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Schroeter J.D.,Hamner Institutes for Health Sciences | Kimbell J.S.,University of North Carolina at Chapel Hill | Asgharian B.,Applied Research Associates Inc. | Tewksbury E.W.,Hamner Institutes for Health Sciences | Singal M.,Research Institute for Fragrance Materials Inc.
Journal of Aerosol Science | Year: 2012

Computational fluid dynamics (CFD) simulations were conducted in a model of the complete nasal passages of an adult male Sprague-Dawley rat to predict regional deposition patterns of inhaled particles in the size range of 1. nm to 10. μm. Steady-state inspiratory airflow rates of 185, 369, and 738. ml/min (equal to 50%, 100%, and 200% of the estimated minute volume during resting breathing) were simulated using Fluent™. The Lagrangian particle tracking method was used to calculate trajectories of individual particles that were passively released from the nostrils. Computational predictions of total nasal deposition compared well with experimental data from the literature when deposition fractions were plotted against the Stokes and Peclet numbers for micro- and nanoparticles, respectively. Regional deposition was assessed by computing deposition efficiency curves for major nasal epithelial cell types. For micrometer particles, maximum olfactory deposition was 27% and occurred at the lowest flow rate with a particle diameter of 7. μm. Maximum deposition on mucus-coated non-olfactory epithelium was 27% for 3.25. μm particles at the highest flow rate. For submicrometer particles, olfactory deposition reached a maximum of 20% with a particle size of 5. nm at the highest flow rate, whereas deposition on mucus-coated non-olfactory epithelium reached a peak of approximately 60% for 1-4. nm particles at all flow rates. These simulations show that regional particle deposition patterns are highly dependent on particle size and flow rate, indicating the importance of accurate quantification of deposition in the rat for extrapolation of results to humans. © 2011 Elsevier Ltd. Source

Roberts D.W.,Liverpool John Moores University | Api A.M.,Research Institute for Fragrance Materials Inc. | Safford R.J.,B Safe Toxicology Consulting | Lalko J.F.,Research Institute for Fragrance Materials Inc.
Regulatory Toxicology and Pharmacology | Year: 2015

An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64μg/cm2 for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST. © 2015 Elsevier Inc.. Source

Shen J.,Research Institute for Fragrance Materials Inc. | Kromidas L.,Research Institute for Fragrance Materials Inc. | Schultz T.,University of Tennessee at Knoxville | Bhatia S.,Research Institute for Fragrance Materials Inc.
Food and Chemical Toxicology | Year: 2014

Fragrance materials are widely used in cosmetics and other consumer products. The Research Institute for Fragrance Materials (RIFM) evaluates the safety of these ingredients and skin absorption is an important parameter in refining systemic exposure. Currently, RIFM's safety assessment process assumes 100% skin absorption when experimental data are lacking. This 100% absorption default is not supportable and alternate default values were proposed. This study aims to develop and validate a practical skin absorption model (SAM) specific for fragrance material. It estimates skin absorption based on the methodology proposed by Kroes etal. SAM uses three default absorption values based on the maximum flux (Jmax) - namely, 10%, 40%, and 80%. Jmax may be calculated by using QSAR models that determine octanol/water partition coefficient (Kow), water solubility (S) and permeability coefficient (Kp). Each of these QSAR models was refined and a semi-quantitative mechanistic model workflow is presented. SAM was validated with a large fragrance-focused data set containing 131 materials. All resulted in predicted values fitting the three-tiered absorption scenario based on Jmax ranges. This conservative SAM may be applied when fragrance material lack skin absorption data. © 2014 Published by Elsevier Ltd. Source

Bhatia S.,Research Institute for Fragrance Materials Inc. | Schultz T.,University of Tennessee at Knoxville | Roberts D.,Liverpool John Moores University | Shen J.,Research Institute for Fragrance Materials Inc. | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2015

The Threshold of Toxicological Concern (TTC) is a pragmatic approach in risk assessment. In the absence of data, it sets up levels of human exposure that are considered to have no appreciable risk to human health. The Cramer decision tree is used extensively to determine these exposure thresholds by categorizing non-carcinogenic chemicals into three different structural classes. Therefore, assigning an accurate Cramer class to a material is a crucial step to preserve the integrity of the risk assessment. In this study the Cramer class of over 1000 fragrance materials across diverse chemical classes were determined by using Toxtree (TT), the OECD QSAR Toolbox (TB), and expert judgment. Disconcordance was observed between TT and the TB. A total of 165 materials (16%) showed different results from the two programs. The overall concordance for Cramer classification between TT and expert judgment is 83%, while the concordance between the TB and expert judgment is 77%. Amines, lactones and heterocycles have the lowest percent agreement with expert judgment for TT and the TB. For amines, the expert judgment agreement is 45% for TT and 55% for the TB. For heterocycles, the expert judgment agreement is 55% for TT and the TB. For lactones, the expert judgment agreement is 56% for TT and 50% for the TB. Additional analyses were conducted to determine the concordance within various chemical classes. Critical checkpoints in the decision tree are identified. Strategies and guidance on determining the Cramer class for various chemical classes are discussed. © 2014 Elsevier Inc. Source

Scognamiglio J.,Research Institute for Fragrance Materials Inc. | Jones L.,Leah Jones Consulting | Letizia C.S.,Research Institute for Fragrance Materials Inc. | Api A.M.,Research Institute for Fragrance Materials Inc.
Food and Chemical Toxicology | Year: 2012

A toxicologic and dermatologic review of 2-phenoxyethanol when used as a fragrance ingredient is presented. 2-Phenoxyethanol is a member of the fragrance structural group Aryl Alkyl Alcohols and is a primary alcohol. The AAAs are a structurally diverse class of fragrance ingredients that includes primary, secondary, and tertiary alkyl alcohols covalently bonded to an aryl (Ar) group, which may be either a substituted or unsubstituted benzene ring. The common structural element for the AAA fragrance ingredients is an alcohol group -C-(R1)(R2)OH and generically the AAA fragrances can be represented as an Ar-C-(R1)(R2)OH or Ar_Alkyl-C-(R1)(R2)OH group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-phenoxyethanol were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, photoallergy, toxicokinetics, repeated dose, and reproductive toxicity data. A safety assessment of the entire Aryl Alkyl Alcohols will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Aryl Alkyl Alcohols in fragrances. © 2011 Elsevier Ltd. Source

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