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Description of key information

No experimental toxico-kinetic data are available for assessing absorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Verdox is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Verdox (20298-69-5) and the assessment of its toxico-kinetic behaviour,

Introduction

The test material Verdox (Cas no 20298-69-5) is an acetate-ester attached to a cyclohexyl ring with a tert-butylgroup attached at the ortho-position (see section 1 on identity). It is used as a liquid but it starts becoming a solid at room temperature. It has a melting point of 30oC and a molecular weight of 198 g/mol that does not preclude absorption. The test substance hydrolyses in ca. 48h at pH 4, 7 and 9, at 25oC. The substance has a low volatility of almost 10 Pa.

Absorption

Oral:The results of the acute oral toxicity test (OECD TG 401), the combined extended to >=10 weeks dietary repeated dose and reproductive toxicity tests (OECD TG 422) and the 90-repeated dose dietary test (OECD TG 408) all show that the substance is being absorbed by the gastro-intestinal tract following oral administration. In the acute oral toxicity test mortality is seen. In the repeated dose toxicity tests non-adverse alpha-hydrocarbon nephropathy specific for the male rate was seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 4.75) and water solubility (10 mg/l) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This shows that Verdox is likely to be absorbed orally and therefore the oral absorption is expected to be >> 50%. 

Skin: In the acute dermal toxicity test no systemic toxicity was seen. Based on the physico-chemical characteristics of the substance, being a viscous liquid, its molecular weight (198), log Kow (4.75) and water solubility (10 mg/l), indicate that (some) dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 g/mol and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Verdox is just outside optimal range and therefore the skin absorption is not expected to exceed oral absorption. This is also indicated in the acute dermal toxicity test where no systemic toxicity was seen at > 5000 mg/kg bw, while in the acute oral toxicity mortality occurred below 5000 mg/kg bw.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought to be minor, because of its low volatility (10 Pa), the octanol/water partition coefficient (4.75), indicates that inhalation absorption is possible. The blood/air (B/A) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed B/A portioning model for humans using the most important and readily available parameters:

Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.

For Verdox the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x 1 – 0.533 x 4.75 – 0.00495 x 198= 2.41

This means that Verdox has a slight tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite Verdox being somewhat out of the applicability domain and the exact B/A portioning may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route and will be close to 100%.

Distribution

The moderate water solubility of the test substance would limit distribution in the body via the water channels. The log Kow would suggest that the substance would pass through the biological cell membrane. Due to the expected hydrolysis and metabolisation the substance as such would not accumulate in the body fat as can be seen in the bioaccumulation study in fish.

Metabolism

There are no actual data on the metabolisation of Verdox. Small chain straight alkyl esters such as this substance (C2), are likely to be metabolized by carboxylesterases in the gut, liver, lungs and skin into the respective 2-tertbutyl-cylohexyl-alchol (Cas no 5448-22-6) and acetic acid (Cas no. 64-19-9) (Belsito et al., 2008). After metabolism into the alcohol Phase 2 conjugation can occur making the substance more water soluble and excretable. In addition, conjugation with alpha-2u globulin occurs, because agglomeration of this globulin is seen in the kidneys as hyaline droplets and were as such identified. The formed Acetic acid is an endogenous component of the intermediary metabolism. 

Fig. 1   The metabolisation pathway of the Verdox is presented. The 2-tert-butyl cyclohexanol (Cas no 5448-22-6) is one of the metabolites and acetic acid the other (Cas no 64-19-7).

 

Excretion

The primary route of excretion is expected to be through the urine due to the anticipated conjugation and sedimentation of alpha-2u globulins seen in the kidney. Any unabsorbed substance will be excreted via the faeces.

Discussion

Verdox is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally based on the physic-chemical properties. The MW and the log Kow are higher than the favourable range for dermal absorption and therefore dermal absorption will not exceed oral absorption.

In view of the absence of adverse effect in the dietary 90-repeated dose study and in the repeated dose / reproscreen study route to route extrapolation is not needed.

Conclusion

Verdox is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route based on toxicity and physico-chemical data. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

References

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008, A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients,Food and Chemical Toxicology(impact factor: 3). 10/2008; 46 Suppl 12:S1-27.

 

Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partition coefficient using basic physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28. 

 

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals,http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf

 

Martinez, M.N., And Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

 

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals,http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf