Tetrahydro-3-pentyl-2H-pyran-4-yl acetate

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Jasmal is expected to be readily absorbed via the oral and inhalation route and 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:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The toxico-kinetic behaviour of Jasmal (18871-14-2)

Toxico-kinetic behaviour of Jasmal

Introduction

The test material Jasmal (Cas no 18871-14-2) is an ester of 3-pentyl tetrahydro-2H-pyran-4-ol and acetic acid. It is a clear colourless liquid with a molecular weight of 214, water solubility (WS) of 242 mg/L and a log Kow of 3.2 that does not preclude absorption. The test material is likely to hydrolyse in alkaline conditions rather than in acidic conditions because it is an ester. The substance has a low volatility of 0.49 Pa.

Absorption

Oral:The relatively low molecular weight (214) and the moderate octanol/water partition coefficient (Log Kow 3.2) and water solubility (242 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 indicates that the oral absorption is likely high but conservatively the 50% is used.

For the analogue of Jasmal: Florosa, the presented effects in the REACH registration show that the substance is being absorbed by the gastro-intestinal tract following oral administration. In this 28-day oral gavage repeated dose toxicity study in rat effects include salivation, presence of ketones in urine of males, increased liver weight, increased adrenal weight in females and decreased plasma glucose levels in males, resulting in a NOAEL of 125 mg/kg bw and a LOAEL of 625 mg/kg bw.

Skin: Based on the physico-chemical characteristics of Jasmal, being a liquid, its molecular weight (214), log Kow (3.2) and water solubility (242 mg/L), indicate that some dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 and in the range of -1 to +4, respectively (ECHA guidance, 7.12, Table R.7.12-3). According to the ECHA guidance, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range -1 to +4, in which case a value of 10% skin absorption is chosen. Based on the physico-chemical properties of Jasmal, the default value of 100% skin absorption could be applied.

For the analogue of Jasmal, Florosa, dermal absorption information is available. At a high dose of 9500 and a low dose of 1000 ug/cm2, 18 and 44% dermal absorption was seen, respectively. This shows that dermal absorption was significant and up to almost 50%. Jasmal has a slightly higher molecular weight and is anticipated to have a slightly lower dermal absorption. For conservative reasons a 50% dermal absorption will be used.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (0.49 Pa) (< 500 Pa as presented in the ECHA guidance 7c, Table R.7.12—2, Nov. 1014), the octanol/water partition coefficient (Log Kow 3.2), indicates that inhalation absorption is possible. In the absence of more relevant data, absorption via the inhalation route is considered to be 100% for risk assessment purposes.

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. The partition coefficient is also indicative for low potential for accumulation. Due to the expected hydrolysis and metabolism Jasmal as such would not accumulate in the body fat.

 

Metabolism

There are no actual data on the metabolism of Jasmal. Small chain straight alkyl esters such as this substance (C12H22O3), which are not hindered by adjacent bulky groups, are likely to be fully metabolised in the gut and in the liver into the respective 3-pentyl tetrahydro-2-H-pyran-4-ol and acetic acid (Toxicological handbooks, Yamada et al., 2013,). The 3-pentyl tetrahydro-2-H-pyran-4-ol and acetic acid are expected to be more water soluble and both have a lower Log Kow. 3-pentyl tetrahydro-2-H-pyran-4-ol will therefore more easily be excreted and acetic acid is expected to be metabolized because it is a natural constituent of the body. In addition, involvement of enzymatic metabolism (CYP450) is predicted by Toxtree (v2.5.0), resulting in an aldehyde and alcohol function as a result of O-dealkylation.

 

CYP450 metabolism in order of most likely (primary, secondary etc.)

1.    O-dealkylation resulting in an aldehyde and alcohol function

2.    O-dealkylation resulting in an aldehyde and alcohol function

3.    Aliphatic hydroxylation

4.      Aliphatic hydroxylation

Fig. 1   The metabolisation pathway of Jasmal as predicted by Toxtree (v2.5.0) is presented.

 

Excretion

Based on the physico-chemical properties of Jasmal, excretion via urine is considered the most likely route of excretion. Any unabsorbed substance will be excreted via the faeces. In addition, the metabolites of Jasmal have lower molecular weights and anticipated lower log Kow will also be excreted via urine (Guidance on Information Requirements and Chemical Safety Assessment R7c Endpoint specific guidance, Toxico-kinetics, 2014).

Biliary excretion involves active secretion rather than passive diffusion. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. In the rat it has been found that substances with molecular weights below around 300 do not tend to be excreted into the bile. Based on the molecular weight of 214 for Jasmal, biliary excretion is considered not to be a main route of excretion.

The excretion processes involved in the kidney are passive glomerular filtration through membrane pores and active tubular secretion via carrier processes. Substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat, mostly anionic and cationic compounds).

Discussion

Jasmal 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 physico-chemical properties. The MW is slightly higher than the favourable range for dermal absorption but significant absorption is likely.

The IGHRC (2006) document of the HSE and mentioned in the ECHA guidance Chapter 8 will be followed to derive the final oral, dermal and inhalation absorption values.

Route to route extrapolation

Though for Jasmal no repeated dose toxicity data are available, there are adequate data on an analogue of Jasmal, which is Florosa. For Florosa no adverse effects in the 90-day repeated dermal dose toxicity and in the dermal developmental toxicity study at >=1000 and >=1000 mg/kg bw were seen. However, slight adverse effects are seen in the 28d-oral gavage toxicity study as indicated on the ECHA dissemination site.

In view of the availability of the 90-day dermal repeated dose toxicity study, being longer than the 28-day oral toxicity study the DNEL for all routes can be based on the 90-day dermal toxicity studies.

For the oral route, the 90-day dermal NOAEL can be converted to a 90-day oral NOAEL using a worst case dermal absorption value of 18%. The 90-day oral NOAEL becomes >= 180 mg/kg bw (=> 360 mg/kg bw). This converted 90-day NOAEL value is higher than the NOAEL in the 28-day gavage study (being 125 mg/kg bw) and therefore we reason that the (slight) effects seen in the oral gavage study are not likely to be adverse. Note that the dermal absorption of Florosa is only used for conversion of the NOAELs and showing that the oral NOAEL 90-days is higher than the oral NOAEL 28-days.

For the inhalation route the reasoning is similar. The inhalation NOAEL can be derived from the 90-day dermal NOAEL using the dermal absorption information. With an 18% dermal absorption the dermal NOAEL of >=1000 mg/kg bw result in a starting NOAEL of >=180 mg/kg bw and a resulting 90-day inhalation NOAEL of >=317 mg/m3. The saturated vapour pressure of Jasmal is 43 mg/m3 and therefore the converted inhalation NOAEL cannot be reached.

Though a conversion for the difference in molecular weight of Jasmal and Florosa could be done resulting in slightly higher values this is not needed.

Overall the 90-day NOAELs for repeated dose toxicity are NOAELs are >=360 mg/kg bw, >=1000 mg/kg bw and >=317 mg/m3 for the oral, dermal and inhalation route respectively, using 50%, 18% and 100% absorption, respectively.

Conclusion

Jasmal is expected to be readily absorbed via the oral, inhalation and the dermal route based on toxicity physico-chemical data and a dermal absorption study. The final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

References

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