Reaction mass of m-terphenyl and o-terphenyl

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

toxicokinetic statement

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

No study covering all the relevant information was available, hence, an extensive assessment of the toxicokinetic behaviour of the registered substance was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of Reaction mass of m-terphenyl and o-terphenyl was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of m-terphenyl and o-terphenyl

EC Number:

904-797-4

Molecular formula:

C36H28

IUPAC Name:

Reaction mass of m-terphenyl and o-terphenyl

Radiolabelling:

other: not applicable

Test animals

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Route of administration:

other: all relevant routes of administration are discussed in the expert statement

Vehicle:

other: not applicable

Doses / concentrations

Remarks:

not applicable

Control animals:

other: not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption
In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, absorption of lipophilic substances with very low water solubility can be limited because they can be poorly soluble in lipids and hence not readily absorbed. Regarding the registered substance, the molecular weight of 230.31 g/mol, the Log Pow values in the range of 3.01 - 5.94 and low water solubility (0.0001 g/L at 20 °C) are supportive for a limited absorption by oral route of exposure. This thesis is supported by the low toxicity potential of the source substance in the oral acute studies.
A moderate absorption into systemic circulation can be deduced from the findings of toxicokinetic studies with single isomers reported in TNO report (2002). A radiolabelled o-terphenyl orally given to rats was excreted primarily via faeces whereby approximately 50% of the radioactivity administered was excreted via the bile within the first 24 hours, indicating the involvement of enterohepatic circulation. At sacrifice, the majority of radioactivity was found in the GI tract, the adipose tissue, and the blood pointing to a certain absorption potential. The source substance was also found in different tissues in an oral chronic (188 day) toxicity study with rats indicating a well absorption through the GI tract (TNO, 2002). In feeding studies with single isomers in diet, a variety of clinical signs, clinical chemistry findings and findings at necropsy are evident for an extensive absorption via oral route of exposure (TNO, 2002).
In a publication of Cornish et al. (1962), the results of a 30-day feeding study indicate that continued ingestion o- and m-terphenyl isomers could result in liver and kidney damage. Para-terphenyl on the other hand was poorly absorbed and a large proportion of that substance was excreted in the faeces.
The effects observed in a 14-day range-finding study with the target substance: the oral combined repeated dose toxicity study and the reproductive / developmental toxicity screening study (Envigo, 2018, Report No TP77DF) point to an absorption by oral route of exposure as well.
Based on these data and the physico-chemical properties which are in the range suggestive of absorption from the gastro-intestinal tract, 100% oral absorption is considered appropriate for the hazard assessment (DNEL derivation).
Absorption by inhalation:
Substances with logPow values above 0 have the potential for absorption directly across the respiratory tract epithelium. Reaction mass of m-terphenyl and o-terphenyl a log Pow value of 3.01 - 5.94. Thus, according to this criterion it is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The vapours of lipophilic substances can reach the deep lung and thus absorption through the huge gas exchange region may occur. Further parameter which should be considered is the volatility. Substances with low volatility have a vapour pressure of less than 0.5 kPa. A vapour pressure of 0.018 Pa is indicative for low volatility, assuming low availability for inhalation and consequently low systemic exposure (ECHA guidance R7.c, 2017). Based on low volatility of the registered substance, exposure by inhalation is not really relevant for this substance. It is unlikely, that considerable amounts of the substance reach the lung and when this occurs, the substance is expected to be absorbed directly across the respiratory tract epithelium or through aqueous pores due to the logPow of 3.01 - 5.94. There is no information on particle size or method of generating vapours or aerosols in the reported inhalation studies with the source substance, but the effects observed in animals exposed by inhalation (nasal congestion with rhinitis and lachrymation with eyes closed, laboured breathing as well as erythema of the ears and paws, acute tracheal necrosis, chronic tracheitis, and acute tracheobronchitis) (NTP, 2002) point to local toxicity effects which prevail over systemic effects.
Based on these data, 100 % absorption is considered for inhalation for the registered substance. Absorption by inhalation is expected not to be higher than absorption by oral route.
Dermal absorption
Based on the physico-chemical properties of the registered substance, it is likely to penetrate the skin. The molecular weight of 230.31 g/mol and Log Pow values in the range of 3.01 to 5.04 are favourable for absorption by the stratum corneum. The substance must be sufficiently soluble in water to partition from the stratum corneum into the viable epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Since the registered substance has low water solubility (0.0001 g/L at 20 °C), dermal uptake may be limited (ECHA guidance R.7C, 2017). Also, for monomers with logPow >4 applies that the rate of their penetration may be limited by the rate of transfer between the stratum corneum and the viable epidermis; nevertheless, an uptake into the stratum corneum will be high.
Low penetration rate is supported by the result of the acute dermal study in rats with the source substance where no systemic effects of toxicity were observed in treated animals. Additionally, the source substance was not irritating to skin in the skin irritation study in rabbits and in the acute dermal study in rats. Therefore, it can be concluded that an enhanced absorption through damaged skin can be ruled out. Based on the absence of the toxicity potential via dermal route of exposure in animal studies and on the non-irritating property of the source substance and taken into account physico-chemical properties, 100 % of dermal absorption is considered appropriate for the purposes of derivation of dermal systemic DNEL.

Details on distribution in tissues:

Distribution and accumulative potential
Based on physico-chemical properties, a significant amount of the registered substance is expected to be available for distribution when administered orally. As the cell membranes require a substance to be soluble in both water and lipids to be taken up, the registered substance is expected to reach the inner cell compartment due to its optimal molecular weight of 230.31 g/mol and its LogPow of 3.01 to 5.04. Its intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. The substance is not expected to distribute in body fluids because of very low water solubility (0.0001 g/L).
The distribution of the absorbed source substance was studies in a toxicokinetic study with rats with 80 mg radiolabelled o-terphenyl/kg bw (TNO, 2002). It was reported that upon sacrifice at 24 hours, 12.5%, 1.5%, and 0.2% of the radiolabel were recovered from the gastrointestinal tract, the adipose tissue, and the blood, respectively, while only very low amounts (<0.03%) were found in the liver, the kidneys, and the brains (Cornisch et al., 1962, cited in TNO, 2002).
In a chronic toxicity study in rats, the source substance administered by oral route for 188 days followed by an exposure-free period of 47 days, resulted in the presence of o- and m-terphenyl in extracts of kidney homogenates, indicating that accumulation may occur at repeated dosing (TNO, 2002).

Details on excretion:

Metabolism and excretion
The registered substance is not expected to undergo hydrolysis in gastrointestinal tract or in body fluids, due to the absence of hydrolysable functional groups. If absorbed, it is not expected to be excreted unchanged via urine due to its very low water solubility (0.0001 g/L mg/L). The substance was reported to circulate in the enterohepatic cycle and be excreted via the faces. In case of entering the cell inner, terphenyls can undergo Phase I and Phase II reactions. It was proved in several toxicokinetic studies with single terphenyl isomers and their mixture, the source substance.
“When 80 mg radiolabelled o-terphenyl/kg was orally (gavage) given to male rats and rabbits, approximately 80% and 90% of the radiolabel administered were eliminated in the first 24 hours by rats and rabbits, respectively, while elimination was almost complete within 48 hours (>94%). In rats, the main excretion route was the faeces from which approximately 75% of the radioactivity was recovered in the first 24 hours. Of this radioactive fraction, 10% were parent compound, 86% were metabolites containing free phenol groups or conjugated products, while the remaining 4% was highly polar, probably conjugated compounds that could not be hydrolysed by ß-glucuronidase or arylsulphatase. It was shown that approximately 50% of the radioactivity administered was excreted via the bile within the first 24 hours, indicating the involvement of enterohepatic circulation. Approximately 6% of the radioactivity was excreted in the first 24-hour urine, consisting mostly of ß-glucuronide conjugates.
In rabbits, the urine was the most important excretion route accounting for approximately 76% of the amount of radiolabel excreted within the first 24 hours. Of this, 12% were parent compound, 79% were metabolites containing free or conjugated phenol groups, and 9% conjugates that could not be hydrolysed by ß-glucuronidase or arylsulphatase. Approximately 12% was excreted in the faeces within the first 24 h. In male rabbits, 15 and 45% of a single oral dose of 1 g of o-terphenyl were excreted within 4 days in the urine as free phenolic and glucuronide derivatives, respectively, while another 8% was found unchanged in the faeces. Following oral administration of m- or p-terphenyl, these figures were 18% (urinary free phenols), 20% (urinary glucuronides), and 15% (faecal unchanged compound), and 0% (urinary free phenols), 4% (urinary glucuronides), and 30% (faecal unchanged compound), respectively. There were no indications for the excretion of ethereal sulphates or mercapturic acids“ (Cornisch et al., 1962, TNO, 2002).

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

please refer to "Details on excretion"

Any other information on results incl. tables

The toxicokinetic profile of Reaction mass of m-terphenyl and o-terphenyl (CAS 904-797-4) (in the following the target substance) was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physico-chemical properties of this substance were integrated with its available toxicological data to create a prediction of the toxicokinetic behaviour. Additionally, published data on toxicokinetic behaviour and toxicity effects in animal studies of single o-, m-, and p-terphenyl isomers and their mixture known under CAS No. 26140-60-3 (TNO, 2002; in the following source substance) have been taken into account.

The target substance contains predominantly o- and m-terphenyls while the source substance contains mainly m-terphenyl, o-terphenyl and only little p-terphenyl as well as a low percentage of quarterphenyls. Both substances are aromatic hydrocarbons and show very similar physico-chemical properties (similar molecular weight, insolubility in water, high LogPow, no hydrolysis in water, low vapour pressure) and are thus believed to behave very similar in aqueous solutions and therefore to have similar ADME parameters in living organisms. The slightly different composition of the isomer’s content of the source substance is considered not to result in different toxicokinetic behaviour when compared to the target substance. Therefore, the findings of the toxicity studies with the source substance would provide an adequate pool of data to assess toxicokinetic behaviour of the target substance.

Toxicological profile of Reaction mass of m-terphenyl and o-terphenyl

 

Reaction mass of m-terphenyl and o-terphenyl is not acutely toxic via oral route of exposure. Oral LD50 values of 2604, 3690 and >5000 mg/kg bw (m/f) were established in several oral OECD 401 guideline studies in rats with the source substance. Toxicity to the nervous system was suggested by several of the clinical abnormalities that were observed. Furthermore, necropsy findings indicated that Mixture of terphenyls and quarterphenyls affected the gastrointestinal tract.

An LC50 of >3.8 mg/L was reported also for the source substance in an acute inhalation study according to OECD 403. This concentration was the maximum attainable concentration. Immediate post exposure observations included red encrustation around eyes and nose, laboured breathing and salivation. On post-exposure days 7 and 14 these observations were no longer evident. No gross pathology abnormalities were observed in any of the animals during necropsy examinations. In a further inhalation study in rats with moderator-coolants o-terphenyl (OTP), m-terphenyl (MTP), p-terphenyl (PTP), terphenyl mixture (OMRE) and irradiated terphenyl mixture (ROMRE), the substances produced respiratory tract irritation displayed also by histopathologic changes. TNO reports that terphenyls may be considered as harmful by inhalation, based on acute inhalation mortality data with individual isomers (TNO, 2002).

In an acute dermal toxicity study, the source substance did not produce systemic effects and findings at necropsy in treated in animals (LD50 >5000 mg/kg bw). There were only mild dermal reactions in several animals. Similarly, the source substance was not irritating to rabbits’ skin after 4-hour exposure in OECD 404 studies and was also not irritating to eyes in OECD 405 studies. In a skin sensitisation study according to Buehler method (OECD 406) and in other less reliable skin sensitisation studies, another source substance (biphenyl-2 -ol; CAS 90 -43 -7) was not sensitising to skin. The results of this study are appropriate for the target substance because biphenyl-2-ol have the same core benzene structure as the terphenyls and no structural alerts that would induce hypersensitivity reactions.

The source substance was not mutagenic in three in vitro mutagenicity studies: Ames Test, mammalian cell gene mutation assay (OECD 476) with CHO cells and in vitro mammalian chromosome aberration test with CHO cells (OECD 473). In an in vivo chromosome aberration assay according to OECD 475, the source substance was negative as well.

The target substance was tested in a 14-day study to select suitable doses for a subsequent OECD 422 study. A NOAEL of 100 mg/kg bw was established for systemic effects and is based on effects observed around parturition.

Toxicokinetic analysis of Reaction mass of m-terphenyl and o-terphenyl

Reaction mass of m-terphenyl and o-terphenyl is a cream coloured solid without specific odour (MW of 230.31 g/mol for single o-, p-, or m-isomers) at 20°C. The substance is insoluble in water (0.0001 g/L at 20 °C) and has a LogPow of 3.01 - 5.94. It has a low vapour pressure of 0.018 Pa at 25 °C and therefore is not volatile. The substance is not expected to undergo hydrolysis in the environment and in body fluids due to the lack of functional groups.

Absorption

Oral absorption

In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, absorption of lipophilic substances with very low water solubility can be limited because they can be poorly soluble in lipids and hence not readily absorbed. Regarding the registered substance, the molecular weight of 230.31 g/mol, the Log Pow values in the range of 3.01 - 5.94 and low water solubility (0.0001 g/L at 20 °C) are supportive for a limited absorption by oral route of exposure. This thesis is supported by the low toxicity potential of the source substance in the oral acute studies.

A moderate absorption into systemic circulation can be deduced from the findings of toxicokinetic studies with single isomers reported in TNO report (2002). A radiolabelled o-terphenyl orally given to rats was excreted primarily via faeces whereby approximately 50% of the radioactivity administered was excreted via the bile within the first 24 hours, indicating the involvement of enterohepatic circulation. At sacrifice, the majority of radioactivity was found in the GI tract, the adipose tissue, and the blood pointing to a certain absorption potential. The source substance was also found in different tissues in an oral chronic (188 day) toxicity study with rats indicating a well absorption through the GI tract (TNO, 2002). In feeding studies with single isomers in diet, a variety of clinical signs, clinical chemistry findings and findings at necropsy are evident for an extensive absorption via oral route of exposure (TNO, 2002).

In a publication of Cornish et al. (1962), the results of a 30-day feeding study indicate that continued ingestion o- and m-terphenyl isomers could result in liver and kidney damage. Para-terphenyl on the other hand was poorly absorbed and a large proportion of that substance was excreted in the faeces.

The effects observed in a 14-day range-finding study with the target substance: the oral combined repeated dose toxicity study and the reproductive / developmental toxicity screening study (Envigo, 2018, Report No TP77DF) point to an absorption by oral route of exposure as well.

Based on these data and the physico-chemical properties which are in the range suggestive of absorption from the gastro-intestinal tract, 100% oral absorption is considered appropriate for the hazard assessment (DNEL derivation).

Absorption by inhalation:

Substances with logPow values above 0 have the potential for absorption directly across the respiratory tract epithelium. Reaction mass of m-terphenyl and o-terphenyl has a log Pow value of 3.01 - 5.94 Thus, according to this criterion it is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The vapours of lipophilic substances can reach the deep lung and thus absorption through the huge gas exchange region may occur. Further parameter which should be considered is the volatility. Substances with low volatility have a vapour pressure of less than 0.5 kPa. A vapour pressure of 0.018 Pa is indicative for low volatility, assuming low availability for inhalation and consequently low systemic exposure (ECHA guidance R7.c, 2017). Based on low volatility of the registered substance, exposure by inhalation is not really relevant for this substance. It is unlikely, that considerable amounts of the substance reach the lung, However, if this occurs, the substance is expected to be absorbed directly across the respiratory tract epithelium or through aqueous pores due to the logPow of 3.01 - 5.94. There is no information on particle size or method of generating vapours or aerosols in the reported inhalation studies with the source substance, but the effects observed in animals exposed by inhalation (nasal congestion with rhinitis and lachrymation with eyes closed, laboured breathing as well as erythema of the ears and paws, acute tracheal necrosis, chronic tracheitis, and acute tracheobronchitis) (NTP, 2002) point to local toxicity effects which prevail over systemic effects.

Based on these data, 100 % absorption is considered for inhalation for the registered substance. Absorption by inhalation is expected not to be higher than absorption by oral route.

Dermal absorption

Based on the physico-chemical properties of the registered substance, it is likely to penetrate the skin. The molecular weight of 230.31 g/mol and Log Pow values in the range of 3.01 to 5.04 are favourable for dermal absorption. The substance must be sufficiently soluble in water to partition from the stratum corneum into the viable epidermis. Therefore, if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Since the registered substance has a low water solubility (0.0001 g/L at 20 °C), dermal uptake may be limited (ECHA guidance R.7C, 2017). Also, for monomers with logPow >4 the rate of their penetration may be limited by the rate of transfer between the stratum corneum and the viable epidermis; nevertheless, an uptake into the stratum corneum will be high.

Low penetration rate is supported by the result of the acute dermal study in rats with the source substance where no systemic effects of toxicity were observed in treated animals. Additionally, the source substance was not irritating to skin in the skin irritation study in rabbits and in the acute dermal study in rats. Therefore, it can be concluded that an enhanced absorption through damaged skin can be ruled out. Based on the absence of the toxicity potential via dermal route of exposure in animal studies and on the non-irritating property of the source substance and taking into account physico-chemical properties, 100 % of dermal absorption is considered appropriate for the purposes of derivation of dermal systemic DNEL.

Distribution and accumulative potential

Based on physico-chemical properties, a significant amount of the registered substance is expected to be available for distribution when administered orally. As the cell membranes require a substance to be soluble in both water and lipids to be taken up, the registered substance is expected to reach the inner cell compartment due to its optimal molecular weight of 230.31 g/mol and its LogPow of 3.01 to 5.04. Its intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. The substance is not expected to distribute in body fluids because of very low water solubility (0.0001 g/L).

The distribution of the absorbed source substance was studies in a toxicokinetic study with rats with 80 mg radiolabelled o-terphenyl/kg bw (TNO, 2002). It was reported that upon sacrifice at 24 hours, 12.5%, 1.5%, and 0.2% of the radiolabel were recovered from the gastrointestinal tract, the adipose tissue, and the blood, respectively, while only very low amounts (<0.03%) were found in the liver, the kidneys, and the brains (Cornisch et al., 1962, cited in TNO, 2002).

In a chronic toxicity study in rats, the source substance administered by oral route for 188 days followed by an exposure-free period of 47 days, resulted in the presence of o- and m-terphenyl in extracts of kidney homogenates, indicating that accumulation may occur at repeated dosing (TNO, 2002).

Metabolism and excretion

The registered substance is not expected to undergo hydrolysis in gastrointestinal tract or in body fluids, due to the absence of hydrolysable functional groups. If absorbed, it is not expected to be excreted unchanged via urine due to its very low water solubility (0.0001 g/L mg/L). The substance was reported to circulate in the enterohepatic cycle and be excreted via the faces. If case of entering the cell inner, terphenyls can undergo Phase I and Phase II reactions. It was proved in several toxicokinetic studies with single terphenyl isomers and their mixture, the source substance.

“When 80 mg radiolabelled o-terphenyl/kg was orally (gavage) given to male rats and rabbits, approximately 80% and 90% of the radiolabel administered were eliminated in the first 24 hours by rats and rabbits, respectively, while elimination was almost complete within 48 hours (>94%). In rats, the main excretion route was the faeces from which approximately 75% of the radioactivity was recovered in the first 24 hours. Of this radioactive fraction, 10% were parent compound, 86% were metabolites containing free phenol groups or conjugated products, while the remaining 4% was highly polar, probably conjugated compounds that could not be hydrolysed by ß-glucuronidase or arylsulphatase. It was shown that approximately 50% of the radioactivity administered was excreted via the bile within the first 24 hours, indicating the involvement of enterohepatic circulation. Approximately 6% of the radioactivity was excreted in the first 24-hour urine, consisting mostly of ß-glucuronide conjugates.

In rabbits, the urine was the most important excretion route accounting for approximately 76% of the amount of radiolabel excreted within the first 24 hours. Of this, 12% were parent compound, 79% were metabolites containing free or conjugated phenol groups, and 9% conjugates that could not be hydrolysed by ß-glucuronidase or arylsulphatase. Approximately 12% was excreted in the faeces within the first 24 h. In male rabbits, 15 and 45% of a single oral dose of 1 g of o-terphenyl were excreted within 4 days in the urine as free phenolic and glucuronide derivatives, respectively, while another 8% was found unchanged in the faeces. Following oral administration of m- or p-terphenyl, these figures were 18% (urinary free phenols), 20% (urinary glucuronides), 15% (faecal unchanged compound), 0% (urinary free phenols), 4% (urinary glucuronides), and 30% (faecal unchanged compound), respectively. There were no indications for the excretion of ethereal sulphates or mercapturic acids“ (Cornisch et al., 1962, TNO, 2002).

Summary

Reaction mass of m-terphenyl and o-terphenyl is expected to be well absorbed orally, based on the systemic effects in the feeding repeated dose toxicity studies, its molecular weight of 230.31 g/mol and Log Pow values in the range of 3.01 to 5.04 of (161.24 g/mol). Concerning the absorption after exposure via inhalation, as the chemical has vapour pressure of 0.018 Pa (a value not indicative for absorption by inhalation), it is clear, that the substance is marginally available for inhalation. Given its lipophilicity (LogPow of 3.01 to 5.04) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium. Reaction mass of m-terphenyl and o-terphenyl is not expected to be absorbed extensively following dermal exposure into the viable epidermis due to the low water solubility of 0.0001 g/L but absorption into stratum corneum is predicted to be high. Moreover, due to the absence of irritating properties of the registered substance absorption through the skin is not enhanced. Reaction mass of m-terphenyl and o-terphenyl is expected to distribute into the inner of cells and to a lesser extent into the intravascular compartment. The substance does not indicate a significant potential for accumulation, but accumulation after repeated exposures cannot be ruled out. The substance is expected to be metabolised via Phase I and Phase II reactions leading to hydroxylated derivatives probably conjugated compounds with glucuronic acid and/or derivatives of oxidative metabolites. The parent compound can be involved into the enterohepatic cycle and be excreted via the faces. Metabolites containing free phenol groups or conjugated products are expected to be eliminated mainly via the urine.

Applicant's summary and conclusion

Conclusions:

Reaction mass of m-terphenyl and o-terphenyl is expected to be well absorbed orally, is marginally available for inhalation, and is predicted to be absorbed into the stratum corneum but not extensively into the viable epidermis. Reaction mass of m-terphenyl and o-terphenyl is expected to distribute into the inner of cells and to the lesser extent into the intravascular compartment. The substance does not indicate a significant potential for accumulation. The substance is expected to be metabolised via Phase I and Phase II reactions and is expected to be excreted via feces (enterohepatic cycle) and urine.

Executive summary:

Reaction mass of m-terphenyl and o-terphenyl is expected to be well absorbed orally, based on the systemic effects in the feeding repeated dose toxicity studies, its molecular weight of 230.31 g/mol and Log Pow values in the range of 3.01 to 5.04. Concerning the absorption after exposure via inhalation, as the chemical has vapour pressure of 0.018 Pa (a value not indicative for absorption by inhalation), it is clear, that the substance is marginally available for inhalation. Given its lipophilicity (LogPow of 3.01 to 5.04) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium. Reaction mass of m-terphenyl and o-terphenyl is not expected to be absorbed extensively following dermal exposure into the epidermis due to the low water solubility of 0.0001 g/L, but absorption into stratum corneum is predicted to be high. Moreover, due to the absence of irritating properties, absorption through the skin of the registered substance is not enhanced. Reaction mass of m-terphenyl and o-terphenyl is expected to distribute into the inner of cells and to the lesser extent into the intravascular compartment. The substance does not indicate a significant potential for accumulation, but accumulation after repeated exposures cannot be ruled out. The substance is expected to be metabolised via Phase I and Phase II reactions leading to hydroxylated derivatives probably conjugated compounds with glucuronic acid and/or derivatives of oxidative metabolites. The parent compound can be involved into the enterohepatic cycle and be excreted via the faces. Metabolites containing free phenol groups or conjugated products are expected to be eliminated mainly via the urine.