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Query: UMLS:C0040822 (tremor)
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Benzyl acetate is used as a flavoring agent in foods, as a fragrance in soaps and perfumes, as a solvent for cellulose acetate and nitrate, and as a component of printing inks and varnish removers. The NTP previously studied the toxicology and carcinogenicity of this chemical in F344/N rats and B6C3F1 mice using the gavage route of administration and corn oil as a vehicle. Benzyl acetate increased the incidences of pancreatic acinar cell adenomas in male rats and the incidences of hepatocellular adenomas and forestomach neoplasms in male and female mice. Because of the confounding effect of corn oil on the incidences of pancreatic neoplasms and because of controversy over the use of the gavage route of administration, the NTP decided to restudy benzyl acetate using the dosed feed route of administration. In these repeat studies, male and female F344/N rats and B6C3F1 mice received benzyl acetate (at least 98% pure) in feed for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium nunnery, cultured Chinese hamster ovary cells, LS178Y mouse lymphoma cells, Drosophila melanogaster, and mouse bone marrow and peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 3,130, 6,250,12,500, 25,000, or 50,000 ppm (0, 230, 460, 900,1,750, or 3,900 mg/kg body weight for males and 0, 240, 480, 930,1,870, or 4,500 mg/kg for females) benzyl acetate for 13 weeks. Nine male and nine female rats receiving 50,000 ppm benzyl acetate died or were killed moribund between weeks 2 and 8 of the study. The mean body weight gain and the final mean body weight of 25,000 ppm males were significantly lower (P</=0.01) than those of the control group. Feed consumption by exposed rats, except the 25,000 and S0,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been due to toxicity or decreased palatability. Tremors and ataxia occurred only in the 50,000 ppm rats. These findings were first observed on day 15 in nine males and six females and continued until the end of the study. Cholesterol levels in 12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were lower than those in the controls. Chemical-related lesions occurred in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles occurred in most male and female 50,000 ppm rats. This effect was observed in the 1,000 mg/kg group in the previous gavage study (NTP, 1986). 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3, 130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 425, 1,000, 2,000, 3,700, or 7,900 mg/kg body weight for males and 0, 650, 1,280, 2,980, 4,300, or 9,400 mg/kg for females) benzyl acetate. One 50,000 ppm male mouse died and one 50,000 ppm female mouse was killed moribund before the end of the study. Mean body weight gains and final mean body weights of all exposed male and female mice were significantly lower than those of the controls and the mean body weight gains decreased with increased exposure level. Feed consumption by 3,130 ppm males and all exposed females was lower than that by the controls. Tremors occurred only in females and were first observed on day 16 in three females receiving 50,000 ppm, day 94 in one female receiving 25,000 ppm, and day 93 in one female receiving 12,500 ppm. The tremors continued until the end of the study. Necrosis of the brain involving the hippocampus occurred in four 50,000 ppm mice, one male and three females. Hepatocellular necrosis also occurred in the male with brain lesions. On reexamination of the previous 13-week gavage study (NTP, 1986), a similar lesion was seen in the brain of one 1,000 mg/kg female mouse; none were seen in 1,000 mg/kg male mi male mice. The lesion was less severe than that described in the present dosed feed study. The highest dose used in the gavage study was 1,000 mg/kg compared to an estimated high dose of 7,200 mg/kg for the feed study. 2-YEAR STUDY IN RATS: The doses selected for the 2-year feed study of benzyl acetate in F344/N rats were based on lower survival, mean body weights, and feed consumption, and on increased incidences of histopathologic brain lesions in 50,000 ppm male and female rats in the 13-week study. Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 3,000, 6,000, or 12,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of exposed rats was similar to that of the controls. The mean body weights of the 12,000 ppm males and exposed females were approximately 5&percnt; lower than those of the controls throughout most of the study. The feed consumption by 12,000 ppm males was slightly lower than that by the controls. Dietary levels of 3,000, 6,000, and 12,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 130, 260, and 510 mg/kg body weight (males) and 145, 290, and 575 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were found that could be attributed to benzyl acetate administration. Pathology Findings: No compound-related increased incidences of neoplasms or nonneoplastic lesions occurred in male or female F344/N rats receiving benzyl acetate for as long as 2 years. 2-YEAR STUDY IN MICE: The doses selected for the 2-year feed study of benzyl acetate in B6C3F1 mice were based primarily on lower body weight gains and lower final mean body weights of exposed mice in the 13-week study. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 330, 1,000, or 3,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of all exposed mice, except the 3,000 ppm females, was similar to that of the control groups. Survival of 3,000 ppm females was significantly higher than that of the control group. Throughout the 2-year study, the mean body weights of 1,000 and 3,000 ppm males and females were 2&percnt; to 14&percnt; lower than those of the control groups. Dietary levels of 330, 1,000, and 3,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 35, 110, and 345 mg/kg (males) and 40, 130, and 375 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were observed in mice receiving 330,1,000, or 3,000 ppm benzyl acetate. Pathology Findings: No increase in neoplasm incidence in mice could be attributed to benzyl acetate administration in feed. This contrasts with the previous finding that administration of benzyl acetate in corn oil by gavage once daily 5 days a week for as long as 2 years was carcinogenic to mice, causing increased incidences of hepatocellular neoplasms and forestomach neoplasms. The contrast in results between the two studies may be due to differences in the dose levels used (highest dose: gavage, 1,000 mg/kg a day; feed, 360 mg/kg a day). Dose-related increased incidences or severities of nonneoplastic nasal lesions occurred in the most posterior portions of the nasal cavity in all exposed groups. The lesions occurred in the majority of the exposed mice and consisted of atrophy and degeneration, primarily of the olfactory epithelium, cystic hyperplasia of the nasal submucosal glands, pigmentation of the mucosal epithelium, and exudate accumulation. GENETIC TOXICOLOGY: Benzyl acetate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). However, a positive response was observed for benzyl acetate, with and without S9, in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. No significant increases in the frequencies of sister chromatid exchanges or chromosomal aberrations occurred in cultured Chinese hamster ovary cells treated with benzyl acetate in vitro, with or without S9, and no increases in either sister chromatid exchanges or chromosomal aberrations occurred in bone marrow cells of male mice treated in vivo by intraperitoneal injection. No increase in sex-linked recessive lethal germ cell mutations occurred in male Drosophila melanogaster administered benzyl acetate in feed or by injection. Tests of benzyl acetate for induction of micronucleated erythrocytes in bone marrow and peripheral blood of mice were also negative. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of benzyl acetate in male or female F344/N rats receiving 3,000, 6,000, or 12,000 ppm; however, rats may have tolerated higher doses. There was no evidence of carcinogenic activity of benzyl acetate in male or female B6C3F1 mice receiving 330, 1,000, or 3,000 ppm. Nasal lesions associated with benzyl acetate exposure in male and female mice included nasal mucosa atrophy and degeneration (primarily of the olfactory epithelium), cystic hyperplasia of the nasal submucosal gland, and luminal exudate and pigmentation of the nasal mucosal epithelium. In previous 2-year gavage studies (TR-250), benzyl acetate increased the incidence of acinar cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenic activity in female F344/N rats receiving 250 or 500 mg/kg a day. There was some evidence of carcinogenic activity in male and female B6C3F1 mice, indicated by the increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. Synonyms: acetic acid benzyl ester, acetic acid phenyl methyl ester, (acetoxymethyl)benzene, acetoxytoluene, benzyl ethanoate, phenylmethyl acetate
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice Feed Studies). 1261

A species-specific isotope dilution (ID) method is described for the determination of mono-, di, and tri-butyltin compounds in sediment by gas chromatography-inductively coupled plasma mass spectrometry (GC-ICP-MS), where the mixture of 118Sn-enriched butyltin compounds synthesized in our laboratory was used as a spike. A correction method for the mass bias, a quantitative extraction of the butyltins from sediment, and an assay for the concentration of the standard solution for the reverse ID procedure were investigated to achieve a reliable ID analysis. The spike solution was added with tri-propyltin (TPrT), and the butyltins were extracted by mechanical shaking into acetic acid-tropolone-toluene. The extracted butyltins were ethylated with sodium tetraethylborate and measured by GC-ICP-MS. The mass bias correction factor for the butyltins was calculated with the measured area ratio of 120Sn/118Sn of TPrT in each chromatographic run, and the correction was carried out. The mass bias was well corrected with this in-run correction (the standard uncertainties of the corrected 120Sn/118Sn for the butyltins were in the range 0.03-0.45%, typically 0.25%, with triplicate measurement corresponding to 0.02-0.37% mass bias). The extraction efficiency of mono-butyltin (MBT) from sediment was improved by using tropolone-toluene as the solvent. Well-defined standard solutions for the reverse-ID procedure could be obtained by an assay for the purities of the natural abundance butyltin chloride reagents used for preparing the standard solutions. Overall uncertainties associated with the present method were estimated, where the sediment certified reference materials, PACS-2 and BCR 646, were analyzed. The uncertainty arising from the extraction was the main contributor to the overall uncertainties for MBT and di-butyltin (DBT) determinations, while with the case of tri-butyltin (TBT) determination the uncertainties arising from the purity of TBT chloride reagent used for preparing the standard solution was a large contributor to the overall uncertainties although the uncertainty arising from the extraction was also a main contributor. The analytical results of MBT, DBT, and TBT in both reference materials, except for MBT results in PACS-2, were in good agreement with the certified values in each. The result of MBT in PACS-2 (0.677 +/- 0.049 microg g(-1) as tin, mean +/- expanded uncertainty) was significantly higher than the certified value (0.45 +/- 0.05 microg g(-1)), but closely matched with the lately reported values (Rajendran, Tao, Nakazato and Miyazaki, Analyst, 2000, 125, 1757: 0.62 +/- 0.02 microg g(-1); Chiron, Roy, Cottier and Jeannot, J. Chromatogr. A, 2000, 879, 137: 0.634 +/- 0.082 microg g(-1); Alonso, Encinar, Gonzalez and Sanz-Medal, Anal. Bioanal. Chem., 2002, 373, 432: 0.64 +/- 0.04 microg g(-1). The present method is concluded to be reliable for the determination of MBT, DBT, and TBT in sediment.
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PMID:Species-specific isotope dilution analysis of mono-, di, and tri-butyltin compounds in sediment using gas chromatography-inductively coupled plasma mass spectrometry with synthesized 118Sn-enriched butyltins. 1270 86

A method for determination of riboflavin in animal feeds using liquid chromatography (LC) was developed for feed samples fortified with riboflavin at 1 mg/lb or greater (up to 10,000 mg/lb). Feed samples were extracted in 0.1 N HCl with heating on a steam bath for 30 min, followed immediately by mechanical shaking for 30 min. Sample extracts were diluted to target volume with 2% acetic acid and filtered; riboflavin was determined by LC on a reversed-phase C18 column with 2% acetic acid-acetonitrile (85 + 15) mobile phase for separation and fluorescence detection with excitation at 460 nm and emission at 530 nm. The extraction was compared with that of the AOAC Official Method for riboflavin in food and feed premixes. The 2 method extractions were not significantly different from each other at the 95% confidence level. The developed method also had good linearity over 4 orders of magnitude, recovery of 95-99% from spiked feed samples, a limit of detection of riboflavin at 0.00034 microg/mL in solution, a limit of quantitation of 0.023 mg/lb in feed, and good ruggedness.
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PMID:Reversed-phase liquid chromatographic determination of riboflavin in feeds. 1272 5

The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.
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PMID:Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent. 1279 25

A convenient method was developed for determination of sulfathiazole (STZ) in Type C medicated swine feed by reversed-phase liquid chromatography (LC) with post-column derivatization. Addition of extractant solution (0.2N HCl and 1.5% diethylamine in 25% methanol) and an internal standard (IS), sulfamethylthiazole (SMZ), to 5 g sample was followed by mechanical shaking for 1 h. The extract was clarified by chilling, centrifugation, and filtering before injection onto a C18 reversed-phase column. The mobile phase components were 2% acetic acid and 1:1 acetonitrile-methanol (83 + 17%, v/v). Run time was about 20 min. Determination and, largely, the method's selectivity were based on detection at 450 nm of the derivative formed by the post-column reaction of dimethylaminobenzaldehyde with the primary amine of the analyte and IS. The IS, SMZ, differs from STZ by a single substituent methyl group, is stable, and is readily resolved from STZ. Although SMZ is not commercially available, it can be synthesized with relative ease from purchased reagents and will be supplied by the authors to interested laboratories. In single-laboratory validation, linearity was demonstrated over the range of 0.055-550 microg/mL, well beyond the target concentration of 5.5 microg/mL. The estimated limit of detection was 0.04 microg/mL; the calculated limit of quantitation was 0.13 microg/mL (feed concentration of 2.4 g/T or 2.7 mg/kg). Wet-spiking trials with a variety of swine feed matrixes showed recovery to be 100-102% for the intended concentration range, 50-200 g/T, with coefficient of variation (CV) < 2%. The method ruggedness was verified with an overall CV of 2.9%.
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PMID:Determination of sulfathiazole in type C medicated swine feed by reversed-phase liquid chromatography with post-column derivatization. 1450 17

Citalopram, a serotonin reuptake inhibitor (SSRI) is one of the widely used antidepressants. Apart from its antidepressant activity citalopram is also used for anxiety, panic disorders, obsessive-compulsive disorder and behavioral disturbances of dementia. Tremor is the second most common neurological adverse effect in patients receiving treatment with SSRIs. Use of these agents in depressed patients with essential tremor has not been studied. The present study was undertaken to investigate the effect of chronic citalopram treatment on harmaline-induced tremors in rats. Female Sprague-Dawley rats weighing 70+/-2 g were given citalopram in doses of 0, 10, 20 and 40 mg/kg by gavage for 2 weeks. On the 15th day, the rats were given harmaline (10 mg/kg, i.p.) 30 min after the last dose of citalopram. The latency of onset, intensity and duration of tremor and EMG were recorded. Serotonin (5HT) and 5-hydroxy indole acetic acid (5HIAA) were measured in brain stem. Citalopram dose dependently exacerbated the duration, intensity and amplitude of EMG of harmaline-induced tremor. A significant decrease in 5HT turnover (5HIAA/5HT ratio) in the brain stem was observed suggesting a possible role of serotoninergic impairment in citalopram-induced augmentation of harmaline-induced tremor. Clinical implications of these observations warrant further investigation.
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PMID:Citalopram, a selective serotonin reuptake inhibitor augments harmaline-induced tremor in rats. 1521 2

The abilities of various extractants to recover four arsenic species [As(iii), As(v), dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA)] from soils spiked with 20 micro g g(-1) As were investigated. The extractants were water, buffer solutions (citrate and ammonium dihydrogen phosphate), acidic solutions (phosphoric acid and acetic acid), a basic solution (sodium hydroxide) and household chemicals (vinegar and Coca Cola). Gentle shaking at room temperature with each extractant for 24 h gave different recoveries for the different arsenic species. With 0.1 M NaOH solution 46% As(iii), 53% DMA, 100% MMA and 84% As(v) were recovered. A rapid extraction procedure using a sonicator probe has been developed to obtain higher extraction efficiencies. Extracts of arsenic-spiked soil, SRM 2711 Montana soil and SRM 2709 San Joaquin soil were analyzed by HPLC-ICP-MS. In the SRM water extracts, DMA and MMA were identified in addition to inorganic arsenic. The solution detection limits (3s) were 0.1, 0.12, 0.13 and 0.15 ng mL(-1) for As(iii), DMA, MMA and As(v), respectively for HPLC-ICP-MS.
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PMID:Extraction of arsenic species from spiked soils and standard reference materials. 1528 14

A modification that entails the use of buffering during extraction was made to further improve results for certain problematic pesticides (e.g., folpet, dichlofluanid, chlorothalonil, and pymetrozine) in a simple, fast, and inexpensive method for the determination of pesticides in produce. The method, known as the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method for pesticide residues in foods, now involves the extraction of the sample with acetonitrile (MeCN) containing 1% acetic acid (HAc) and simultaneous liquid-liquid partitioning formed by adding anhydrous MgSO4 plus sodium acetate (NaAc). The extraction method is carried out by shaking a centrifuge tube which contains 1 mL of 1% HAc in MeCN plus 0.4 g anhydrous MgSO4 and 0.1 g anhydrous NaAc per g sample. The tube is then centrifuged, and a portion of the extract is transferred to a tube containing 50 mg primary secondary amine sorbent plus 150 mg anhydrous MgSO4/mL of extract. After a mixing and centrifugation step, the extract is transferred to autosampler vials for concurrent analysis by gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/tandem mass spectrometry. Independent of the original sample pH, the use of buffering during the extraction yields pH <4 in the MeCN extract and >5 in the water phase, which increases recoveries of both acid- and base-sensitive pesticides. The method was evaluated for 32 diverse pesticides in different matrixes, and typical percent recoveries were 95 +/- 10, even for some problematic pesticides. Optional solvent exchange to toluene prior to GC/MS analysis was also evaluated, showing equally good results with the benefit of lower detection limits, but at the cost of more time, material, labor, and expense.
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PMID:Use of buffering and other means to improve results of problematic pesticides in a fast and easy method for residue analysis of fruits and vegetables. 1585 90

Imipramine is a well-established tricyclic antidepressant which was first approved for the treatment of depression in the late fifties. Antidepressant effect of imipramine is attributed to inhibition of serotonin (5HT) and noradrenaline (NA) reuptake in brain. These monoamines have been implicated in a variety of neurological disorders including tremor. In the present investigation attempt was made to study the effect of imipramine on harmaline-induced tremor in rats. Male Sprague Dawley rats weighing 115+/-2.5 g were given harmaline (10 mg/kg, i.p.) alone or along with imipramine (30 min before harmaline) in doses of 60 and 90 mg/kg respectively. The latency of onset, intensity and duration of tremor and EMG were recorded. To substantiate the role of 5HT in aetiopathology of tremor the above experiment was repeated in the rats pretreated with P-chlorophenylalanine (PCPA), a potent 5HT depleter. The levels of 5HT and 5-hydroxyindole acetic acid (5HIAA) in the brain stem were measured using high performance liquid chromatography. Imipramine dose-dependently exacerbated the duration, intensity and amplitude of EMG following harmaline-induced tremor. Imipramine treatment further decreased harmaline-induced 5HT turnover in the brain stem. However, this was statistically insignificant. Depletion of 5HT produced a significant reduction in the intensity and duration of harmaline-induced tremor. In conclusion, this study suggests that imipramine exacerbates harmaline-induced tremor. Clinical use of imipramine for the treatment of depression in patients who also suffer from tremors may require a close monitoring.
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PMID:Exacerbation of harmaline-induced tremor by imipramine. 1589 58

Azospirillum brasilense, a nitrogen-fixing bacterium found in the rhizosphere of various grass species, was investigated to establish the effect on plant growth of growth substances produced by the bacteria. Thin-layer chromatography, high-pressure liquid chromatography, and bioassay were used to separate and identify plant growth substances produced by the bacteria in liquid culture. Indole acetic acid and indole lactic acid were produced by A. brasilense from tryptophan. Indole acetic acid production increased with increasing tryptophan concentration from 1 to 100 mug/ml. Indole acetic acid concentration also increased with the age of the culture until bacteria reached the stationary phase. Shaking favored the production of indole acetic acid, especially in a medium containing nitrogen. A small but biologically significant amount of gibberellin was detected in the culture medium. Also at least three cytokinin-like substances, equivalent to about 0.001 mug of kinetin per ml, were present. The morphology of pearl millet roots changed when plants in solution culture were inoculated. The number of lateral roots was increased, and all lateral roots were densely covered with root hairs. Experiments with pure plant hormones showed that gibberellin causes increased production of lateral roots. Cytokinin stimulated root hair formation, but reduced lateral root production and elongation of the main root. Combinations of indole acetic acid, gibberellin, and kinetin produced changes in root morphology of pearl millet similar to those produced by inoculation with A. brasilense.
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PMID:Plant Growth Substances Produced by Azospirillum brasilense and Their Effect on the Growth of Pearl Millet (Pennisetum americanum L.). 1634 72


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