RIFM fragrance ingredient safety assessment, 2-Hydroxy-α,α,4-trimethylcyclohexanemethanol, CAS Registry Number 42822-86-6.

Food and Chemical Toxicology 97 (2016) S209eS215Contents lists available at ScienceDirectFood and Chemical Toxicologyjournal homepage: /locate/foodchemtoxShort reviewRIFM fragrance ingredient safety assessment, 2-Hydroxy-a,a,4-trimethylcyclohexanemethanol, CAS Registry Number 42822-86-6A.M. Api a, *, D. Belsito b, S. Bhatia a, M. Bruze c, G.A. Burton Jr. d, J. Buschmann e, P. Calow f,M.L. Dagli g, W. Dekant h, A.D. Fryer i, L. Kromidas a, S. La Cava a, A. Lapczynski a,D.C. Liebler j, D. OBrien a, R. Parakhia a, T.M. Penning k, V.T. Politano a, G. Ritacco a,D. Salvito a, T.W. Schultz l, J. Shen a, I.G. Sipes m, B. Wall a, D.K. Wilcox aabcResearch Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USAMember RIFM Expert Panel, Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USAMember RIFM Expert Panel, Malmo University Hospital, Department of Occupational p-3,8-; 2-(1-Hydroxy-1-methylethyl)-5-methylcyclohexanol.4 Molecular Formula: CHO.5 Molecular Weight: 172.27.6 RIFM Number: 6431.2. Physical data1. Identication1 Chemical Name: 2-Hydroxy-a,a,4-trimethylcyclohexanemethanol.2 CAS Registry Number: 42822-86-6.3 Synonyms: Geranodyle; p-Menthane-3,8-diol; Cyclo-hexanemethanol,2-hydroxy-a,a,4-trimethyl-; 2-(20Hydroxypropan-20-yl)-5-methylcyclohexanol; 2-Hydroxy-1234567Boiling Point: 264.67 C EPI Suite.Flash Point: 93 C GHS.Log KOW: 1.8e4.0 RIFM, 1999b, 2.29 EPI Suite.Melting Point: 46.57 C EPI Suite.Water Solubility: 670.7 mg/L EPI Suite.Specic Gravity: 0.97600 to 0.98200 25.00 C*.Vapor Pressure: 0.000239 mmHg 20 C EPI Suite 4.0, 0.29 Pa 25 C RIFM, 2000c, 2.14 10(-3) Pa 25 C RIFM, 2000c,0.000479 mm Hg 25 C EPI Suite.* Corresponding author.E-mail address: AA (A.M. Api)./10.1016/j.fct.2016.10.0090278-6915/ 2016 Elsevier Ltd. All rights reserved.8 UV Spectra: No signicant absorbance between 290 and700 nm; molar absorption coefcient below the benchmark(1000 L mol 1 cm 1).S210 A.M. Api et al. / Food and Chemical Toxicology 97 (2016) S209eS215Version: 091516. This version replaces any previous versions.Name: 2-Hydroxy-a,a,4-trimethylcyclohexanemethanol CAS Registry Number: 42822-86-6Abbreviation list:2-Box Model e a RIFM, Inc. proprietary in silico tool used to calculate fragrance air exposure concentrationAF e Assessment FactorBCF e Bioconcentration FactorCreme RIFM model e The Creme RIFM model uses probabilistic (Monte Carlo) simulations to allow full distributions of data sets, providing a more realistic estimate ofaggregate exposure to individuals across a population (Comiskey et al., 2015; Safford et al., 2015) compared to a deterministic aggregate approachDEREK e Derek nexus is an in silico tool used to identify structural alertsDST e Dermal Sensitization ThresholdECHA e European Chemicals AgencyEU e Europe/European UnionGLP e Good Laboratory PracticeIFRA e The International Fragrance AssociationLOEL e Lowest Observable Effect LevelMOE e Margin of ExposureMPPD e Multiple-Path Particle Dosimetry. An in silico model for inhaled vapors used to simulate fragrance lung depositionNA e North AmericaNESIL e No Expected Sensitization Induction LevelNOAEC e No Observed Adverse Effect ConcentrationNOAEL e No Observed Adverse Effect LevelNOEC e No Observed Effect ConcentrationOECD e Organisation for Economic Co-operation and DevelopmentOECD TG e Organisation for Economic Co-operation and Development Testing GuidelinesPBT e Persistent, Bioaccumulative, and ToxicPEC/PNEC e Predicted Environmental Concentration/Predicted No Effect ConcentrationQRA e quantitative risk assessmentREACH e Registration, Evaluation, Authorisation, and Restriction of ChemicalsRIFM e Research Institute for Fragrance MaterialsRQ e Risk QuotientTTC e Threshold of Toxicological ConcernUV/Vis Spectra e Ultra Violet/Visible spectraVCF e Volatile Compounds in FoodVoU e Volume of UsevPvB e (very) Persistent, (very) BioaccumulativeWOE e Weight of EvidenceRIFMs Expert Panel* concludes that this material is safe under the limits described in this safety assessment.This safety assessment is based on the RIFM Criteria Document (Api et al., 2015) which should be referred to for clarications.Each endpoint discussed in this safety assessment reviews the relevant data that were available at the time of writing (version number in the top box is indicative of thedate of approval based on a two digit month/day/year), both in the RIFM database (consisting of publicly available and proprietary data) and through publiclyavailable information sources (i.e., SciFinder and PubMed). Studies selected for this safety assessment were based on appropriate test criteria, such as acceptableguidelines, sample size, study duration, route of exposure, relevant animal species, most relevant testing endpoints, etc. A key study for each endpoint was selectedbased on the most conservative end-point value (e.g., PNEC, NOAEL, LOEL, and NESIL).*RIFMs Expert Panel is an independent body that selects its own members and establishes its own operating procedures. The Expert Panel is comprised ofinternationally known scientists that provide RIFM guidance relevant to human health and environmental protection.Summary: The use of this material under current conditions is supported by existing information.This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skinsensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential and provided a MOE 100 forthe repeated dose endpoint. The developmental and reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of ToxicologicalConcern) for a Cramer Class I material (0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoint was completed based onsuitable UV spectra along with data on the target material. The environmental endpoint was completed as described in the RIFM Framework.Human health safety assessment.Genotoxicity: Not genotoxic.Repeated dose toxicity: NOEL 67 mg/kg/dayDevelopmental and Reproductive Toxicity: No NOAEL available. Exposure is below the TTC.Skin sensitization: Not Sensitizing(RIFM, 1995a; RIFM, 2000a)(RIFM, 2000b)(RIFM, 1995b; RIFM, 1999a,c; RIFM, 1985a)Phototoxicity/photoallergenicity: Not phototoxic/photoallergenic (UV Spectra, RIFM DB; RIFM, 1995b; RIFM, 1985b; RIFM, 1985c)Local respiratory toxicity: No NOAEC available. Exposure is below the TTC.Environmental safety assessmentHazard assessment:Persistence: Critical Measured Value: 94% (OECD 301C) (RIFM, 1996)Bioaccumulation: Screening Level: 14.95 l/kg (EpiSuite ver 4.1)Ecotoxicity: Screening Level: 96 h Algae EC50: 37.99 mg/l (EpiSuite ver 4.1)A.M. Api et al. / Food and Chemical Toxicology 97 (2016) S209eS215(continued)Conclusion: Not PBT or vPvB as per IFRA Environmental StandardsRisk assessment:S211Screening-Level: PEC/PNEC (North America and Europe) 1Critical Ecotoxicity Endpoint: 96 h Algae EC50: 37.99 mg/lRIFM PNEC is: 3.799 mg/LRevised PEC/PNECs (2011 IFRA VoU): North America and Europe 1).A screening-level hazard assessment using EPISUITE ver 4.1 didnot identify 2-hydroxy-a,a,4-trimethylcyclohexanemethanol aseither being possibly persistent nor bioaccumulative based on itsstructure and physical-chemical properties. This screening levelhazard assessment is a weight of evidence review of a materialsphysical-chemical properties, available data on environmental fate(e.g., OECD Guideline biodegradation studies or die-away studies)and sh bioaccumulation, and review of model outputs (e.g., USE-PAs BIOWIN and BCFBAF found in EPISUITEver.4.1). Specic keydata on biodegradation and fate and bioaccumulation are reportedbelow and summarized in the Environmental Safety Assessmentsection prior to Section I.10.7.1. Risk assessment:Based on current Volume of Use (2011), 2-hydroxy-a,a,4-trimethylcyclohexanemethanol presents a risk to the aquaticcompartment in the screening level assessment.Key Studies:10.8. Biodegradation:RIFM, 1996: The test was conducted to evaluate the biode-gradability of the test material by microorganisms according to theOECD 301C method. Average percentage biodegradation of the testmaterial after 28 days was 73% and 94% by BOD and TOC,respectively.RIFM, 1999a,b,c: The Ready Biodegradability of the test materialwas determined by the Manometric Respirometry Test according tothe OECD 301F. Mineral medium inoculated with activated sludgefrom a biological wastewater treatment plant was incubated with100 mg/l of 2-hydroxy-a,a,4-trimethylcyclohexanemethanol. 2-Hydroxy-a,a,4-trimethylcyclohexanemethanol underwent 77%biodegradation after 37 days (75% after 28 days).10.9. EcotoxicityRIFM, 2000a: The acute toxicity of the test material to zebra sh(Brachydanio rerio) was determined in a 96 h semi-static studyaccording to the OECD 203 method. The 96-h LC50 was based onmean measured concentration was 62 mg/l.RIFM, 2000b: An algal growth inhibition test was conductedaccording to OECD 201 guideline. The 72 h EC50 was calculated tobe 34 mg/l (biomass) and 52 mg/l (growth rate).RIFM, 2000c: The acute toxicity of the test material to Daphniamagna was evaluated according to the OECD 202 I method understatic conditions. The 48-h EC50 value based on total meanmeasured test material concentration was 68 mg/l.10.9.1. Other available data:2Hydroxy-a,a,4-trimethylcyclohexanemethanol has been pre-registered for REACH with no additional data at this time.10.9.2. Risk assessment renement:Since 2-hydroxy-a,a,4-trimethylcyclohexanemethanol haspassed the screening criteria (Tier 2), measured data has beenincluded in this document for completeness only and has not beenused in PNEC derivation.Ecotoxicological data and PNEC derivation (all endpoints re-ported in mg/L; PNECs in mg/L).Endpoints used to calculate PNEC are underlined.S214 A.M. Api et al. / Food and Chemical Toxicology 97 (2016) S209eS215Exposure information and PEC calculation (following RIFMEnvironmental Framework: Salvito et al., 2002).carbohydrate? No.Q6. Benzene derivative with certain substituents? No.Q7. Heterocyclic? No.Q16. Common terpene? No.Q17. Readily hydrolysed to a common terpene? No.ExposureLog Kow usedBiodegradation Factor UsedDilution FactorRegional Volume of Use Tonnage BandRisk Characterization: PEC/PNECEurope (EU)4.0131e101North America (NA)4.0131e101Q19. Open chain? No.Q23. Aromatic? No.Q24. Monocarbocyclic with simple substituents? Yes.Q18. One of the list (Question 18 examines the terpenes, andlater the open-chain and mononuclear substances by reference, todetermine whether they contain certain structural features gener-Based on available data, the RQ for this material is 1. No furtherassessment is necessary.The RIFM PNEC is 3.799 mg/L. The revised PEC/PNECs for EUand NA are 1 and therefore, does not present a risk to theaquatic environment at the current reported volumes of use.Literature Search and Risk Assessment Completed on: 2/24/15.11. Literature search*RIFM database: target, Fragrance Structure Activity Group ma-terials, other references, JECFA, CIR, SIDS.ECHA: http:/echa.europa.eu/.NTP: /ntp_tox/index.cfm.OECD Toolbox.SciFinder: /scinder/view/scinder/scinderExplore.jsfPUBMED: /pubmed.TOXNET: /.IARC (http:/monographs.iarc.fr):OECD SIDS: http:/www.chem.unep.ch/irptc/sids/oecdsids/sidspub.html.EPA Actor: /actor/faces/ACToRHome.jsp;jsessionid0EF5C212B7906229F477472A9A4D05B7US EPA HPVIS: /hpv/hpvis/index.html.US EPA Robust Summary: /hpv-s/.Japanese NITE: http:/www.safe.nite.go.jp/english/db.html.Japan Existing Chemical Data Base: http:/dra4.nihs.go.jp/mhlw_data/jsp/SearchPageENG.jspGoogle: /webhp?tabww Maximization-test. Unpublishedreport from Givaudan. RIFM report number 43443. RIFM, Woodcliff Lake, NJ,USA.RIFM (Research Institute for Fragrance Materials, Inc., 1999b. Partition Coefcient N-octanol/water of Geranodyle. Unpublished report from Givaudan. RIFM reportnumber 43450. RIFM, Woodcliff Lake, NJ, USA.RIFM (Research Institute for Fragrance Materials, Inc., 1999c. Ready Biodegradabilityof 2-hydroxy-alpha,alpha,4-trimethylcyclohexanemethanol (Geranodyle). Un-published report from Givaudan. RIFM report number 57082. RIFM, WoodcliffLake, NJ, USA.RIFM (Research Institute for Fragrance Materials, Inc., 2000a. Geranodyle: 28-DayOral Toxicity (Gavage) Study in the Wistar Rat. Unpublished report fromGivaudan. RIFM report number 41536. RIFM, Woodcliff Lake, NJ, USA.RIFM (Research Institute for Fragrance Materials, Inc., 2000b. In Vitro ChromosomeAberration Assay in Chinese Hamster V79 Cells with Geranodyle. Unpublishedreport from Givaudan. RIFM report number 43444. RIFM, Woodcliff Lake, NJ,USA.RIFM (Research Institute for Fragrance Materials, Inc., 2000c. Determination of theVapour Pressure of Geranodyle. Unpublished report from Givaudan. RIFMreport number 43452. RIFM, Woodcliff Lake, NJ, USA.RIFM (Research Institute for Fragrance Materials, Inc., 2000d. Acute Toxicity of 2-hydroxy-alpha,alpha,4-trimethylcyclohexanemethanol (Geranodyle) to ZebraFish. Unpublished report from Givau