RIFM fragrance ingredient safety assessment, 1-heptanethiol, CAS Registry Number 1639-09-4.

1-Heptanethiol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 1-octanethiol (CAS # 111-88-6) show that 1-heptanethiol is not expected to be genotoxic and provide a calculated MOE >100 for the reproductive toxicity endpoint. Data on read-across analog dodecanethiol (CAS # 112-55-0) provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data show that there are no safety concerns for 1-heptanethiol for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra for read-across analog methyl mercaptan (CAS # 74-93-1); 1-heptanethiol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 1-heptanethiol 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.

Fragrance material review on 1-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)ethane-1-one.

A toxicologic and dermatologic review of 1-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)ethane-1-one when used as a fragrance ingredient is presented. 1-(3,3-Dimethylbicyclo[2.2.1]hept-2-yl)ethane-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. 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 1-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)ethane-1-one were evaluated then summarized and includes physical properties, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones When Used as Fragrance Ingredients (submitted for publication) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances.

Fragrance material review on 2-benzylheptanol.

A toxicologic and dermatologic review of 2-benzylheptanol when used as a fragrance ingredient is presented. 2-Benzylheptanol 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. 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 other branched chain saturated alcohols in fragrances.

Multimedia modeling of human exposure to chemical substances: the roles of food web biomagnification and biotransformation.

The Risk Assessment IDentification And Ranking (RAIDAR) model is refined to calculate relative human exposures as expressed by total intake, intake fraction (iF), and total body burden (TBB) metrics. The RAIDAR model is applied to three persistent organic pollutants (POPs) and six petrochemicals using four mode-of-entry emission scenarios to evaluate the effect of metabolic biotransformation estimates on human exposure calculations. When biotransformation rates are assumed to be negligible, daily intake and iFs for the nine substances ranged over six orders of magnitude and TBBs ranged over 10 orders of magnitude. Including biotransformation estimates for fish, birds, and mammals reduced substance-specific daily intake and iF by up to 4.5 orders of magnitude and TBB by more than eight orders of magnitude. The RAIDAR iF calculations are compared to the European Union System for the Evaluation of Substances (EUSES) model iF calculations and differences are discussed, especially the treatment of food web bioaccumulation. Model selection and application assumptions result in different rankings of human exposure potential. These results suggest a need to critically consider model selection and to include reliable biotransformation rate estimates when assessing relative human exposure and ranking substances for priority setting. Recommendations for further model evaluations and revisions are discussed.

Synthesis of yashabushidiol and its analogues and their cytotoxic activity against cancer cell lines.

A total synthesis of yashabushidiol (1a), a linear diarylheptanoid having 1,3- diol system and its analogues has been achieved by alkynylation of 3-hydroxy-5-phenyl pentanal with substituted phenyl acetylenes. All the compounds have shown significant anti-proliferative activity on human leukemia (THP-1, U-937) and melanoma (A-375) cell lines. Compounds 2a and 2b were found to be most potent with an IC(50) of 12.82 microg/mL and 12.62 microg/mL, respectively, on THP-1 leukemia cell line.

Cytotoxicity of chloroquine in isolated rat hepatocytes.

Chloroquine is a synthetic quinoline being used as an antimalaria and antirheumatoid agent. Several cases of hepatotoxicity have been reported with the use of chloroquine. However, the mechanism(s) of its hepatotoxic effect is unknown. The purpose of this study was to investigate the cytotoxic mechanism of chloroquine. Cytotoxicity was studied using freshly isolated rat hepatocytes incubated in Krebs-Henseleit buffer under a flow of 95% O(2) and 5% CO(2). Chloroquine was toxic towards hepatocytes and caused cell death with an ED(50) of about 100 mm in 2 h. The events before cell death were rapid GSH depletion and lipid peroxidation. Cytochrome P-450 inhibitors, troleandromycine, cimetidine and quinidine increased the cytotoxicity of chloroquine. Antioxidants significantly prevented the cytotoxicity of chloroquine. Depleting the hepatocyte GSH beforehand increased the chloroquine cytotoxicity. Preventing chloroquine metabolism by specific P-450 inhibitors increased its toxicity, suggesting that a major part of its toxicity is mediated by chloroquine and not by its metabolites. A depletion of the antioxidant defense system is involved in the mechanism of cytotoxicity.

Role of the GLT-1 subtype of glutamate transporter in glutamate homeostasis: the GLT-1-preferring inhibitor WAY-855 produces marginal neurotoxicity in the rat hippocampus.

Glutamate is the major excitatory neurotransmitter in the central nervous system and is tightly regulated by cell surface transporters to avoid increases in concentration and associated neurotoxicity. Selective blockers of glutamate transporter subtypes are sparse and so knock-out animals and antisense techniques have been used to study their specific roles. Here we used WAY-855, a GLT-1-preferring blocker, to assess the role of GLT-1 in rat hippocampus. GLT-1 was the most abundant transporter in the hippocampus at the mRNA level. According to [(3)H]-l-glutamate uptake data, GLT-1 was responsible for approximately 80% of the GLAST-, GLT-1-, and EAAC1-mediated uptake that occurs within dissociated hippocampal tissue, yet when this transporter was preferentially blocked for 120 h with WAY-855 (100 microm), no significant neurotoxicity was observed in hippocampal slices. This is in stark contrast to results obtained with TBOA, a broad-spectrum transport blocker, which, at concentrations that caused a similar inhibition of glutamate uptake (10 and 30 microm), caused substantial neuronal death when exposed to the slices for 24 h or longer. Likewise, WAY-855, did not significantly exacerbate neurotoxicity associated with simulated ischemia, whereas TBOA did. Finally, intrahippocampal microinjection of WAY-855 (200 and 300 nmol) in vivo resulted in marginal damage compared with TBOA (20 and 200 nmol), which killed the majority of both CA1-4 pyramidal cells and dentate gyrus granule cells. These results indicate that selective inhibition of GLT-1 is insufficient to provoke glutamate build-up, leading to NMDA receptor-mediated neurotoxic effects, and suggest a prominent role of GLAST and/or EAAC1 in extracellular glutamate maintenance.

In vivo percutaneous absorption, skin barrier perturbation, and irritation from JP-8 jet fuel components.

JP-8 jet fuel has been reported to cause systemic and dermal toxicities in animal models and humans. There is a great potential for human exposure to JP-8. In this study, we determined percutaneous absorption and dermal toxicity of three components of JP-8 (i.e., xylene, heptane, and hexadecane) in vivo in weanling pigs. In vivo percutaneous absorption results suggest a greater absorption of hexadecane (0.43%) than xylene (0.17%) or heptane (0.14%) of the applied dose after 30 min exposure. Transepidermal water loss (TEWL) provides a robust method for assessing damage to the stratum corneum. Heptane showed greater increase in TEWL than the other two chemicals. No significant (p < 0.05) increase in temperature was observed at the chemically treated site than the control site. Heptane showed greater TEWL values and erythema score than other two chemicals (xylene and hexadecane). We did not observe any skin reactions or edema from these chemicals. Erythema was completely resolved after 24 h of the patch removal in case of xylene and hexadecane.

Survival in soil of different toluene-degrading Pseudomonas strains after solvent shock.

We assayed the tolerance to solvents of three toluene-degrading Pseudomonas putida strains and Pseudomonas mendocina KR1 in liquid and soil systems. P. putida DOT-T1 tolerated concentrations of heptane, propylbenzene, octanol, and toluene of at least 10% (vol/vol), while P. putida F1 and EEZ15 grew well in the presence of 1% (vol/vol) propylbenzene or 10% (vol/vol) heptane, but not in the presence of similar concentrations of octanol or toluene. P. mendocina KR1 grew only in the presence of heptane. All three P. putida strains were able to become established in a fluvisol soil from the Granada, Spain, area, whereas P. mendocina KR1 did not survive in this soil. The tolerance to organic solvents of all three P. putida strains was therefore assayed in soil. The addition to soil of 10% (vol/wt) heptane or 10% (vol/wt) propylbenzene did not affect the survival of the three P. putida strains. However, the addition of 10% (vol/wt) toluene led to an immediate decrease of several log units in the number of CFU per gram of soil for all of the strains, although P. putida F1 and DOT-T1 subsequently recovered. This recovery was influenced by the humidity of the soil and the incubation temperature. P. putida DOT-T1 recovered from the shock faster than P. putida F1; this allowed the former strain to become established at higher densities in polluted sites into which both strains had been introduced.

Four weeks inhalation exposure to n-heptane causes loss of auditory sensitivity in rats.

The effects of exposure to 800 or 4000 p.p.m. of n-heptane, CAS No. [142-82-5]) 6 hr per day during a period of 28 days, on the function of the auditory system were examined by measurements of auditory brain stem response (ABR) in Long Evans rats. The ABR was measured simultaneously with both needle electrodes and implanted electrodes. The wave forms recorded with the two types of electrodes were similar, but the amplitudes were largest on the recordings with implanted electrodes. The overall ratio between the amplitudes obtained with implanted electrodes and with needle electrodes was 1.4 for peak Ia and 2.5 for peak IV of the ABR. The exposure to n-heptane (4000 p.p.m.) reduced the amplitudes of components Ia and IV of the ABR. The reduction was most consistent for component IV and most pronounced at higher frequencies and intensities. The reduction in ABR corresponds to an increase in the auditory threshold of approximately 10 dB at all frequencies. Neither the latencies nor the interpeak latencies of components Ia and IV were changed. No significant changes in ABR were observed in the group exposed to 800 p.p.m. The mechanism behind the ototoxicity of organic solvents is discussed.

Identification of volatile metabolites of inhaled n-heptane in rat urine.

Alkanes, alcohols, and ketones which are metabolized to a gamma-diketone can produce peripheral neuropathy in experimental animals and in man. A study was conducted to obtain information about the metabolic pathway of n-heptane and its potential neurotoxicity. Female Wistar rats were exposed to 2000 ppm n-heptane inhalation for 12 weeks. Metabolites in urine were identified by gas chromatography-mass spectrometry. Urinary metabolites were quantified following 6-hr n-heptane exposures. n-Heptane metabolites were 1-, 2-, 3-, and 4-heptanols, 2- and 3-heptanones, 2,5- and 2,6-heptanediols, 5-hydroxy-2-heptanone, 6-hydroxy-2-heptanone, 6-hydroxy-3-heptanone, 2,5- and 2,6-heptanediones, and gamma-valerolactone. The amount of urinary metabolites increased greatly after the second exposure day, achieving a steady-state concentration on subsequent exposure days over the 12 weeks of the exposure regimen. These results showed that n-heptane was metabolized mainly by hydroxylation at omega- 1 carbon atom and to a lesser extent at the omega- 2 carbon atom. 2-Heptanol, 6-hydroxy-2-heptanone, and 3-heptanol were the major metabolites and were excreted as sulfates and glucuronides. 2,5-Heptanedione, which is a neurotoxic agent, was the metabolite found in least amounts (2.4 +/- 2 micrograms/rat) in the urine. No clinical evidence of neurotoxicity was observed after n-heptane exposure. Apparently, the lack of neurotoxicity was due to a low production of 2,5-heptanedione, the toxic metabolite.

[Neurotoxic workshop materials: II. Organic substances--a review of the years 1970 to 1982]. / Neurotoxische Arbeitsstoffe: II. Organische Substanzen--Eine Ubersicht der Jahre 1970 bis 1982.

This paper summarizes the knowledge and recent research of some organic neurotoxic substances at the workplace concerning peripheral nervous system. The review covers the substances: acrylamide, n-hexane, methyl-n-butylketone, n-pentane, n-heptane, carbondisulfide, styrene, toluene, trichloroethylene, tri-ortho-cresylphosphate and other organophosphorus compounds, polyhalogenated and complex organic compounds and solvent-mixtures. First the chemical and physical properties, the toxicokinetic and biotransformation as well as possibilities of exposure at the workplace are given. Following the characteristics after acute and chronic intoxications. The effects to the peripheral nervous systems due to short- and longtime exposure of the substance are described. Field studies in exposed workers and neurophysiological investigations with evaluation of dose-effect-relationships are reviewed especially. Each section is discussed and evaluated in respect to occupational medicine.

Toxicity of n-hexane and n-heptane: some biochemical changes in liver and serum.

The toxic effects of i.p. administered n-hexane and n-heptane on biochemical processes in rat liver, as indicated by the increase in alkaline phosphatase activity and decrease in FDP aldolase activity, and their reflection on blood chemistry, were studied. Serum cholinesterase activity and albumin and cholesterol content showed statistically significant decreases with the increase in FDP aldolase activity. The significance of the findings is discussed.