4,4'-cyclohexylidenedi-o-cresol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

No toxicokinetic studies are available that directly address absorption, distribution, metabolism, or excretion of Bis(3-methyl 4-hydroxyphenyl) cyclohexane (DMBPC, CAS# 2362-14-3) following oral administration; however information is available from existing toxicology studies and the physical chemical properties to infer potential toxicokinetic properties.

Absorption

The main physical chemical properties that influence absorption are molecular weight, and water and lipid solubility. DMBPC has a molecular weight of 294, a water solubility of 1.26 mg/L at 20 °C and Log Pow of 3.1. The substance contains two ionisable hydroxyl groups. Although ionized substances do not readily diffuse across biological membranes, the estimates of pKa values of DMBPC [ca. 10.5 (pKa 1) and ca. 10.7 (pKa 2)] indicate that the hydroxyl groups will not significantly be dissociated at biologically relevant pH values (up to pH 8). These properties suggest DMBPC would be absorbed by the gastro-intestinal tract following oral exposure although the limited water solubility will preclude complete systemic availability. The acute oral toxicity study showed low inherent systemic toxicity, and repeated oral toxicity studies revealed only non-specific systemic toxicity manifested as effects on body weight gain at the limit dose of 1000 mg/kg bw/day. In the absence of quantitative data oral absorption of DMBPC is considered moderate (50 %) for risk assessment purposes. Based on relatively high boiling point (336.2 °C) and extremely low vapour pressure (4.85x 10^-09 Pa at 25 °C) DMBPC is unlikely to volatilize or be released into the air. In addition, DMBPC is a solid with a mass median diameter of 35.9 µm and therefore it can be expected to reach just the thoracic tract of the respiratory system, but not the alveolar region. However, the low water solubility, the relatively low molecular weight and optimal Log Pow indicate inhalation as another possible route of absorption. It is likely that DMBPC will be absorbed if it is inhaled, based on available toxicity data showing a degree of bioavailability after oral exposure.  As a worst-case assumption, inhalation absorption of DMBPC is considered high (100 %) for risk assessment purposes. Dermal absorption is likely to be moderate at most, because DMBPC is a solid, and will have to dissolve into the surface moisture of the skin before uptake can begin. The molecular weight is not excessive and the lipophilicity is appropriate for allowing the substance to cross the stratum corneum of the skin. However the low water solubility suggests that permeation through the stratum corneum into the epidermis would be low to moderate. In the absence of quantitative information and absence of effects in the acute dermal toxicity study, estimation of mammalian dermal absorption is made at 25 % in accordance with principles adopted by the EFSA guidance on estimating dermal absorption of pesticide active substances.

Distribution

Any DMBPC that is absorbed will be distributed via the blood to the liver and other organs and tissues because the molecular weight is not excessive.The moderate lipophilic character indicates that DMBPC is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration.

Metabolism and excretion

No specific target organ of toxicity has been identified in the repeated oral toxicity study, and the only possible indication of liver involvement in the metabolism of DMBPC in the OECD 422 study was a slight increase of alanine aminotransferase noted in females only treated at the limit dose of 1000 mg/kg bw/day.  Phase I reactions including demethylation, hydroxylation and further oxidation are expected to occur, and Phase II reactions, including glucuronidation and sulfonation, will increase water solubility. Finally, based on the relatively low molecular weight, DMBPC and its conjugation products are expected to be mainly excreted in the urine. Overall, potential for bioaccumulation is considered low.