1-Methyl-4-[(trans,trans)-4'-propyl[1,1'-bicyclohexyl]-4-yl] -benzene

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance R .7c

Version / remarks:

2017

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on absorption:

Oral route
Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with a logPow greater than 6.5 the substance would be expected to not passively pass biological membranes. In addition, the substance is highly insoluble in water (0.047 mg/L). However, micellular formation in the gastrointestinal tract (GIT) could enable absorption processes. Moreover, the molecular weight of the substances is well below 500 g/mol and could thus contribute to a favored absorption. In addition, the substance is not expected to undergo hydrolysis based on its chemical structure. Abiotic degradation is thus not relevant for the oral route of exposure. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption cannot be completely ruled out.
The above considerations are confirmed by findings of toxicity studies with the test substance.
In an acute oral toxicity study with rats no mortality or other signs of toxicity were observed up to the limit dose of 2000 mg/kg bw.
Oral administration of the test material for 4 weeks followed by a 2-week treatment-free recovery period at doses of 0, 100, 300, and 1000 mg/kg bw / day (4) induced treatment-related reduction of body weight at 1000 mg/kg and a slight change of behaviour parameters. Haematology revealed treatment-related changes of red and white blood cells that were fully reversible at the end of recovery in the top dose. Clinical chemistry showed indications of increase liver metabolism mainly at 1000 mg/kg. At gross pathology only spontaneous findings were observed. A dose-dependent liver weight increase was observed correlating with centrilobular hypertrophy in female animals of all dose groups that was considered to be an adaptive response of metabolic activation. The liver weight increase showed a tendency towards reversibility after the 2-week recovery period. Therefore, there is clear indication that the test item and/or its metabolites become systemically available via the oral route.

Dermal route
Regarding dermal exposure, the substance is considered to unlikely permeate the skin. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability, but a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the molecular weight, the test item would not be critical, however, its logPow of > 6.5 will probably not favor dermal permeation.

These estimates are strongly supported by the calculation of the dermal exposure based on phys chem parameters. Transdermal skin permeability is a crucial parameter for the transdermal delivery of substances also including dermal accidental exposure. The relationship between physicochemical parameters of organic substances and their skin permeability has been intensively explored through the assembly of human skin permeability coefficients and the octanol-water partition coeffi-cient (logP) for a large set of chemicals. It was shown, that the logP value can be used to obtain a first estimate of the skin permeability coefficient (KP). This initial work was further refined to show, that the permeability coefficient could be reasonably represented by a multiple regression relationship involving logP and the molar mass M:

log(Kp)=0.71*logP-0.0061*M-2.72 (eq. 1)

from: Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992 May;9(5):663–9. and Guy RH, Potts RO. Penetration of industrial chemicals across the skin: a predictive model. Am J Ind Med. 1993 May;23(5):711–9.


Using eq. 1 a human skin permeability coefficients of 1.18 cm/h can be derived.
This allows an estimation of the dermal uptake (m sys) of compounds from a saturated aqueous environment through the stratum corneum according to
(eq. 2):

m sys = Kp * A * Cwater * t (eq. 2),

where A denotes the exposed skin area, Cwater is the concentration of the compound in the aqueous environment and t is the exposure time. Taking a manual task lasting for 1 hour, exposing an area equivalent to the surface area of both hands (960 cm2) to an aqueous saturated environment using the water solubility limit into account yields dermal uptakes of 53.5 µg per person, respectively.

Taken together, this indicates that the test item will not readily penetrate skin layers.

Inhalation route
The vapour pressure of the test item was calculated to be 4.6E-5 Pa at 20 °C, 9.7E-5 Pa at 25 °C and 3.0E-5 Pa at 50 °C, respectively.
Due to the very low vapor pressure it is very unlikely that the substance becomes available as a vapor and the boiling point of the substance was determined to be 428-430 °C at 1013 hPa. The substance is a solid of very low dustiness. Therefore, exposure via inhalation is considered not relevant for the substance. However, in the unlikely case of inhalation, the substance would be expected to pass biological membranes taking into account same considerations as for the oral route.

Details on distribution in tissues:

As mentioned above, no or very poor bioavailability is expected for the test item via the dermal route, whereas absorption upon ingestion is considered to be likely based on physicochemical properties and as confirmed by in vivo toxicity studies. Repeated dose toxicity studies revealed effects in liver, indicating that either the substance reached this tissue following oral administration. Based on its low water solubility and high logPow value the test item is expected to be absorbed by micellular formation and as such taken up and transported via the lymph system, similar to other lipophilic constituents of the diet. Further, protein binding is expected rather than dissolution in the plasma in terms of distribution via the blood stream.
Based on its low water solubility and high logPow value, bioaccumulating potential cannot completely be ruled out for the test item. However, based on a experimental study in fish, a steady state BCF mean value of 39 was determined, confirming that the test item is of no concern in regards to bioaccumulation (reference 5.3.1-1).

Details on excretion:

The based on its low water solubility test item is not expected to be eliminated via the urine unless it undergoes metabolic transformation increasing its hydrophilicity. Elimination via the bile would thus be more likely.

Metabolites identified:

not measured

Details on metabolites:

There is no experimental data available regarding potential metabolism of the test item.
Considering its chemical structure oxidation of the double bound of the aromatic ring by phase I enzymes such as CYP 450 can be anticipated and will predominantly occur in the liver. Further, conjugation reactions by phase II enzymes such as glutathione-S-transferase in order to increase water solubility and thus facilitate excretion might occur. Nascent (cyclo-) alcohol groups might further represent a substrate for Alcohol as well as Aldehyde dehydrogenases.
Metabolism of the test item in the liver can be assumed, because the liver was found to be a target organ in the repeated dose toxicity studies as a result of metabolic adaptation. Because of the reversibility of the observed effects (e.g. on liver), the substance is most likely eliminated from the organism. Based on results of in vitro tests where experiments were conducted with as well as without exogenous metabolic activation it can be stated that adding rat liver S9 did not lead to an increased (cyto-) toxicity in any of the tests. Therefore, activation of toxicity by metabolic transformation is considered unlikely to occur in the organism.

Conclusions:

Based on the physicochemical properties, particularly water solubility, logPow and molecular weight, absorption via the gastrointestinal tract is possible for the test substance, whereas uptake following dermal exposure is less relevant. Based on its very low vapor pressure it is highly unlikely that the test substance will become systemically available after inhalation. Abiotic transformation e.g. hydrolysis is not expected. If absorbed, the test item would be distributed by binding to plasma protein due to its low water solubility and be eliminated via bile or the urine following metabolic transformation. Bioaccumulation is excluded based on experimental data.

Executive summary:

Toxicokinetic analysis of the test item

There are no experimental studies available on toxicokinetics of the test item. Therefore its toxicokinetic properties are assessed based on its physico-chemical properties as well as from data available from toxicity studies and in accordance with ECHA Guidance R .7c (2017).

The test substance is a crystalline white solid at room temperature and of low dustiness. The test item, being a mono-constituent substance, has a molecular weight of 298.5 g/mol and a relative density of 0.961. Its melting point was determined to be 177 °C and whereas the boiling point is at 428 -430 °C at 1013 hPa. The substance is considered highly insoluble in water, as water solubility was found to be low (0.047 mg/L). Partition coefficient (logPow) of the substance was estimated to exceed 6.5 being the highest calibration standard of the method applied. Vapor pressure of the substance was determined to be 9.7E-5 Pa at 25 °C. 

1.1 Absorption

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4.  Thus, with a logPow greater than 6.5 the substance would be expected to not passively pass biological membranes. In addition, the substance is highly insoluble in water (0.047 mg/L). However, micellular formation in the gastrointestinal tract (GIT) could enable absorption processes. Moreover, the molecular weight of the substances is well below 500 g/mol and could thus contribute to a favored absorption. In addition, the substance is not expected to undergo hydrolysis based on its chemical structure. Abiotic degradation is thus not relevant for the oral route of exposure. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption cannot be completely ruled out.

The above considerations are confirmed by findings of toxicity studies with the test substance.

In an acute oral toxicity study with rats no mortality or other signs of toxicity were observed up to the limit dose of 2000 mg/kg bw.

Oral administration of the test material for 4 weeks followed by a 2-week treatment-free recovery period at doses of 0, 100, 300, and 1000 mg/kg bw / day (4) induced treatment-related reduction of body weight at 1000 mg/kg and a slight change of behaviour parameters. Haematology revealed treatment-related changes of red and white blood cells that were fully reversible at the end of recovery in the top dose. Clinical chemistry showed indications of increase liver metabolism mainly at 1000 mg/kg. At gross pathology only spontaneous findings were observed. A dose-dependent liver weight increase was observed correlating with centrilobular hypertrophy in female animals of all dose groups that was considered to be an adaptive response of metabolic activation. The liver weight increase showed a tendency towards reversibility after the 2-week recovery period. Therefore, there is clear indication that the test item and/or its metabolites become systemically available via the oral route.

Dermal route

Regarding dermal exposure, the substance is considered to unlikely permeate the skin. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability, but a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the molecular weight, the test item would not be critical, however, its logPow of > 6.5 will probably not favor dermal permeation.

These estimates are strongly supported by the calculation of the dermal exposure based on phys chem parameters. Transdermal skin permeability is a crucial parameter for the transdermal delivery of substances also including dermal accidental exposure. The relationship between physicochemical parameters of organic substances and their skin permeability has been intensively explored through the assembly of human skin permeability coefficients and the octanol-water partition coeffi-cient (logP) for a large set of chemicals. It was shown, that the logP value can be used to obtain a first estimate of the skin permeability coefficient (KP). This initial work was further refined to show, that the permeability coefficient could be reasonably represented by a multiple regression relationship involving logP and the molar mass M:

log(Kp)=0.71*logP-0.0061*M-2.72   (eq. 1)

(Ref: Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992 May;9(5):663–9. and Guy RH, Potts RO. Penetration of industrial chemicals across the skin: a predictive model. Am J Ind Med. 1993 May;23(5):711–9.)

Using eq. 1, a human skin permeability coefficients of 1.18 cm/h can be derived. This allows an estimation of the dermal uptake (m sys) of compounds from a saturated aqueous environment through the stratum corneum according to (eq. 2):

m sys = Kp * A * Cwater * t       (eq. 2),

where A denotes the exposed skin area, Cwater is the concentration of the compound in the aqueous environment and t is the exposure time. Taking a manual task lasting for 1 hour, exposing an area equivalent to the surface area of both hands (960 cm2) to an aqueous saturated environment using the water solubility limit into account yields dermal uptakes of 53.5 µg per person, respectively.

Taken together, this indicates that the test item will not readily penetrate skin layers.

Inhalation route

Due to a very low vapor pressure of 9.7E-5 Pa it is very unlikely that the substance becomes available as a vapor and the boiling point of the substance was determined to be 430 °C at 1013 hPa. The substance is a solid of very low dustiness. Therefore, exposure via inhalation is considered not relevant for the substance. However, in the unlikely case of inhalation, the substance would be expected to pass biological membranes taking into account same considerations as for the oral route.

 

1.3 Distribution

As mentioned above, no or very poor bioavailability is expected for the test item via the dermal route, whereas absorption upon ingestion is considered to be likely based on physicochemical properties and as confirmed by in vivo toxicity studies. Repeated dose toxicity studies revealed effects in liver, indicating that either the substance reached this tissue following oral administration. Based on its low water solubility and high logPow value the test item is expected to be absorbed by micellular formation and as such taken up and transported via the lymph system, similar to other lipophilic constituents of the diet. Further, protein binding is expected rather than dissolution in the plasma in terms of distribution via the blood stream.

Based on its low water solubility and high logPow value, bioaccumulating potential cannot completely be ruled out for the test item. However, based on a experimental study in fish, a steady state BCF mean value of 39 was determined, confirming that the test item is of no concern in regards to bioaccumulation.

1.4 Metabolism

There is no experimental data available regarding potential metabolism of the test item.

Considering its chemical structure oxidation of the double bound of the aromatic ring by phase I enzymes such as CYP 450 can be anticipated and will predominantly occur in the liver. Further, conjugation reactions by phase II enzymes such as glutathione-S-transferase in order to increase water solubility and thus facilitate excretion might occur. Nascent (cyclo-) alcohol groups might further represent a substrate for Alcohol as well as Aldehyde dehydrogenases.

Metabolism of the test item in the liver can be assumed, because the liver was found to be a target organ in the repeated dose toxicity studies as a result of metabolic adaptation. Because of the reversibility of the observed effects (e.g. on liver), the substance is most likely eliminated from the organism. Based on results of in vitro tests where experiments were conducted with as well as without exogenous metabolic activation it can be stated that adding rat liver S9 did not lead to an increased (cyto-) toxicity in any of the tests. Therefore, activation of toxicity by metabolic transformation is considered unlikely to occur in the organism.

 

1.5 Elimination

The based on its low water solubility test item is not expected to be eliminated via the urine unless it undergoes metabolic transformation increasing its hydrophilicity. Elimination via the bile would thus be more likely.

Description of key information

Based on its physicochemical properties, absorption via the gastrointestinal tract is possible for the test substance, whereas uptake following dermal exposure is less relevant.

Based on its very low vapor pressure it is highly unlikely that the test substance will become available via inhalation. Abiotic transformation e.g. hydrolysis is not expected. If absorbed, the test item would be distributed by binding to plasma protein and be eliminated via bile or the urine following metabolic transformation. Bioaccumulation is excluded based on experimental data.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic analysis of the test item

There are no experimental studies available on toxicokinetics of the test item. Therefore its toxicokinetic properties are assessed based on its physico-chemical properties as well as from data available from toxicity studies and in accordance with ECHA Guidance R .7c (2017).

The test substance is a crystalline white solid at room temperature and of low dustiness. The test item, being a mono-constituent substance, has a molecular weight of 298.5 g/mol and a relative density of 0.961. Its melting point was determined to be 177 °C and whereas the boiling point is at 428 -430 °C at 1013 hPa. The substance is considered highly insoluble in water, as water solubility was found to be low (0.047 mg/L). Partition coefficient (logPow) of the substance was estimated to exceed 6.5 being the highest calibration standard of the method applied. Vapor pressure of the substance was determined to be 9.7E-5 Pa at 25 °C. 

1.1 Absorption

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4.  Thus, with a logPow greater than 6.5 the substance would be expected to not passively pass biological membranes. In addition, the substance is highly insoluble in water (0.047 mg/L). However, micellular formation in the gastrointestinal tract (GIT) could enable absorption processes. Moreover, the molecular weight of the substances is well below 500 g/mol and could thus contribute to a favored absorption. In addition, the substance is not expected to undergo hydrolysis based on its chemical structure. Abiotic degradation is thus not relevant for the oral route of exposure. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption cannot be completely ruled out.

The above considerations are confirmed by findings of toxicity studies with the test substance.

In an acute oral toxicity study with rats no mortality or other signs of toxicity were observed up to the limit dose of 2000 mg/kg bw.

Oral administration of the test material for 4 weeks followed by a 2-week treatment-free recovery period at doses of 0, 100, 300, and 1000 mg/kg bw / day (4) induced treatment-related reduction of body weight at 1000 mg/kg and a slight change of behaviour parameters. Haematology revealed treatment-related changes of red and white blood cells that were fully reversible at the end of recovery in the top dose. Clinical chemistry showed indications of increase liver metabolism mainly at 1000 mg/kg. At gross pathology only spontaneous findings were observed. A dose-dependent liver weight increase was observed correlating with centrilobular hypertrophy in female animals of all dose groups that was considered to be an adaptive response of metabolic activation. The liver weight increase showed a tendency towards reversibility after the 2-week recovery period. Therefore, there is clear indication that the test item and/or its metabolites become systemically available via the oral route.

Dermal route

Regarding dermal exposure, the substance is considered to unlikely permeate the skin. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability, but a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the molecular weight, the test item would not be critical, however, its logPow of > 6.5 will probably not favor dermal permeation.

These estimates are strongly supported by the calculation of the dermal exposure based on phys chem parameters. Transdermal skin permeability is a crucial parameter for the transdermal delivery of substances also including dermal accidental exposure. The relationship between physicochemical parameters of organic substances and their skin permeability has been intensively explored through the assembly of human skin permeability coefficients and the octanol-water partition coeffi-cient (logP) for a large set of chemicals. It was shown, that the logP value can be used to obtain a first estimate of the skin permeability coefficient (KP). This initial work was further refined to show, that the permeability coefficient could be reasonably represented by a multiple regression relationship involving logP and the molar mass M:

log(Kp)=0.71*logP-0.0061*M-2.72   (eq. 1)

(Ref: Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992 May;9(5):663–9. and Guy RH, Potts RO. Penetration of industrial chemicals across the skin: a predictive model. Am J Ind Med. 1993 May;23(5):711–9.)

Using eq. 1, a human skin permeability coefficients of 1.18 cm/h can be derived. This allows an estimation of the dermal uptake (m sys) of compounds from a saturated aqueous environment through the stratum corneum according to (eq. 2):

m sys = Kp * A * Cwater * t       (eq. 2),

where A denotes the exposed skin area, Cwater is the concentration of the compound in the aqueous environment and t is the exposure time. Taking a manual task lasting for 1 hour, exposing an area equivalent to the surface area of both hands (960 cm2) to an aqueous saturated environment using the water solubility limit into account yields dermal uptakes of 53.5 µg per person, respectively.

Taken together, this indicates that the test item will not readily penetrate skin layers.

Inhalation route

Due to a very low vapor pressure of 9.7E-5 Pa it is very unlikely that the substance becomes available as a vapor and the boiling point of the substance was determined to be 430 °C at 1013 hPa. The substance is a solid of very low dustiness. Therefore, exposure via inhalation is considered not relevant for the substance. However, in the unlikely case of inhalation, the substance would be expected to pass biological membranes taking into account same considerations as for the oral route.

 

1.3 Distribution

As mentioned above, no or very poor bioavailability is expected for the test item via the dermal route, whereas absorption upon ingestion is considered to be likely based on physicochemical properties and as confirmed by in vivo toxicity studies. Repeated dose toxicity studies revealed effects in liver, indicating that either the substance reached this tissue following oral administration. Based on its low water solubility and high logPow value the test item is expected to be absorbed by micellular formation and as such taken up and transported via the lymph system, similar to other lipophilic constituents of the diet. Further, protein binding is expected rather than dissolution in the plasma in terms of distribution via the blood stream.

Based on its low water solubility and high logPow value, bioaccumulating potential cannot completely be ruled out for the test item. However, based on a experimental study in fish, a steady state BCF mean value of 39 was determined, confirming that the test item is of no concern in regards to bioaccumulation.

1.4 Metabolism

There is no experimental data available regarding potential metabolism of the test item.

Considering its chemical structure oxidation of the double bound of the aromatic ring by phase I enzymes such as CYP 450 can be anticipated and will predominantly occur in the liver. Further, conjugation reactions by phase II enzymes such as glutathione-S-transferase in order to increase water solubility and thus facilitate excretion might occur. Nascent (cyclo-) alcohol groups might further represent a substrate for Alcohol as well as Aldehyde dehydrogenases.

Metabolism of the test item in the liver can be assumed, because the liver was found to be a target organ in the repeated dose toxicity studies as a result of metabolic adaptation. Because of the reversibility of the observed effects (e.g. on liver), the substance is most likely eliminated from the organism. Based on results of in vitro tests where experiments were conducted with as well as without exogenous metabolic activation it can be stated that adding rat liver S9 did not lead to an increased (cyto-) toxicity in any of the tests. Therefore, activation of toxicity by metabolic transformation is considered unlikely to occur in the organism.

 

1.5 Elimination

The based on its low water solubility test item is not expected to be eliminated via the urine unless it undergoes metabolic transformation increasing its hydrophilicity. Elimination via the bile would thus be more likely.

2. Summary

Based on the physicochemical properties, particularly water solubility, logPow and molecular weight, absorption via the gastrointestinal tract is possible for the test substance, whereas uptake following dermal exposure is less relevant. Based on its very low vapor pressure it is highly unlikely that the test substance will become systemically available after inhalation. Abiotic transformation e.g. hydrolysis is not expected. If absorbed, the test item would be distributed by binding to plasma protein due to its low water solubility and be eliminated via bile or the urine following metabolic transformation. Bioaccumulation is excluded based on experimental data.