Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: reliable statement supported by experimental data

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
no guideline required
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: flakes
Radiolabelling:
no

Test animals

Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Preliminary studies:
The following tests (as detailed below in the executive summary) assisted in the toxicokinetik evaluation: acute oral and dermal toxicity, repeated dose oral toxicity, skin irritation and skin sensitisation studies.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on the low water solubility and the high log Pow, CCPIB is not likely to be absorbed in the GI tract. Nevertheless, although very unlikely, minor amounts of substance may be taken up by micellular solubilisation by bile salts since this mechanism suits highly lipophilic compounds (log Pow > 4) that are poorly soluble in water. However, no systemic effects were observed in acute (OECD 423) and repeated dose toxicity (OECD 408) studies as well as a prenatal developmental toxicity study (OECD 414) after oral administration of CCPIB. A respective LD50 value of > 2000 mg/kg with no local or systemic effects and a NOAEL value of 1000 mg/kg bw/d (highest dose tested) were determined. Similarily, for the reproduction/ developmental toxicity screening test the NOAEL for general/systemic toxicity in males and female rats as well as for reproductive and developmental toxicity were estimated to be 1000 mg/kg bw/d (highest dose administered).
Overall, with regard to the physicochemical properties and the absence of systemic effects in the toxicological investigation, CCPIB is not expected to be absorbed in the gastrointestinal tract and it is unlikely that relevant amounts of the CCPIB substance will reach the systemic circulation. Even if certain amounts become bioavailable no systemic toxicity is expected.
The physicochemical properties of the substance such as the high logPow and low water solubility, do not favour dermal absorption. The dry particulates have to dissolve first into the surface moisture of the skin before any uptake is possible. Moreover, the low water solubility will also hinder the transfer from the straum corneum to the underlying epidermis and this, in turn, will drastically limit the amount available for percutaneous absorption. Additionally, CCPIB has a molecular weight greater than 100 g/mol which also hinders dermal uptake. Again, the assumption that no considerable dermal absorption occurs is
further strengthened by the results obtained in the dermal toxicity testing. In an acute dermal toxicity study (OECD 402), the substance did not cause any local or systemic effects and the LD50 was determined to be greater than the limit dose (2000 mg/kg bw). Additionally, CCPIB showed no skin irritation properties that could enhanced/contribute to the dermal absorption. Furthermore, no indication of systemic absorption was evident with respect to the results obtained in a traditional sensitising test with guinea pigs (Maximisation test OECD 406) as no immunological response was triggered and no signs of systemic toxicity were present.
Overall, the physicochemical properties and the results of the toxicological studies support the notion that absorption into the systemic circulation is expected to be negligible.
CCPIB has a low volatility (a very low vapour pressure of < 1.3 x 10E-04 Pa at 25°C and a boiling point above 150°C). Therefore, exposure of the substance as vapour is very limited if handled at room temperature. When used in its solid scales/ flakes form, dust particles, if inhaled, are not expected to reach the lower lung region (alveoli) in order to become systemically available. Even if inhaled, the poor water solubility and the molecular size of the compound would prevent the substance particles to dissolve into the mucus lining of the respiratory tract. Therefore, absorption is expected to be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract.
Details on distribution in tissues:
Based on the physicochemical properties and the results obtained in a comprehensive toxicity testing (absence of systemic effects and no evidence for any potential target organ), CCPIB is unlikely to be systemically available or to be distributed throughout the extracellular compartments of the body. Therefore, the substance will not be distributed inside the body.
Due to the high log Pow value and the very low water solubility, a long biological half-life in tissues could be expected, but it is excluded due to the poor absorption (caused by the same two phys-chem. characteristics). Thus, CCPIB has no bioaccumulation potential.
Details on excretion:
As mentioned before, CCPIB is not expected to be absorbed following oral, dermal and inhalation exposure. After oral intake, the substance will not be absorbed through the walls of the gastrointestinal tract but will be readily excreted via the faeces. Similarily, after inhalation exposure inhaled particles of the substance are likely to be coughed or sneased out of the respiratory system.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Because absorption of CCPIB into the interior part of the body cells is considered to be negligible, considerable contact of the substance with intracellular metabolising enzymes is unlikely. However, in the unlikely event that minor fractions of the substance reach the systemic circulation it cannot be ruled out that they are metabolised by Phase I enzymes while undergoing functionalisation reactions aiming to increase their hydrophilicity e.g., oxidative degradation by hydroxylation of the benzene ring by phase I enzymes (peroxidase or monooxygenases). Sequentially, phase II conjugation reactions may covalently link an endogenous substrate to phase I metabolites in order to ultimately facilitate excretion. No conversion into a metabolite that is more toxic than the parent is expected as no increases in toxicity were noted in the presence of metabolic activation during the in vitro mutagenicity (Ames, CA and HPRT).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on its physicochemical properties and the results obtained from the comprehensive toxicological investigation, CCPIB will not become systemically available following oral, dermal or exhalative exposure. Consequently, the substance will not be distributed or metabolised within the body. When taken up by the oral route, the substance will not be absorbed through the walls of the gastrointestinal tract and, in turn will be readily excreted via the faeces. In addition, bioaccumulation is unlikely due to negligible absorption of the substance.
Executive summary:

1,1'-(2,3-dimethylbutane-2,3-diyl)bis[4-(propan-2-yl)benzene] (CCPIB) appears as solid white fine scales with a molecular weight of approximately 320 g/mol (dimer, n = 2) and an absolute density of 1.02 g/cm³ at 23°C. The substance has a melting point between 122 - 215°C, water solubility of < 1 µg/L at pH: 7.0, 20 °C and a log Pow of 9.2. The vapour pressure was estimated to be < 1.3 x 10E-04 Pa at 25°C. Hydrolysis of CCPIB is not expected based on the chemical structure.

Absorption:

Based on the low water solubility and the high log Pow, CCPIB is not likely to be absorbed in the GI tract. Nevertheless, although very unlikely, minor amounts of substance may be taken up by micellular solubilisation by bile salts since this mechanism suits highly lipophilic compounds (log Pow > 4) that are poorly soluble in water. However, no systemic effects were observed in acute (OECD 423) and repeated dose toxicity (OECD 408) studies as well as a prenatal developmental toxicity study (OECD 414) after oral administration of CCPIB. A respective LD50 value of > 2000 mg/kg with no local or systemic effects and a NOAEL value of 1000 mg/kg bw/d (highest dose tested) were determined. Similarily, for the reproduction/ developmental toxicity screening test the NOAEL for general/systemic toxicity in males and female rats as well as for reproductive and developmental toxicity were estimated to be 1000 mg/kg bw/d (highest dose administered).

Overall, with regard to the physicochemical properties and the absence of systemic effects in the toxicological investigation, CCPIB is not expected to be absorbed in the gastrointestinal tract and it is unlikely that relevant amounts of the CCPIB substance will reach the systemic circulation. Even if certain amounts become bioavailable no systemic toxicity is expected.

The physicochemical properties of the substance such as the high logPow and low water solubility, do not favour dermal absorption. The dry particulates have to dissolve first into the surface moisture of the skin before any uptake is possible. Moreover, the low water solubility will also hinder the transfer from the stratum corneum to the underlying epidermis and this, in turn, will drastically limit the amount available for percutaneous absorption. Additionally, CCPIB has a molecular weight greater than 100 g/mol which also hinders dermal uptake. Again, the assumption that no considerable dermal absorption occurs is further strengthened by the results obtained in the dermal toxicity testing. In an acute dermal toxicity study (OECD 402), the substance did not cause any local or systemic effects and the LD50 was determined to be greater than the limit dose (2000 mg/kg bw). Additionally, CCPIB showed no skin irritation properties that could enhanced/contribute to the dermal absorption. Furthermore, no indication of systemic absorption was evident with respect to the results obtained in a traditional sensitising test with guinea pigs (Maximisation test OECD 406) as no immunological response was triggered and no signs of systemic toxicity were present.

Overall, the physicochemical properties and the results of the toxicological studies support the notion that absorption into the systemic circulation is expected to be negligible.

CCPIB has a low volatility (a very low vapour pressure of < 1.3 x 10E-04 Pa at 25°C and a boiling point above 150°C). Therefore, exposure of the substance as vapour is very limited if handled at room temperature. When used in its solid scales/ flakes form, dust particles, if inhaled, are not expected to reach the lower lung region (alveoli) in order to become systemically available. Even if inhaled, the poor water solubility and the molecular size of the compound would prevent the substance particles to dissolve into the mucus lining of the respiratory tract. Therefore, absorption is expected to be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract.

Distribution:

Based on the physicochemical properties and the results obtained in a comprehensive toxicity testing (absence of systemic effects and no evidence for any potential target organ), CCPIB is unlikely to be systemically available or to be distributed throughout the extracellular compartments of the body. Therefore, the substance will not be distributed inside the body.

Due to the high log Pow value and the very low water solubility, a long biological half-life in tissues could be expected, but it is excluded due to the poor absorption (caused by the same two phys-chem. characteristics). Thus, CCPIB has no bioaccumulation potential.

Metabolism:

Because absorption of CCPIB into the interior part of the body cells is considered to be negligible, considerable contact of the substance with intracellular metabolising enzymes is unlikely. However, in the unlikely event that minor fractions of the substance reach the systemic circulation it cannot be ruled out that they are metabolised by Phase I enzymes while undergoing functionalisation reactions aiming to increase their hydrophilicity e.g., oxidative degradation by hydroxylation of the benzene ring by phase I enzymes (peroxidase or monooxygenases). Sequentially, phase II conjugation reactions may covalently link an endogenous substrate to phase I metabolites in order to ultimately facilitate excretion. No conversion into a metabolite that is more toxic than the parent is expected as no increases in toxicity were noted in the presence of metabolic activation during the in vitro mutagenicity (Ames, CA and HPRT).

Excretion:

As mentioned before, CCPIB is not expected to be absorbed following oral, dermal and inhalation exposure. After oral intake, the substance will not be absorbed through the walls of the gastrointestinal tract but will be readily excreted via the faeces. Similarily, after inhalation exposure inhaled particles of the substance are likely to be coughed or sneased out of the respiratory system.

Summary:

Based on its physicochemical properties and the results obtained from the comprehensive toxicological investigation, CCPIB will not become systemically available following oral, dermal or exhalative exposure. Consequently, the substance will not be distributed or metabolised within the body. When taken up by the oral route, the substance will not be absorbed through the walls of the gastrointestinal tract and, in turn will be readily excreted via the faeces. In addition, bioaccumulation is unlikely due to negligible absorption of the substance.