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EC number: 251-649-3
CAS number: 33704-61-9
No experimental toxicokinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Cashmeran 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.
Cashmeran toxico-kinetic assessment
Introduction:The test material Cashmeran (Cas no. 3704-61-9) is a
bicycle-ring, a hexylring with an alpha beta-conjugated ketone bond,
which is part of the 2nd5-pentyl ring. On this 5-pentyl ring
methyl groups are attached to each C atom. The substance is a liquid
with a molecular weight of 206 that does not preclude absorption. The
test material is not likely to hydrolyse and has a low volatility (1 Pa).
Absorption:Oral: The results of the 90-day repeat oral
dose (gavage) and oral (dietary) reproductive toxicity show that the
substance is being absorbed by the gastro-intestinal tract following
oral administration because effects on especially kidneys were seen at
the mid dose: 50 mg/kg bw. The relatively low molecular weight and the
moderate octanol/water partition coefficient (Log Kow 4.2 and water
solubility (49 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 Cashmeran is likely to be
absorbed orally and therefore the oral absorption is expected to be >
Skin: The substance is a skin and eye irritant and is a weak skin
sensitizer which indicates that absorption occurs. Also based on the
physico-chemical characteristics of the substance, being a liquid, its
molecular weight (206), log Kow (4.2) and water solubility (49),
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 1-4,
respectively (ECHA guidance, 7.12, Table R.7.12-3). Cashmeran is just
outside this range optimal range and therefore the skin absorption is
not expected to exceed 50%.
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 (1 Pa), the octanol/water
partition coefficient (4.2), indicates that inhalation absorption is
possible. The blood/air (BA) partition coefficient is another partition
coefficient indicating lung absorption. Buist et al. 2012 have developed
BA model for humans using the most important and readily available
Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.
For Cashmeran the B/A partition coefficient would result in:
Log P (BA) = 6.96 – 1 x 0 – 0.533 x 4.2 – 0.00495 x 206 = 6.96 – 1.066
-1 = 4.9.
This means that Cashmeran has a high 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
Cashmeran being somewhat out of the applicability domain and the exact
B/A 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 metabolisation
the substance as such would limitedly accumulate in the body fat which
is confirmed with the low bioaccumulation experimental data (BCF is 157)
Metabolism:The metabolisation of Cashmeran is assessed using OECD
Toolbox 3 liver metabolism simulator. One of the metabolites is
presented below (or in the IUCLID 7.1 attached file in the Endpoint
summary) as an example in which an OH group is attached to one of the
methyl groups of the 5-pentyl ring. Such an OH group maybe attached to
every methyl group. An acid group may also be attached to the middle
C-atom in the pentyl ring. These metabolites are expected to be more
water soluble, have a lower Log Kow values and will therefore be more
easily excreted. Some metabolisation expectation of Cashmeran can also
be based on the BCF value of 157. This BCF is much lower than predicted
for the parent substance using the standard model for neutral organics
and assuming no biotransformation, that is BCF 1607 (e.g. Arnot and
Gobas calculation in EpiSuite (BCFBAFv3.01 or 741 when based on the
Veith model, 1979: log BCF = 0.85 logKow - 0.70).
only be seen in the attached file in IUCLID section 7.1, Endpoint
summary) The theoretical metabolisation of Cashmeran can occur via
hydroxylation of the methyl groups of the pentyl ring and/or an acid
group can be formed at C4 as predicted by the OECD Toolbox 3.0 liver
Excretion:Effects seen in the kidney of the rats indicate that
the primary route of excretion is through the urine. Any unabsorbed
substance will be excreted via the faeces.
Discussion:The substance is expected to be readily absorbed,
orally and via inhalation, based on the human toxicological information
and physico-chemical parameters. Cashmeran also is expected to be
absorbed dermally due to the observed skin and eye irritation and skin
sensitization properties. The MW and the log Kow are
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 absorption values for the
Oral to dermal extrapolation:There are adequate data via the oral
route and the critical toxic effect is related to systemic effects and
therefore route to route extrapolation is applicable. The toxicity of
the substance will be due to the parent compound but also to its
metabolites. The overriding principle will be to avoid situations where
the extrapolation of data would underestimate toxicity resulting from
human exposure to a chemical by the route to route extrapolation.
Cashmeran is not expected to be detoxified in the gut because it is
hydrolytically stable. Though some first pass effect via the liver may
occur the toxicity via the dermal route will not be underestimated
because absorption will be slower and the compound will also pass the
liver. Therefore it will be assumed that the oral absorption will equal
dermal absorption. Using the asymmetric handling of uncertainty the oral
absorption will be considered 50% (though likely to be higher) and the
dermal absorption will be considered also 50% (though likely to be
Oral to inhalation extrapolation:Though Cashmeran is not a
volatile liquid some inhalation exposure will be calculated. Cashmeran
is not a corrosive for skin and eye and the systemic effect will
overrule the effects at the site of contact. In the absence of
bioavailability data it is most precautionary that 100% of the inhaled
vapour is bioavailable. For the oral absorption 50% has been used for
route to route extrapolation to be precautionary for the dermal route.
For inhalation absorption 100% will be used for route to route
extrapolation, because this will be precautionary for the inhalation
Conclusion:Cashmeran 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%
Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012,
Predicting blood:air partion coefficient using basis physico-chemical
properties, Regul. Toxicol. Pharmacol., 62, 23-28.
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
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