Cedrol

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TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1230(SRC), determined from a structure estimation method(2), indicates that cedrol is expected to have low mobility in soil(SRC). Volatilization of cedrol from moist soil surfaces may occur(SRC) given an estimated Henry's Law constant of 1.8X10-6 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Cedrol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.6X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Utilizing the OECD 301F test (manometric respirometry), 88% of the Theoretical BOD was reached in 4 weeks(3) indicating that biodegradation is an important environmental fate process(SRC); results of the test classified cedrol as readily biodegradable(3).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1230(SRC), determined from a structure estimation method(2), indicates that cedrol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.8X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 31 and 230 days, respectively(SRC). According to a classification scheme(4), an estimated BCF of 330(SRC), from an estimated log Kow of 4.33(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Utilizing the OECD 301F test (manometric respirometry), 88% of the Theoretical BOD was reached in 4 weeks(5) indicating that biodegradation is an important environmental fate process(SRC); results of the test classified cedrol as readily biodegradable(5). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(3).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cedrol, which has an estimated vapor pressure of 8.6X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase cedrol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 19 hours(SRC), calculated from its rate constant of 2.0X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase cedrol may be removed from the air by wet and dry deposition(SRC). Cedrol does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Cedrol forms colorless crystals. It is found in the wood of cypresses and cedars such as Cedrus atlantica, Cupressus sempervirens, and Juniperus virginiana. It is used in fragnances and as a flavor ingredient in foods and traditional medicine. HUMAN EXPOSURE AND TOXICITY: In an exposure study, odorized and blank air was presented to 26 healthy adult volunteers. A constant concentration of cedrol was presented for 10 minutes with 8 minute blank air intervals. Cedrol caused a relaxant effect with decreased heart rate, respiratory rate, systolic and diastolic blood pressure and increased baroreflex activity. Parasympathetic activity was increased and sympathetic activity was decreased. In another exposure study, a maximization test was carried out with 8% cedrol in petrolatum on 25 male volunteers. Sensitization reactions were observed in 2/25 volunteers. In a pre-test for a human maximization study, no irritation was observed to 8% cedrol, when applied for 48 hr under occlusion on five volunteers. In another study, Pyrolae herba (PHVO) was evaluated for antiproliferative activity against human chondrosarcoma cells. A total of 12 components in PHVO were identified. The major compounds included cedrol (17.08%). PHVO demonstrated potent antitumor activity against SW1353 cells, suggesting its potential use as a therapeutic agent in the treatment of chondrosarcoma. In another study, the aim was to investigate the inhibitory effects of cedrol on the activities of eight major human cytochrome P-450 (CYP) enzymes to assess potential cedrol drug interactions. Cedrol, was found to be a potent competitive inhibitor of CYP2B6-mediated bupropion hydroxylase with inhibition constant (Ki) values of 0.9 uM, comparable with that of a selective CYP2B6 inhibitor, thioTEPA (Ki, 2.9 uM). Cedrol also markedly inhibited CYP3A4-mediated midazolam hydroxylation with a Ki value of 3.4 uM, whereas beta-cedrene moderately blocked CYP3A4. Cedrol at 100 microM negligibly inhibited CYP1A2, CYP2A6, and CYP2D6 activities. Cedrol weakly inhibited CYP2C8, CYP2C9, and CYP2C19 activities, but beta-cedrene did not. These in vitro results indicate that cedrol should be examined for potential pharmacokinetic drug interactions in vivo due to their potent inhibition of CYP2B6 and CYP3A4. ANIMAL STUDIES: A 28-day oral toxicity study was conducted to evaluate toxicity of cedrol in rats. Sixty rats were randomly divided into five groups (10 males or 10 females per group) and a control group of 10 animals. Approximately 0.169% w/v of cedrol was administered at dose of 8.4 mg/kg/day in 20 rats (10/sex) seven days per week via gavage to all the animals for 30 days. Crooked incisors and a swollen mouth were observed in one male rat on day 28. Decrease in absolute brain weight and brain-and ovary-to body weight was observed in female rats. However, these findings were not consistent between the sexes and absence of correlative clinical changes made the consideration of these non-adverse findings of limited toxicological significance. Open epicutaneous tests were carried out in outbred male and female guinea pigs with 8% cedrol, no sensitization reactions were observed. In another study on the sedative effects of cedrol, rats and mice were exposed at 1.0 liter/ minute for 30 minutes. Cumulative spontaneous motor activity was found to be significantly decreased in the cedrol exposed group.

Cedrol is reported to occur in European calamus (Acorus calamus var calamus; Acoraceae) at 1,900 mg/kg and in cinnamon (Cinnamomum verum) at concentrations up to 100 mg/kg(1).

The volatile oil from Western juniper has been reported to contain 15-40% cedrol(1). Texas and Virginia cedarwood oils are reported to contain 19.0 and 15.8% cedrol respectively(1). Cedrol was detected in the chemical constituents of the flowering plants of Sinningia canescens and Sinningia warmingii(2). Analysis of the essential oil of Dalbergia odorifera (fragrant rosewood) found cedrol at a concentration of 1.65%(3).

Cedrol detections in plants(1).[Table#8249]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of cedrol can be estimated to be 1230(SRC). According to a classification scheme(2), this estimated Koc value suggests that cedrol is expected to have low mobility in soil.

Cedrol occurs naturally in the wood of several conifers, particularly cypress and cedar (Cedrus atlantica, Cupressus sempervirens, Juniperus virginiana and others)(1). Cedrol occurs naturally in cedar wood oil from Texas (Juniperus mexicana) and China (Cupressus funebris)(2).

/HUMAN EXPOSURE STUDIES/ Odorized and blank air was presented to 26 healthy adult volunteers using an olfactometer with separate teflon-coated tubing and face mask systems to prevent deposition of cedrol particles. A constant concentration of 14.20 +/- 1.7 ug/L; 64 +/- 7.7x10-9 cedrol was presented for 10 minutes with 8 minute blank air intervals. Measurements of the subjects' ECGs, heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure and respiratory rate (RR) were recorded. Statistical differences between control air and odorized air were based on the paired t-test. Cedrol caused a relaxant effect with decreased heart rate, respiratory rate, systolic and diastolic blood pressure and increased baroreflex activity. Parasympathetic activity was increased and sympathetic activity was decreased.

/HUMAN EXPOSURE STUDIES/ A maximization test was carried out with 8% (5520 ug/sq cm) cedrol in petrolatum on 25 male volunteers. Cedrol was applied under occlusion to the same site on the forearms of all subjects for five alternate-day 48-hour periods. Patch sites were pretreated for 24 hr with 5% aqueous sodium lauryl solution (SLS) under occlusion. Following a 10-day rest period, a challenge patch was applied to a fresh site for 48 hr under occlusion. Challenge test sites were pre-tested with 10% aqueous SLS for one hour under occlusion. The challenge sites were read at patch removal and 24 hr after patch removal. Sensitization reactions were observed in 2/25 volunteers. However, when this same test was repeated, using the same method and cedrol concentration, no sensitization reactions were observed.

/HUMAN EXPOSURE STUDIES/ In a pre-test for a human maximization study, no irritation was observed to 8% cedrol, when applied for 48-hr under occlusion on five male volunteers.

/ALTERNATIVE and IN VITRO TESTS/ The objective of the present study was to identify chemical constituents of volatile oil from Pyrolae herba (PHVO) and evaluate the antiproliferative activity of PHVO against SW1353 human chondrosarcoma cells. The volatile oil from Pyrolae herba was prepared by hydrodistillation and characterized by gas chromatography-mass spectroscopy (GC-MS). A total of 12 components in PHVO were identified representing 81.62% of the total integrated chromatographic peaks. The major compounds were found to be n-hexadecanoic acid (29.29%), cedrol (17.08%), 6,10,14-trimethyl-2-pentadecanone (9.59%) and cis-9-octadecadienoic acid (8.23%). The antiproliferative activity of PHVO against SW1353 cells was investigated using MTT assay, flow cytometry and western blot analysis. Our results demonstrated that PHVO inhibited SW1353 cell viability in a dose- and time-dependent manner. Furthermore, PHVO treatment decreased the number of cells entering the S phase and caused a reduction in the expression of cyclin D1, cyclin-dependent kinase (CDK)4 and CDK6, whereas it caused an increase in the expression of p21. PHVO demonstrated potent antitumor activity against SW1353 cells, suggesting its potential use as a therapeutic agent in the treatment of chondrosarcoma. /PHVO/

Cedrol's production and use as a feedstock for the manufacture of perfumery compounds(1) and use as a flavoring compound in foods(2) may result in its release to the environment through various waste streams(SRC). Its use as a perfumery compound and odorant for disinfectants(3) will result in its direct release to the environment(SRC).

AEROBIC: Cedrol, present at 100 mg/L, reached 88% of its theoretical BOD in 4 weeks using a sludge inoculum at 30 mg/L in the OECD 301F method (Manometric Respirometry) which classifies cedrol as readily biodegradable; a primary half-life of 2.9 days was determined from the screening results(1).

An estimated BCF of 330 was calculated in fish for cedrol(SRC), using an estimated log Kow of 4.33(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for cedrol is estimated as 1.8X10-6 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that cedrol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 31 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 230 days(SRC). Cedrol's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Cedrol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.6X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(1).

/LABORATORY ANIMALS: Acute Exposure/ To study the sedative effects of cedrol, male rats, as well as male mice were exposed at 1.0 liters/ minute for 30 minutes. Cumulative spontaneous motor activity was measured every 5 minutes until 30 minutes after the initiation of exposure, and found to be significantly decreased in the cedrol exposed group. ...

/LABORATORY ANIMALS: Acute Exposure/ The acute dermal LD50 study was evaluated in six rabbits. A single dermal application of neat cedrol at 5 g/kg/body weight was made to the skin of each animal. Observations were made for a period of 14 days. The LD50 exceeded 5 g/kg based on no death at this dose.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A 28-day oral toxicity study was conducted to evaluate toxicity of cedrol in rats. Sixty rats (30/sex) were randomly divided into five groups (10 males or 10 females per group) and a control group of 10 animals. Cedrol was prepared as a 0.22% w/v mixture in 1% carboxymethycellulose (CMC) in distilled water. Approximately 0.169% w/v of cedrol was administered at dose of 8.4 mg/kg/day in 20 rats (10/sex) seven days per week via gavage to all the animals for 30 days. Control animals received only the vehicle 1% CMC in distilled water. Animals were observed daily for viability, signs of gross toxicity, behavioral changes and weekly for a battery of detailed observations. Blood samples were taken during the fourth week of the study and prior to terminal sacrifice for hematology, clinical biochemistry, and serology assessments. Gross necropsy was performed on all animals. Crooked incisors and a swollen mouth were observed in one male rat on day 28. Decrease in absolute brain weight and brain-and ovary-to body weight was observed in female rats. These differences were statistically significant by an unpaired t-test. However, these findings were not consistent between the sexes and absence of correlative clinical changes made the consideration of these non-adverse findings of limited toxicological significance. No other statistically significant changes in organ weights were observed. Hence, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) of cedrol was determined to be 8.4 mg/kg/day for both male and female rats. This study was conducted according to the US FDA and OECD GLP.

/OTHER TOXICITY INFORMATION/ Open epicutaneous tests were carried out in outbred male and female guinea pigs (6-8/group) with 8% cedrol (vehicle used not reported). Induction applications consisted of 0.1 mL of 8% cedrol applied onto an 8 sq cm area. Challenge applications were made with 0.025 mL of cedrol onto a skin area measuring 2 sq cm. No sensitization reactions were observed to 8% cedrol.

/OTHER TOXICITY INFORMATION/ Evidence of microsomal enzyme induction in mice and rats exposed to cedarwood bedding. Animals exhibited reductions in hexobarbitone and pentobarbitone sleeping times and elevated activities of hepatic microsomal enzymes. /Cedarwood bedding/

The rate constant for the vapor-phase reaction of cedrol with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 19 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Cedrol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Cedrol does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).