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EC number: 915-730-3
CAS number: -
OTNE is absorbed via the oral route and
dermal route for 86 and 15%, respectively, based on experimental in vivo
toxico-kinetic information using radiolabel. Using the precautionary
principle for the inhalation route 100% inhalation absorption will be
selected. The radiolabelled substance is fully metabolised into more
hydrophilic metabolites, as is shown in HPLC chromatograms and it is
reasoned that these are (partly) glucuronic conjugates of the substance.
The DT50 of the substance after oral exposure is 34.3 hours (20 mg/kg
bw), after dermal exposure it is 70 (55 mg/kg bw) and 40 (550 mg/kg bw)
hours after application, respectively. Via oral exposure the main the
main excretion pathways are via urine and bile. Via dermal exposure the
urine is the main excretion pathway.
The toxico-kinetic assessment of OTNE for humans and air
In this toxico-kinetic assessment the experimental and theoretical
consideration of the fate of OTNE in humans and mammals will be
presented. There is oral and dermal kinetic information available from
several kinetic and repeated dose toxicity studies. First the overall
toxico-kinetic assessment is presented and thereafter the executive
summaries of the experimental studies.
The toxico-kinetic assessment of OTNE, with its constituents and
impurities (it is a reaction mass) is presented below.
Structure description: The test material OTNE
has three main constituents which all have a double hexyl-ring, two
methyl groups are attached to one C atom in the first ring. The second
ring has one C atom with one methyl group and one C atom with a methyl
group and a ketone-methyl group. Also the impurities have a similar
structure. There is one impurity where the right ring is open instead of
closed. The double bond is either between the two rings or on the left
or right ring.
Relevance of information derived from radiolabelled OTNE:
The toxico-kinetic experiments are carried out with radiolabelled OTNE.
In view of OTNE being a multi-constituent it is considered appropriate
to derive the kinetic values on this radioactivity because the
assessment then includes all constituents and impurities. It is also
considered conservative because also metabolites and residual carbons
will be included in this assessment.
Physico-chemical properties: The substance is
a liquid with a molecular weight of 234.4, a volatility of (0.233 Pa), a
water solubility of (2.68 mg/l) and a log Kow of 5.65.
Oral: the absorption of OTNE was studied by
the NTP (2014) using [14C]OTNE (β-isomer) in male F344 rats following
gavage administration of 20 mg/kg bw, resulting in an oral absorption of
86%, which will be forwarded to the risk characterisation.
Skin: Key information is an in an in vivo skin
absorption study with male F344 rats following a single dermal
application of 55 or 550 mg/kg bw [14C]β-OTNE in ethanol to covered
sites after 24, 48, or 96 hours. The dermal absorption of 15% is used
(derived from 550 mg/kg bw) because the recovery was highest for this
dose. The information from the supporting in vitro study is in line with
this 15% value showing 16.5% skin absorption, but with a lower recovery
compared to the in vivo study. Therefore the in vivo study is selected
as key and 15% dermal absorption is selected for the risk
Lungs: Absorption via the lungsis also
indicated based on the physico-chemical properties. Though the
inhalation exposure route is considered to be of minor relevance,
because of its low volatility (0.233 Pa), the potential for lung
absorption is assessed. The blood/air (BA) partition coefficient is
thought to be relevant for humans and mammals because when the substance
enters the airways the first partitioning step is between blood and air.
Buist et al. 2012 have developed BA 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 OTNE the B/A partition coefficient would result in:
Log P (BA) = 6.96 – 1.04*Log (0.233) – 0.533*5.65 – 0.00495*234.4
This means that the substance has a 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. From
these calculations we would expect absorption via inhalation to be 100%.
In the oral in vivo toxico-kinetic studies in
rats (NTP, 2014) it is shown that the oral DT50 is 34.3 hours (at 20
mg/kg bw). Tmax via oral exposure is at 8 hours and Cmax is almost 1
mg/l blood after 20 mg/kg bw exposure, (843 ng/g tissue) again based on
In the dermal in vivo toxico-kinetic study in
rats (NTP, 2014) the DT50 values are 70 and 40 hours, for the low and
high dose of 55 and 550 mg/kg bw, respectively. Tmax via
dermal exposure is reached within 24 hours and Cmax is 0.9 mg/l at the
low dose (55 mg/kg bw). OTNE is distributed in all organs blood/tissue
concentrations. Via oral dosing blood/tissue concentration after 24
hours are 1:10 in liver, bladder and pancreas. In adipose tissue it is
1:3, in testes it is 1: 0.5, in brain it is 1: 0.2. In all other organs
the distribution is roughly 1:1 based on radioactivity. In the in vivo
dermal studies the substance was distributed as follows: 1:17 in skin;
1:14 in bladder; 1:7 in kidney, liver, pancreas (roughly) also in
adipose tissue; in brain it is 1:0.5. In all other tissues it is 1:1
based on radioactivity.
Adipose tissue: This shows that in adipose
tissue the distribution is 1:3 and 1:7 after 24 hours via oral and
dermal route respectively showing that it is limitedly distributed in
body fat. In addition, in the NTP studies no parent OTNE could be found.
The determination of the peaks showed that the likely metabolites were
glucuronic conjugates of OTNE, indicating full metabolism of OTNE.
Milk transfer: In a RIFM study (2001) the
transfer of OTNE to milk and placenta is studied during and after
pregnancy using radiolabelled OTNE. The parent compound, OTNE, was not
detected in extracted milk samples at both dose levels but
radioactivity. Exposure to 2 and 20 mg/kg bw resulted roughly in 0.2 and
2 ppm radioactivity in the milk. From the HPLC chromatograms of the milk
samples it can be seen that the metabolites have lower retention times
and therefore are more hydrophilic . This indicates that radioactivity
detected is related to metabolites of OTNE. In a Chinese study OTNE has
been detected at low levels in mother’s milk (3.9 ng/g lipid ca 0.175
ug/l milk assuming 3.5% fat in milk) (Yin et al., 2016). The exposure in
this paper is related to exposure via cosmetics.
Whole body autoradiographs: OTNE related
radioactivity has been measured in whole-body autoradiographs showed
barely detectable radioactivity in placenta and foetuses at 4 and 24
hours post dosing, indicating negligible transfer of parent OTNE or
metabolites across the placenta. Highest levels of radioactivity were
observed in the content of the small intestine and in preputial glands,
followed by stomach, liver, large intestinal contents, thyroid, and
Metabolism for humans and air breathing mammals
OTNE is fully metabolized as no parent OTNE is detected in several
in vivo toxico-kinetic studies. The substance is extensively conjugated
as is measured in male rats using bile cannulated rats. The alpha-2u
hydrocarbon nephropathy seen in the kidneys show that the substance is
partly metabolized in the lysosomes. Due to the low pH in the lysosomes,
the ketone becomes reduced to a secondary alcohol which is then
conjugated with alpha-2u globulin and transported to the kidneys.
There is no possibility of the formation of a gamma-diketone,
because OTNE has no ethyl groups at the side of the ketone functional
groups. This gamma-diketone is the likely metabolite of AETT (Acetyl
ethyl tetramethyl tetralin: Cas no 88-29-9) causing
neurotoxicity at low doses (see neurotoxicity section).
Excretion for humans and air breathing mammals
The in vivo oral toxico-kinetic study shows the majority of the
administered dose was excreted in urine (28%) and faeces (39%) after 48
hours following gavage administration of 20 mg/kg. Approximately 73% of
the 20 mg/kg dose was eliminated in bile in 48 hours confirming that the
faecal excretion was not due to poor absorption but biliary excretion.
Additionally, approximately 80% of the dose in the bile was excreted
within the first 4 hours, while the faecal excretion continued through
48 hours suggesting some enterohepatic recirculation of OTNE. The in
vivo dermal kinetic study shows that OTNE is mainly excreted via the
Discussion for humans and air breathing mammals
Key information on bioaccumulation including air breathing
According to the criteria in the PBT guidance on air breathing
organisms (2017) OTNE fulfils the screening criteria for concern for
bioaccumulation in air breathing organisms: log Kow (5.6: > 2) and log
Koa (6.9: > 5). The concern for air-breathing organisms is relevant for
non-metabolising substances, which are not excreted via kidneys and for
which the ventilation rate between air and blood is lower than for fish.
This type of bioaccumulation is not relevant for metabolizing substances
as Gobas et al. explicitly mentions (2020, figure 6, D, assessing oxygen
containing substances). The half-life in fish in the BCF test is 1.2
days. OTNE is an oxygen (ketone) substance with a hydrocarbon
unsaturated backbone with two-ring structures. The ketone is expected to
be reduced to an alcohol because glucuronidation is the key excretion
pathway and this acid can only conjugate with an alcohol bond. This
transformation is expected to occur in all (air-breathing) organisms.
Glucuronic acid has a low log Kow (<-1) and also OTNE-glucuronidated
will have the acidic group and therefore this log Kow < -1. This
glucuronate will be excreted via the kidneys. In addition, in mammals
(rat) the DT50 was 1.4 days after oral doses of 20 mg/kg bw showing
absence of bioaccumulating in fish and in air-breathing organisms. This
means that OTNE and its degradants or metabolites are not a concern for
Other criteria indicating not a concern for air breathing
organisms are met: 1) extensive metabolisation is seen in all studies
(no parent substance detected, anticipated glucuronic metabolites are
found using radiolabel); 2) low distribution in body fat such as
mother’s milk and adipose tissue (based on radiolabel and therefore
concerning metabolites and residual carbon) and; 3) low DT50 < 1.4 and 3
days (based on radiolabel from in vivo oral and dermal studies
respectively); is supported with the experimental DT50 in fish being 1.2
days and a BCF value: 391.
Key information on absorptionwhich will be
brought forward to the risk characterisation: The substance is readily
absorbed orally up to 86% and via inhalation expected to be up to 100%,
based on the available human toxicological information and
physico-chemical parameters. Based on the key in vivo dermal absorption
study the absorption via this route is 15%.
In view of the available experimental in vivo toxico-kinetic
information the IGHRC (2006) document of the HSE and mentioned in the
ECHA Guidance Chapter R.8 will be followed only for the inhalation route.
Oral to inhalation extrapolation: Though OTNE
is not a volatile liquid some inhalation exposure will be calculated.
OTNE is not corrosive to skin and eye and the systemic effect will
overrule the effects at the site of contact. In the absence of
inhalation absorption data it is most precautionary that 100% of the
inhaled vapour is bioavailable. For the oral absorption 86% will be used
and 15% for the dermal route when using route to route extrapolation.
Oral to dermal extrapolation: The experimental
oral and dermal absorption values will be used: 86 and 15%, respectively.
OTNE is absorbed via the oral route and dermal route for 86 and
15%, respectively, based on experimental in vivo toxico-kinetic
information using radiolabel. Using the precautionary principle for the
inhalation route 100% inhalation absorption will be selected. The
radiolabelled substance is fully metabolised into more hydrophilic
metabolites, as is shown in HPLC chromatograms and it is reasoned that
these are (partly) glucuronic conjugates of the substance. The DT50 of
the substance after oral exposure is 34.3 hours (20 mg/kg bw), after
dermal exposure it is 70 (55 mg/kg bw) and 40 (550 mg/kg bw) hours after
application, respectively. Via oral exposure the main the main excretion
pathways are via urine and bile. Via dermal exposure the urine is the
main excretion pathway.
- Buist, H. E., Wit-Bos de, L., Bouwman, T., Vaes, W. H. J., 2012,
Predicting blood: air partition coefficient using basis physico-chemical
properties, Regul. Toxicol. Pharmacol., 62, 23-28.
Gobas, F.A.P.C, Lee, Y-S, Lo, J.C., Parkerton, T., Letinsky, D.,
2020, A toxicokinetic framework and analysis tool for interpreting
Organisation for Economic Co-operation and Development Guideline 305
Dietary Bioaccumulation test, Env. Toxicol. Chem., 39, 171-188.
- 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. Pdf
- NTP, 2014, Waidyanatha, S., and Ryan, K, Disposition of
in male Fisher rats following oral administration and dermal application
Xenobiotica Vol. 44 , Iss. 8, 749-756.
- Yin, J., Wang, H., Li, J., Wu, Y., Shao, B., 2016, Occurrence
of synthetic musks in human breast milk samples from 12 provinces in
Additives & Contaminants: Part A,Volume 33 (7), Pages
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