Short reviewRIFM fragrance ingredient safety assessment, isocyclocitral, CAS Registry number 1335-66-6
Section snippets
Identification
Chemical Name: Isocyclocitral Chemical Name: 2,4,6-Trimethylcyclohex-3-enecarbaldehyde Chemical Name: 3,5,6-Trimethylcyclohex-3-ene-1-carbaldehyde CAS Registry Number: 1335-66-6 CAS Registry Number: 1423-46-7 CAS Registry Number: 67634-07-5 Synonyms: 1-Formyl-[2,4,6-]&[3,5,6-]trimethyl-3-cyclohexene; [2,4,6-]&[3,5,6-]Trimethyl-3-cyclohexene-1-carboxaldehyde; 4,5,6-Trimethylcyclohex-3-ene-1-carbaldehyde; Neocyclocitral/Corps 343; Neocyclocitral; Isocyclocitral Synonyms:
Physical data*
- 1.
Boiling Point: 195.5 °C (FMA Database), 214.38 °C (US EPA, 2012a), 203 ± 1 °C (476 ± 1 K) at 100.9 kPa (RIFM, 2015e)
- 2.
Flash Point: 67 °C (GHS), 152 °F; CC (FMA Database), 66 ± 2 °C (RIFM, 2015i)
- 3.
Log KOW: 3.1 (RIFM, 2013a), 3.27 (US EPA, 2012a)
- 4.
Melting Point: 2.5 °C (US EPA, 2012a), <-20 °C (<253 K) (RIFM, 2015e)
- 5.
Water Solubility: 119.3 mg/L (US EPA, 2012a)
- 6.
Specific Gravity: 0.920 (FMA Database)
- 7.
Vapor Pressure: 0.116 mm Hg @ 20 °C (US EPA, 2012a, US EPA, 2012b 4.0), 0.1 mm Hg 20 °C (FMA Database),
Volume of use (worldwide band)
- 1.
Volume of Use (worldwide band): 10–100 metric tons per year (IFRA, 2015)
Exposure to fragrance ingredient*** (Creme rifm aggregate exposure model v2.0)
- 1.
95th Percentile Concentration in Hydroalcoholics: 0.035% (RIFM, 2016)
- 2.
Inhalation Exposure*: 0.00057 mg/kg/day or 0.044 mg/day (RIFM, 2016)
- 3.
Total Systemic Exposure**: 0.0012 mg/kg/day (RIFM, 2016)
*95th percentile calculated exposure derived from concentration survey data in the Creme RIFM Aggregate Exposure Model (Comiskey, 2015, 2017; Safford, 2015, 2017).
**95th percentile calculated exposure; assumes 100% absorption unless modified by dermal absorption data as reported in Section V. It is
Derivation of systemic absorption
- 1.
Dermal: Assumed 100%
- 2.
Oral: Assumed 100%
- 3.
Inhalation: Assumed 100%
Computational toxicology evaluation
- 1.
Cramer Classification: Class I, Low
Expert Judgment | Toxtree v 2.6 | OECD QSAR Toolbox v 3.2 |
---|---|---|
I | I | I |
- 2.
Analogs Selected:
- a.
Genotoxicity: 2,6,6-trimethyl-1-cyclohexen-1-acetaldehyde (CAS # 472-66-2)
- b.
Repeated Dose Toxicity: None
- c.
Reproductive Toxicity: None
- d.
Skin Sensitization: None
- e.
Phototoxicity/Photoallergenicity: None
- f.
Local Respiratory Toxicity: None
- g.
Environmental Toxicity: None
- a.
- 3.
Read-across Justification: See Appendix below
Metabolism
Not considered for this risk assessment.
Natural occurrence (discrete chemical) or Composition (NCS)
Isocyclocitral, 2,4,6-trimethylcyclohex-3-enecarbaldehyde, and 3,5,6-trimethylcyclohex-3-ene-1-carbaldehyde are not reported to occur in food by the VCF*.
*VCF Volatile Compounds in Food: database/Nijssen, L.M.; Ingen-Visscher, C.A. van; Donders, J.J.H. (eds). – Version 15.1 – Zeist (The Netherlands): TNO Triskelion, 1963–2014. A continually updated database containing information on published volatile compounds that have been found in natural (processed) food products. Includes FEMA GRAS and
Reach dossier
Available for 2,4,6-trimethylcyclohex-3-enecarbaldehyde (https://echa.europa.eu/registration-dossier/-/registered-dossier/17539 ECHA, 2016b); accessed 02/17/19. Isocyclocitral and 3,5,6-trimethylcyclohex-3-ene-1-carbaldehyde are pre-registered for 11/30/10; no dossiers available as of 02/17/19.
Conclusion
The maximum acceptable concentrationsa in finished products for isocyclocitral are detailed below.IFRA
CategorybDescription of Product Type Maximum Acceptable Concentrationsa in Finished Products (%) 1 Products applied to the lips (lipstick) 0.54 2 Products applied to the axillae 0.16 3 Products applied to the face/body using fingertips 3.2 4 Products related to fine fragrances 3.0 5A Body lotion products applied to the face and body using the hands (palms), primarily leave-on 0.76 5B Face moisturizer products
Genotoxicity
Based on the current data, isocyclocitral does not present a concern for genotoxicity.
Risk assessment
The mutagenic activity of isocyclocitral has been evaluated in a bacterial reverse mutation assay conducted in compliance with GLP regulations and equivalent to OECD TG 471 using the standard plate incorporation and preincubation method. Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and Escherichia coli strain WP2uvrA were treated with isocyclocitral in dimethyl sulfoxide (DMSO) at concentrations
Literature Search*
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RIFM Database: Target, Fragrance Structure Activity Group materials, other references, JECFA, CIR, SIDS
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ECHA: https://echa.europa.eu/
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OECD Toolbox
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SciFinder: https://scifinder.cas.org/scifinder/view/scifinder/scifinderExplore.jsf
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TOXNET: https://toxnet.nlm.nih.gov/
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EPA ACToR: https://actor.epa.gov/actor/home.xhtml
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Conflicts of interest
The authors declare that they have no conflicts of interest.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small
References (57)
- et al.
Criteria for the Research Institute for fragrance materials, Inc. (RIFM) safety evaluation process for fragrance ingredients
Food Chem. Toxicol.
(2015) - et al.
Novel database for exposure to fragrance ingredients in cosmetics and personal care products
Regul. Toxicol. Pharmacol.
(2015) - et al.
Integrating habits and practices data for soaps, cosmetics and air care products into an existing aggregate exposure model
Regul. Toxicol. Pharmacol.
(2017) - et al.
Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule?
J. Photochem. Photobiol. B Biol.
(2009) - et al.
Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients
Food Chem. Toxicol.
(2007) - et al.
Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern
Regul. Toxicol. Pharmacol.
(2012) - et al.
Use of an aggregate exposure model to estimate consumer exposure to fragrance ingredients in personal care and cosmetic products
Regul. Toxicol. Pharmacol.
(2015) - et al.
Application of the expanded Creme RIFM consumer exposure model to fragrance ingredients in cosmetic, personal care and air care products
Regul. Toxicol. Pharmacol.
(2017) - et al.
A strategy for structuring and reporting a read-across prediction of toxicity
Regul. Toxicol. Pharmacol.
(2015) - et al.
An in silico skin absorption model for fragrance materials
Food Chem. Toxicol.
(2014)