-diol, it is hardly expected that particles of the registered substance will reach the lower respiratory tract..

However, when considering the absorption rate of the particle in the point of contact in the respiratory tract (if it is reached), other parameters should be also considered. The particle size suggests that the registered substance is of adequate molecular size to participate in endogenous absorption mechanisms (active transport) within the mammalian respiratory tract. Being moderately lipophilic, absorption by diffusion across the gastrointestinal epithelial barriers cannot be excluded. In additions, the absorption may be potentiated by the ability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface.

 

In light of these data, and the lack of specific information on absorption in the respiratory tract, the substance was conservatively assumed to present a rate of absorption of 100% at the point of contact for the purposes of human health risk assessment.

 

Distribution

 

After absorption, any material will be distributed via the blood to the liver, and other organs and tissues.

Systemic distribution of the substance can be predicted from its physical chemical characteristics but in the case of the registered substance, repeated toxicity studies available demonstrate distribution as test-item related adverse effects have been identified in the kidney and in the liver.

Considering that the substance is slightly water soluble, it is suggested that, upon systemic absorption by oral or dermal route, or by inhalation, the substance may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule.

Based on its moderate lipophilic character, the substance may readily cross cellular barriers or may be distributed into fatty tissues with a low potential to accumulate (Log Kow < 4).

 

Metabolism

Specific data on metabolism of the substance is not available. The only publicly available informations identified where the registered substance is mentioned are related to biphenyl (CAS 92-52-4). In these two publications by Halpaap (1978) and by Halpaap-wood (1981) the metabolism of biphenyl was investigated using gas chromatographic and mass spectrometric analysis. 4,4'-dihydroxybiphenyl (or biphenyl-4,4'-diol), was identified as a second stage metabolic product of biphenyl with and without co-administration of other substances.

The presence (or absence) of metabolic activation did not influence in vitro genotoxicity tests (Ames test, Chromosome Aberration tests or Mammalian Cell Gene Mutation test): the registered substance was demonstrated not to be mutagenic in vitro, in the absence and presence of S9 mix. However, the results of the combined repeated dose toxicity with the reproduction/developmental screening test repeated oral toxicity study in the Sprague-Dawley rat showed liver changes that are consistent with the increased metabolism associated with detoxification of a xenobiotic. Indeed, at necropsy the medium dose male animals (200 mg/kg bw/day), affected male livers - increased relative weights, darkening and enlarged macroscopic appearance, and altered the histopathological appearance, including development of centrilobular hepatocyte hypertrophy and reduction in occurrence of periportal fatty change. Fourteen days after the final treatment the recovery group of males demonstrated that all of the changes caused by the compound had disappeared and no delayed toxicity was evident.

 

Bioaccumulation potential

 

As the log Kow of biphenyl-4,4'-diol is 2.7, bioaccumulation is not considered likely. As such, the substance is not considered to be bioaccumulative (B) or very bioaccumulative (vB) in the environment either.

 

Excretion

 

The registered substance, having a molecular weight lower than 300 g/mol (ie. 186.21 g/mol) and being moderately lipophilic, is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.

 

Increased specific gravity, turbidity and crystals content in females at 500 mg/kg/day (highest dose) was shown at the end of the dosing period of the 90-day repeated toxicity study in Wistar rats after oral exposure. The nature of the crystals is unknown but the incidence was test-item related.