Update to RIFM fragrance ingredient safety assessment, 2,4-dimethylbenzyl acetate, CAS Registry Number 62346-96-7.

The MOE is greater than 100. Without adjustment for specific uncertainty factors related to inter-species and intra-species variation, the material exposure by inhalation at 0.0040 mg/day is deemed to be safe under the most conservative consumer exposure scenario.

The RIFM approach to evaluating Natural Complex Substances (NCS).

The Research Institute for Fragrance Materials, Inc. (RIFM) has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS; 2) verify whether the Threshold of Toxicological Concern (TTC) can be applied; 3) verify whether the NCS risk assessment can be achieved on a component basis; and 4) determine whether data must be generated. Using in silico tools, RIFM examined NCS similarities based on the plant part, processing, and composition of materials across 81 plant families to address data gaps. Data generated from the Creme RIFM Aggregate Exposure Model for over 900 fragrance NCS demonstrate that dermal exposure is the primary route of human exposure for NCS fragrance uses. Over a third of materials are below the most conservative TTC limits. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

RIFM fragrance ingredient safety assessment, p-tolyl acetate, CAS Registry Number 140-39-6.

The existing information supports the use of this material as described in this safety assessment. p-Tolyl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl p-tolyl carbonate (CAS # 22719-81-9) show that p-tolyl acetate is not expected to be genotoxic. Data on read-across materials p-cresol (CAS # 106-44-5) and acetic acid (CAS # 64-19-7) provide a calculated MOE >100 for the repeated dose and reproductive toxicity endpoints. The skin sensitization endpoint was completed using DST for reactive materials (64 µg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; p-tolyl acetate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to p-tolyl acetate is below the TTC (1.4 mg/day).The environmental endpoints were evaluated; p-tolyl acetate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, 4-(p-hydroxyphenyl)-2-butanone, CAS Registry Number 5471-51-2.

The existing information supports the use of this material as described in this safety assessment. 4-(p-Hydroxyphenyl)-2-butanone was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(p-hydroxyphenyl)-2-butanone is not genotoxic. Data on 4-(p-hydroxyphenyl)-2-butanone provide a calculated MOE >100 for the repeated dose toxicity endpoint. The developmental and reproductive toxicity and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to 4-(p-hydroxyphenyl)-2-butanone is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data from 4-(p-hydroxyphenyl)-2-butanone show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 4-(p-hydroxyphenyl)-2-butanone is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-(p-hydroxyphenyl)-2-butanone was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, methyl 2-octynoate, CAS Registry Number 111-12-6.

Methyl 2-octynoate was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that methyl 2-octynoate is not genotoxic. Data provided methyl 2-octynoate a NESIL of 110 µg/cm2 for the skin sensitization endpoint. The repeated dose, developmental and reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class II material, and the exposure to methyl 2-octynoate is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; methyl 2-octynoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-octynoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, methyl ionone (mixture of isomers), CAS registry number 1335-46-2.

Methyl ionone (mixture of isomers) was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from methyl ionone (mixture of isomers) show that the material is not genotoxic and provided a NESIL of 70,000 µg/cm2 for the skin sensitization endpoint. Data provided a calculated MOE >100 for the repeated dose toxicity and developmental toxicity endpoints, and data from read-across material (E)-ß-ionone (CAS # 79-77-6) provided a calculated MOE >100 for the reproductive toxicity endpoint. For the local respiratory endpoint, a calculated MOE >100 was provided by the read-across material ß-ionone (CAS # 14901-07-6). The phototoxicity/photoallergenicity endpoints were evaluated based on data and UV spectra; the material is not phototoxic/photoallergenic. The environmental endpoints were evaluated with data from the target chemical and read-across material α-allylionone (CAS # 79-78-7), and the material was not found to be PBT; its risk quotients, based on current volume of use in Europe and North America (PEC/PNEC), are <1.

Echocardiographic evaluation of intracardiac venous gas emboli following in-water recompression.

Decompression sickness is a potentially fatal illness. Optimal treatment is dry recompression with hyperbaric oxygen. In-water recompression (IWR) offers expedited treatment but has insufficient evidence to recommend it as a treatment option. This trial compares IWR to standard surface oxygen treatment using 2D echocardiography as the semi-quantitative measurement for inert gas loading. Divers were randomly assigned to either IWR or normobaric oxygen (NBO2). A provocative dive profile to 33.5 meters for 25 minutes was used to stimulate bubble formation. After 60 minutes on the surface, bubble scoring was obtained using 2D echocardiography. Divers underwent either the IWR or NBO2 treatment for 82 minutes. Echocardiography was then repeated. Pre-treatment mean bubble counts were 28.1 bpf (bubbles per echo frame), [+/- 13.2 to 43.0 95% CI] for IWR, and 18.3 bpf [+/- 0.0 to 39.6 95% CI] for NBO2. After treatment, mean bubble score dropped to 0.1 bpf [+/- 0.0 to 0.2 95% CI] (p < 0.01) and 1.8 bpf [0.0 to 3.8 95% CI] (p = 0.103) respectively. IWR vs. NBO2 reduction of bubble counts was 99.7% vs. 90.1%; however, this was not found to be statistically significant. IWR reduced the central VGE load compared to NBO2, suggesting that IWR is a viable emergency treatment when a recompression chamber is unavailable.

Attenuation of acute lung injury caused by hind-limb ischemia-reperfusion injury by butyrolactone anti-inflammatory agent FL1003.

OBJECTIVE: Activation of systemic inflammation after reperfusion of ischemic tissue results in severe acute lung injury. Neutrophil activation and oxygen radical generation have been implicated in the pathogenesis. This study tested the hypothesis that treatment with FL1003, a butyrolactone with in vitro antioxidant properties, will down-regulate this response and abrogate acute lung injury. METHODS: Male Sprague-Dawley rats (n = 16) were divided into a surgical sham group (n = 4), a group that received 2 hours of ischemia by infrarenal aortic clip followed by 1 hour of reperfusion (n = 7), and an ischemia-reperfusion (I/R) group that received FL1003 100 mg/kg intravenously before ischemia (n = 5). After reperfusion, the heart and lungs were excised en bloc in an isolated lung perfusion apparatus for 1.5 hours of perfusion, while pulmonary artery pressures were held between 5 and 12 mm Hg and venous effluent was collected. Bronchoalveolar lavage fluid and both lungs were harvested at death for determination of tissue water content, pulmonary microvascular permeability, and indicators of neutrophil activation and tissue oxidation. RESULTS: After I/R, there were significant (p < 0.05) increases in intravenous fluid (IVF) requirements (18 +/- 1.2 mL) to maintain hemodynamic stability, wet weight/dry weight ratio of lung tissue, and isolated-lung lavage Ficoll concentrations (0.58 +/- 0.02 microg/mL) compared with sham animals (IVF, 0 mL; Ficoll concentration, 0.08 +/- 0.03 microg/mL). In addition, lung myeloperoxidase activity (0.60 +/- 0.03 vs. 0.12 +/- 0.02 units/g of tissue) and levels of lipid-conjugated dienes (0.042 +/- 0.012 vs. 0.018 +/- 0.006 optical density of 233 nm (OD233)/mL) were significantly higher (p < 0.05) compared with the sham group. In I/R animals treated with FL1003, the IVF requirement (8.5 +/- 1.0 mL), wet weight/dry weight ratio, lung tissue Ficoll concentration (0.21 +/- 0.02 microg/mL), myeloperoxidase concentration (0.217 +/- 0.02 units/g), and lipid-conjugated diene levels (0.012 +/- 0.005 OD233/ mL) were all significantly lower (p < 0.05) than after untreated I/R. CONCLUSION: A pulmonary microvascular permeability defect with pulmonary edema, neutrophil aggregation, and cell membrane damage resulted from ischemia and reperfusion. Treatment of animals with FL1003 significantly attenuated the inflammatory response associated with acute lung injury.