Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 226-040-0
CAS number: 5240-32-4
Acute oral toxicity: Based on read across information from Ambrate (similar to OECD TG 401):LD50 = 680 mg/kg bw.
In an acute oral toxicity study, performed similar to OECD TG 401
(pre-OECD, pre-GLP, rated Klimisch 2), 4 groups of 10 rats were orally
exposed to the test substance and observed for signs of toxicity for a
period of 11 days. At 300, 600, 1220 and 5000 mg/kg bw, respectively
2/10, 4/10, 8/10 and 10/10 animals died. Deaths occurred on day 1, 2, 3,
10 and 11. Clinical signs observed were lethargy, ptosis, piloerection,
flaccid tone, ataxia and coma. At necropsy following effects were
observed: exudate from nose/mouth and anogenital exudate, in the
intestines red and yellow areas were observed and bloated intestines,
dark livers and mottled livers, dark lungs and dark areas in the lungs,
dark kidneys and mottled kidneys, large spleens, and blood in the
bladder. Based on the results, a LD50 of 680 mg/kg bw was obtained in
the acute oral toxicity study with rats.
First the experimental information of Ambrate is presented being used
for read across to Herbacet #1 and thereafter the read across
Ambrate acute oral toxicity:
Read across justification:
acute oral toxicity of Herbacet#1 (CAS 5240-32-4) using read across from
Ambrate (CAS 37172-05-7)
and hypothesis for the analogue approach
Herbacet#1 is a cyclohexane with an ethynyl
and acetate group attached to the same carbon atom. For this substance
no acute oral toxicity data are available.
In accordance with Article 13 of REACH,
lacking information should be generated whenever possible by means other
than vertebrate animal tests, i.e. applying alternative methods such as
in vitro tests, QSARs, grouping and read-across. For assessing the acute
oral toxicity of Herbacet#1 the analogue approach is selected because
for one closely related analogue acute oral toxicity information is
available which can be used for read across.
Hypothesis: Herbacet#1 has similar acute oral
toxicity compared to Ambrate resulting in a similar LD50.
Available information: The source chemical
Ambrate (Cas no. 37172-05-7) has been tested in an acute oral toxicity
test up to 5000 mg/kg bw, similar to OECDTG 401, with an 11-day
observation period, resulting in a LD50 of 680 mg/kg bw. The test result
receives a reliability of 2 (pre-GLP).
Target chemical and source chemical(s)
Chemical structures of Herbacet#1 and Ambrate are shown in the
data matrix, including physico-chemical properties and toxicological
information, thought relevant for acute oral toxicity, of both
Purity / Impurities
Herbacet#1 is a mono-constituent. The purity and impurities do not
indicate acute oral toxicity potential other than indicated by the
parent substance. The impurities are all below < 10%.
Analogue approach justification
According to Annex XI 1.5 read across can be used to replace
testing when the similarity can be based on a common backbone and a
common functional group. When using read across the result derived
should be applicable for C&L and/or risk assessment and it should be
presented with adequate and reliable documentation.
Analogue selection:In order to identify
possible RA candidates, the RIFM database and OECD QSAR toolbox were
used for a search of analogues.From the RIFM database two analogues were
found of which only Ambrate has an ethynyl group.In the OECD QSAR
toolbox, using Tanimoto with 60% threshold for similarity, 10 additional
structures were found.From the identified analogues, Ambrate is most
similar in structure to Herbacet#1 (Tanimoto 65%; ethynyl and acetate
group) and has reliable acute oral toxicity data.
Structural similarities and differences:Herbacet#1
and Ambrate have a similar backbone and functional group, i.e.
cyclohexane with an ethynyl group and an acetate ester on C1. The
difference between both substances is that Ambrate has an additional
sec-butyl group on C2. This group does not stericallcy hinder the
ethynyl or the ester group as can be seen when looking into the 3-D
structure of the molecule.
andAmbrateindicate similar absorption based on the similarity in
chemical structure and physico-chemical properties. Herbacet#1 and
Ambrate have molecular weights and log Kows favorable for uptake via the
oral route. The extra sec-butyl group in Ambrate results in a somewhat
higher log Kow and lower water solubility than Herbacet#1, but both
substances are in the same range for good oral absorption.Metabolism:
The ester bond in Herbacet#1 and Ambratewill hydrolyse into the
respective alcohol, 1-ethynylcyclohexanol and
2-sec-butyl-1-ethynylcyclohexanol respectively, and acetic acid due to
activity of carboxylases in the gut and liver (Belsito et al., 2008, Wu
et al., 2010). This hydrolysis is depicted in Figure 1.
Fig.1 Herbacet#1 and its analogues are presented together with
the measured and anticipated acute oral rat LD50s.
addition, according to De Vito (2012) theethynyl
also metabolise via an oxirene intermediate into a ketene metabolite:
reactive site of Herbacet#1 and Ambrate is the ethynyl group which is
similar in both substances.The
after the metabolisation of the ethynyl group is highly electrophilic,
the toxicity (De Vito, 2012).
Uncertainty of the prediction:The derived LD50
for Herbacet#1 is supported with LD50 information from
1-ethynylcyclohexanol (Cas no. 78-27-3, ECHA dissemination site), the
hydrolysis product of Herbacet#1, which has an LD50 of 600 mg/kg bw
(test is similar to OECD TG 401). There is also other LD50 information
from Ambrate: 364 mg/kg bw. This LD50 is in the same toxicity range as
the 680 mg/kg bw LD50 of the selected study. This latter LD50 is more
similar to the 600 mg/kg bw from Herbacet’s hydrolysis product and
therefore this 680 mg/kg bw is selected as key value. In view of Ambrate
and 1-ethynylcyclohexanol having almost the same LD50 it can be assumed
that the additional sec-butyl group in Ambrate, but not in Herbacet#1,
is not affecting a difference in LD50. Based on this a conversion of the
LD50 value is also not needed.
relevant information on physico-chemical properties and toxicological
characteristics are presented in the Data Matrix.
per endpoint for Hazard Assessment
using read across the result derived should be applicable for C&L and/or
risk assessment and be presented with adequate and reliable
documentation, as is shown above. For Ambrate a well conducted acute
oral toxicity test is available (Reliability 2) with a LD50 of 680 mg/kg
bw which can be used for read across to Herbacet#1. Based on these data
for Herbacet#1 also a LD50 of about 680 mg/kg bw can be derived for the
endpoint acute oral toxicity.
conclusion on Hazard:Herbacet#1
has an acute oral LD50 of 680 mg/kg bw.
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 46, Suppl 12:S1-27.
Vito, S., 2012, Structural and toxic mechanism-based approaches to
designing safer chemicals, Green Processes, Eds. Boethling, R. and
Vouchkova, A., Volume 9, Chapter 4, 77-106 (page 82 and 83, specifically)
S., Blackburn, K., Amburgery, J., Jaworska, J., and Federle, T., 2010, A
framework for using structural, reactivity, metabolic and
physico-chemical similarity to evaluate the suitability of analogs for
SAR-based toxicological assessments, Regul. Toxicol. Pharmacol., 56,
matrix for the read across to Herbacet#1 from Ambrate.
Water solubility, mg/L
Human health endpoints
Acute oral tox (LD50), mg/kg bw
The substance needs to be classified for acute oral toxicity category 4
and labelled with H302: Harmful if swallowed according to EU CLP
Regulation (EC) No. 1272/2008 and its amendments.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again