6,8-Dioxabicyclo[3.2.1]octan-4-one, (1S,5R)-

Endpoint summary

Additional information

There are no in vitro or in vivo data on the toxicokinetics of Cyrene™.

When Cyrene^TM is in aqueous solution, the keto group (C=O) gains water (H₂O) to form the corresponding Gem Diol {(1S,5R)-6,8-dioxabicyclo[3.2.1]octane-4,4-diol}. An equilibrium is established rapidly (meaning that the reaction is rapidly reversible). The ratio of the two forms is dependent upon the amount of water present. Further information is available in the Physical and chemical properties endpoint summary (IUCLID Section 13).

The relevant physiochemical properties are as follows: vapour pressure 28 Pa at 20°C for Cyrene™ (measured) and 0.4 Pa at 25°C for Gem Diol (predicted), water solubility of ≥560 g/L for both Cyrene™ and Gem Diol (measured) and log K_ow

of -1.52 at 22°C and pH 5.18 to 5.24 for both Cyrene™ and Gem Diol (measured).

Human exposure can occur via the inhalation or dermal routes. Exposure via these routes will largely be to the Cyrene™ form, although some hydration to Gem Diol is likely in moist air. After absorption, concentrations of the substance in vivo will be low and the Gem Diol will be formed due to the presence of water. The equilibrium between Cyrene™ and its Gem Diol form is completely reversible and is established rapidly.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and the Gem Diol, using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or predictions will be made. The main input variable for the majority of these algorithms is log K_ow

so by using this, and, where appropriate, other known or predicted physicochemical properties of Cyrene™ and its Gem Diol form, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Absorption

Oral

Significant oral exposure is not expected for this substance.

When oral exposure takes place it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Therefore, if oral exposure did occur, the molecular weight of Cyrene™ (128.13) is in the favourable range and the water solubility (560 g/L) would favour absorption, so some exposure by this route is likely.

Oral exposure is more likely to be to the Gem Diol form, which also has favourable molecular weight (146.14) and water solubility value (560 g/L) for absorption so exposure to this is also likely.

No signs of systemic toxicity were evident in the acute toxicity (Harlan Laboratories, 2014a) and repeat dose toxicity (Covance Laboratories, 2018b) oral studies.

Dermal

Dermal exposure would, in practice, be principally to Cyrene™, although exposure to the Gem Diol is also possible due to the presence of moisture in the air and on the skin surface.

The fat solubility and the potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

Although both Cyrene™ and the Gem Diol are highly soluble (560 g/L), the log K_ow value (-1.52) indicates it that they are unlikely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be minimal.

Inhalation

There is a Quantitative Structure-Property Relationship (QSPR) to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry’s Law coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Exposure via the inhalation route would be to both Cyrene™ and to the Gem Diol due to the presence of moisture in the air and lungs. Using the relevant dimensionless Henry’s Law coefficient values predicts a blood:air partition coefficient of approximately 2.8E+09:1 for the Gem Diol and approximately 1.75E+05 for Cyrene™ meaning that, if lung exposure occurred, there would be uptake into the systemic circulation for both forms. The water solubility (560 g/L) also suggests that both substances could be dissolved in the mucous of the respiratory tract lining, so may also be passively absorbed from the mucous, further increasing the potential for absorption.

In the acute inhalation toxicity study (Envigo, 2018a) decreased respiratory rate was noted in the surviving animals during exposure and up to 1-hour post-exposure. At necropsy, pale, abnormally red, dark patches, dark red patches were seen in the lungs of the surviving animals. These effects were considered to be indicative of local toxicity rather than true systemic effects.

 

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (K_ow) is described. Once absorbed into the blood,concentrations of Cyrene™ in vivo will be low and the Gem Diol will be formed due to the presence of water. A log K_owvalue of -1.52 is relevant for the Gem Diol and indicates that, should systemic exposure occur, potential distribution into the main body compartments would be minimal.

Table: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Gem Diol	-1.52	3.02E-02	0.6	0.7	0	0.7	0.8

 

Metabolism

There are no data on the metabolism of Cyrene™ or the Gem Diol.

Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Excretion

Once absorbed into the body, concentrations of Cyrene™ in vivo will be low and the Gem Diol will be formed due to the presence of water. A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log K_ow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

 

Using the algorithm, the soluble fraction ofthe Gem Diol formin blood is >99% meaning that, once absorbed, the substance is likely to be eliminated via the kidneys in urine and accumulation is unlikely.

                                                                                  

 

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.