The biotransformation of 1,8-cineole was investigated using human liver microsomes. The metabolite was established as 2-exo-hydroxy-1,8-cineole. 1,8-cineole 2-hydroxylation catalyzed by human liver microsomes was found to be efficiently conducted.
Cineole was administered to male rats once daily by gastric intubation for 20 days. Urine was collected and major metabolites identified as methyl ester of 1,8-dihydroxy-10-carboxy p-methane, 2-hydroxy cineole and 3-hydroxy cineole.
IDENTIFICATION AND USE: Cineole is an essential oil that is used as a fragrance or flavoring agent in: foods, candies, pharmaceutical aid (flavor), cough drops, and personal care products. It has a history of being used as an expectorant and an antiseptic. HUMAN EXPOSURE AND TOXICITY: Cineole is the main constituent of eucalyptus oil, and it is mainly used as a mucolytic agent in inflammatory airway diseases. ANIMAL STUDIES: A study was performed to assess the ocular irritancy potential of eucalyptol to the isolated bovine cornea. The corneas treated with eucalyptol were clear post treatment and had cloudy areas post incubation. Eucalyptol was considered not to be an ocular corrosive or severe irritant. Cineole was administered by gavage to three groups, each of five male and five female rats, for twenty-eight consecutive days, at dose levels of 30, 300 and 600 mg/kg bw/day. For both sexes at 300 and 600 mg/kg bw/day, examination of the liver revealed a dosage dependent incidence of centrilobular hypertrophy of the hepatocytes; no other indicators of liver damage were apparent. Following the two week recovery period, hypertrophy of hepatocytes was no longer present at 600 mg/kg bw/day for either sex. 1,8-Cineole induced accumulation of protein droplets in proximal tubular epithelial cells in male rats. The renal changes were specific to the male rat and of no toxicological relevance to man. Eucalyptol was tested as a constituent of toothpaste in an oral long-term study with mice. Groups of 52 male mice were given 0, 8 and 32 mg/kg bw/day eucalyptol in toothpaste base by gavage for 80 weeks followed by an observation period between 16 and 24 weeks. No treatment-related effects on body weight, food consumption, survival, weight of adrenals, kidneys, liver, lungs or spleen, or on the microscopic appearance of brain, lungs, liver and kidneys or on tumor incidence was observed.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 急性溶剂综合征
Neurotoxin - Acute solvent syndrome
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Infant rats express conditioned responses to an odor experienced prenatally as a chemosensory cue associated with moderate alcohol intoxication. This study examined postnatal intake of a chemosensory cue (cineole) that had been paired with alcohol's unconditioned effects. It also tested the interaction between prenatal association and postnatal conditioning with cineole and alcohol. Pregnant female rats intubated with cineole were given ethanol (EtOH).25 or 4.0 hr later. Other groups received only water or water paired with ethanol. During postnatal day 15 (PD15), infant consumption of cineole solution was assessed. After the cineole drinking test, pups were intubated with EtOH or water to assess infant conditioning. On PD16, all pups were tested for mouthing to milk alone or to a milk-cineole solution. Statistical analysis confirmed fetal associative conditioning attributable to the unconditioned effects of prenatal alcohol. Fetuses given explicit pairings of cineole and alcohol ingested less cineole on PD15 than control fetuses given a 4-hr interval between cineole and alcohol. On PD16, consumption of cineole was significantly increased by prenatal exposure to cineole. Teratogenic effects of this dose of prenatal alcohol did not affect postnatal associative or nonassociative behavior. Prenatal associative learning can be established through temporal contiguity between fetal chemosensory stimulation and alcohol's unconditioned properties. This associative memory survives to infancy and modulates intake patterns and behavioral reactivity to substances that were prenatally paired with alcohol intoxication.
Cineole was administered by gavage to three groups, each of ten male and ten female Wistar Han (TM): RCCHan(TM): WIST strain rats, for up to eleven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females) at dose levels of 30, 300 and 600 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP). Clinical signs, bodyweight change, dietary intake and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 5 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. An additional pairing for high dose females that failed to achieve pregnancy was performed to fully assess mating performance and fertility. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Adult males were terminated on Day 52 of the study following the completion of the second pairing at 600 mg/kg bw/day. Females and offspring were terminated on day 5 post partum. Any female which did not produce a pregnancy (unless allocated to a further mating phase) was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed. Additional male organ weight and detailed histopathological examination of the testes were performed to more fully assess male fertility. Adult response: Mortality: There were no unscheduled deaths in the study. Clinical observations: Transient post-dosing salivation was observed from Day 7 at 600 mg/kg bw/day and Day 13 at 300 mg/kg bw/day. This sign was observed regularly throughout the treatment period with all animals being affected at both dosages, although the incidence of this finding was greatest at the high dosage. Transient post dosing salivation was also observed at 30 mg/kg bw/day for two females on Day 2 and one male on Day 50 of this study. Bodyweight: At 600 mg/kg bw/day body weight gain of males was statistically significantly lower than control during the first week of treatment. Subsequent body weight gains were considered to reflect normal biological varaition, but overall gain at termination remained lower than control. Bodyweight gain of males at 30 and 300 mg/kg bw/day and for females at all dosages, throughout the pre-pairing, gestation and lactation phases of the study, were considered to have been unaffected by treatment. Food consumption: Food consumption for both sexes was considered to have been unaffected by treatment throughout the study, and including gestation and lactation phases for females, at 30, 300 and 600 mg/kg bw/day. Food efficiency: At 600 mg/kg bw/day food conversation efficiency for males was lower than control during week 1; subsequent food utilisation was similar to control. Food conversation efficiency of males at 30 and 300 mg/kg bw/day and for females at all dosages, throughout the pre-pairing, gestation and lactation phases of the study, were considered to have been unaffected by the treatment. Reproductive performance: Mating: Pre-coital interval and mating evidence at the times of conception did not indicate any adverse effect of treatment on mating performance at 30, 300 and 600 mg/kg bw/day. Fertility: At 600 mg/kg bw/day, only seven females delivered a litter following the initial pairing but subsequent re-mating and additional assessment of male organ weight and detailed testicular histopathology did not indicate any treatment related effect on fertility for either sex. There was also no effect of treatment on fertility at 30 and 300 mg/kg bw/day. Gestation lengths: Gestation length was considered to be unaffected by treatment at 30, 300 and 600 mg/kg bw/day. Litter responses: Offspring litter size, sex ratio and viability: There was no effect of maternal treatment on corpora lutea and implantations counts, pre- and post-implantation loss, number of offspring born, sex ratio or subsequent survival to Day 4 of age at 30, 300 and 600 mg/kg bw/day. Offspring growth and development: At 600 mg/kg bw/day initial offspring body weight was similar to control but weight gain to Day 4 was statistically significantly lower than control. Mean offspring body weights, litter weight and weight gains to Day 4 of age were unaffected by maternal treatment at 30 and 300 mg/kg bw/day. Offspring observations: Assessment of surface righting ability on Day 1; offspring clinical signs and necropsy findings and did not indicate any effect of maternal treatment. Pathology: Necropsy: Macroscpoic necropsy findings did not indicate any effect of treatment at 30, 300 and 600 mg/kg bw/day. Organ weights: Male reproductive organ weights were unaffected by treatment at 30, 300 and 600 mg/kg bw/day and did not indicate any effect on fertility. Histopathology: Histopathological examinations did not indicate any effect of treatment at 600 mg/kg bw/day and these examinations, including detailed assessment of the spermatogenetic cycle for the testes did not indicate any effect on male fertility. Within the context of this study, the No Observed Adverse Effect Level (NOAEL) for adult toxicity, reproduction and offspring survival, growth and development was considered to be 600 mg/kg bw/day.
Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Camphor and Related Compounds/
