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PubMed2003

UV solvatochromic shifts of 4-hydroxy-benzophenone and 2,4-dihydroxy-benzophenone in ethanol-acetonitrile mixtures.

The anomalous UV spectroscopic behavior of 4-hydroxy-benzophenone and 2,4-dihydroxy-benzophenone in ethanol-acetonitrile mixtures has been investigated using theoretical and experimental methods. Band I of these compounds, associated to strong pi-->pi* transitions, suffers a blue shift when the polarity of the ethanol-acetonitrile solutions increases. The magnitude of the solvatochromic shifts suffered by the analyzed benzophenones (BPs) changes inversely with the planarity of their molecules. The experimental solvatochromic shifts of the compounds were correlated with the permittivity and the solvation parameters alpha and pi* that characterize the ethanol-acetonitrile mixtures used. In order to explain theoretically the observed solvatochromic shifts, it was proposed that in solution, the two compounds form an association complex of stoichiometry 1:1 with a molecule of ethanol. These complexes are formed by means of an intermolecular hydrogen bond between the hydrogen atom of 4-OH group of the solutes and the oxygen atom of ethanol. The calculations performed at the HRF/6-31G(d) level of theory using Onsager's and Tomasi's models showed that these solute-ethanol association complexes have an elevated thermodynamic stability. Good linear relations were obtained between the experimental absorption frequencies of BPs and the theoretical absorption frequencies of the association complexes. These frequencies were also very satisfactorily correlated with the properties of the above mentioned ethanol-acetonitrile mixtures. It was concluded that the magnitude of the analyzed solvatochromic shifts is determined by the degree of occurrence of solute-solvent interactions, which essentially depend on the polarity, polarizability and hydrogen bond donating ability of the ethanol-acetonitrile mixtures.

Acetonitriles↗
PubMed2004

Effects of estradiol, benzophenone-2 and benzophenone-3 on the expression pattern of the estrogen receptors (ER) alpha and beta, the estrogen receptor-related receptor 1 (ERR1) and the aryl hydrocarbon receptor (AhR) in adult ovariectomized rats.

The estrogen receptors (ERs) are members of a super family of ligand-activated transcription factors mediating estrogenic responses. A close functional kinship was found for the structurally related estrogen receptor-related receptor1 (ERR1), a constitutively active transcription factor. The aryl hydrocarbon receptor (AhR) mediates the toxic and estrogenic effects of a wide variety of environmental contaminants and industrial pollutants. Both the ERR1 and the AhR are known to modulate the ER's signalling pathways in multiple ways. Organic chemicals with a certain structural relationship to steroid hormones often induce a tissue- or cell-specific variety of responses distinct from estrogenic responses and this may involve ERR1 and AhR. The UV-screens benzophenone-2 and benzophenone-3 (BP2, BP3), structurally related to known steroid receptor ligands, are used in cosmetics and plastics to improve product stability and durability. Both BP2 and BP3 were shown to exert uterotrophic effects and BP2 was shown to bind to the estrogen receptors. Whether such effects are also exerted in other organs is unknown. Therefore, an approach to a multi-organic risk assessment for these substances was made by measuring the gene-expression of the four mentioned receptors in the pituitary, the uterus and the thyroid after a five-day treatment in comparison to estradiol. Though BP2 seems to exert an estrogen-like effect while BP3 does not, there are regulatory effects on receptor expression for both substances that indicate a kind of endocrine disruption that is not assessed by "classical" estrogenic markers.

Animals↗
PubMed1990

Benzophenone dicarboxylic acid antagonists of leukotriene B4. 1. Structure-activity relationships of the benzophenone nucleus.

A series of lipophilic benzophenone dicarboxylic acid derivatives was prepared which inhibited the binding of the potent chemotaxin leukotriene B4 to its receptor(s) on intact human neutrophils. With a radioligand-binding assay as a measure of receptor affinity, a structure-activity relationship for this series was investigated. Both acidic residues were required for receptor-binding activity. The relative orientation of the two acidic groups was important for optimal binding. Replacement of the carbonyl group of the benzophenone with a variety of polar and nonpolar linking groups led to only small changes in binding affinity, indicating the linking group may not be involved in receptor recognition. Further structure-activity relationships within this series are reported in an accompanying paper.

Benzophenones↗
PubMed1976

Synthesis and pharmacology of novel anxiolytic agents derived from 2-[(dialkylamino)methyl-4H-triazol-4-yl] benzophenones and related heterocyclic benzophenones.

A series of novel [(dialkylamino)methyl-4H-1,2,4-triazol-4-yl]benzophenones and related compounds has been prepared via total synthesis from substituted aminodiphenylmethanes or by hydrolysis and subsequent methylation of triazolobenzodiazepines. These new triazole compounds were found to have potent sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes). In addition, the title compounds antagonized the clonic convulsions induced in mice by the administration of pentylenetratrazole (Metrazol, 85 mg/kg), with ED50's varying from 2.0 to 23.0 mg/kg, and the lethality induced by thiosemicarbazide, with ED50's varying from 0.02 to 9.0 mg/kg. In several biological tests, the potency of seven new benzophenone derivatives approached or exceed that of diazepam (35a) or its glycylaminobenzophenone analogue 36.

Animals↗
PubMed1982

Simultaneous determination of triazolo-benzophenone [2',5-dichloro-2-(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone] and its major blood metabolite, triazolam, in monkey plasma by electron-capture gas--liquid chromatography.

A gas--liquid chromatographic method for the simultaneous determination of triazolo-benzophenone [2',5-dichloro-2-(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone. TB] and its major blood metabolite, triazolam, 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]fenzodiazepine (TZ), in monkey plasma was developed. Decomposition of TB was observed during gas--liquid chromatography. In alkaline medium, TB in plasma was submitted to ring closure reaction to yield triazolo-aminoquinoline, [4-amino-7-chloro-5-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a]quinoline (TAQ), while TZ remained unaffected, and TAQ and TZ in the benzene extract were assayed by gas--liquid chromatography using an electron-capture detector. The concentration ranges studied were from 5 to 40 ng of TB per 0.5 ml of plasma and from 2 to 20 ng of TZ per 0.5 ml of plasma. This method could be applied to the determination of the plasma levels of TB and TZ in monkeys following intravenous administration of a single 0.2 mg/kg dose of TB.

Animals↗
PubMed1992

[Anti-arrhythmic action of some amidinohydrazone substituted benzophenones. 1. Synthesis of new amidinohydrazone and N-phenylamidinohydrazone substituted benzophenones].

The title compounds are synthesized as a rule by condensation of substituted benzophenones and derivatives of aminoguanidine in the presence of up to 2.5 moles of an anorganic acid. They can be obtained alternatively via corresponding hydrazones, thiosemicarbazones or methylthiothiocarbonylhydrazones.

Anti-Arrhythmia Agents↗
PubMed2006

Toxicology and carcinogenesis studies of benzophenone (CAS No. 119-61-9) in F344/N rats and B6C3F1 mice (feed studies).

UNLABELLED: Benzophenone is used as a photoinitiator, a fragrance enhancer, an ultraviolet curing agent, and occasionally as a flavor ingredient; it is also used in the manufacture of insecticides, agricultural chemicals, and hypnotics, antihistamines, and other pharmaceuticals; and it is used as an additive in plastics, coatings, and adhesive formulations. Benzophenone was nominated for study by the National Institute of Environmental Health Sciences based on its potential for occupational and consumer exposure and the lack of long-term toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to benzophenone (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse bone marrow cells, and mouse peripheral blood erythrocytes. Results of 14-week toxicity studies in F344/N rats and B6C3F1 mice were reported earlier (NTP, 2000). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 15, 30, and 60 mg benzophenone/kg body weight to males and 15, 30, and 65 mg/kg to females) for 105 weeks. Survival of 1,250 ppm males was significantly less than that of controls. Mean body weights of 1,250 ppm males were markedly less than those of the controls during year 2 of the study, and weights of exposed females were consistently less than controls throughout the study. Feed consumption by 1,250 ppm males was less than that by the controls after week 70; feed consumption by 1,250 ppm females was generally less than that by the controls throughout the study. There was a positive trend in the incidences of renal tubule adenoma in males, and the incidences in 625 and 1,250 ppm males exceeded the historical control range for all routes; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Due to these findings, additional kidney sections were evaluated; results indicated additional renal tubule adenomas in all groups of males and renal tubule hyperplasia in all groups of males and females. The incidences of pelvic transitional epithelium hyperplasia and the severity of nephropathy were significantly increased in all exposed groups of male rats. Increased incidences of mononuclear cell leukemia in all exposed groups of females exceeded the historical control range from feed studies, and the incidence in 625 ppm females was significantly greater than that in the controls. Male rats exposed to 312 or 625 ppm had significantly increased incidences of mononuclear cell leukemia. One 625 ppm female and two 1,250 ppm females had histiocytic sarcomas, and the incidence in the 1,250 ppm group exceeded the range in the historical controls. Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1,250 ppm males, and bile duct hyperplasia in all exposed groups of females. Incidences of mammary gland fibroadenoma in females exposed to 625 or 1,250 ppm were lower than expected after adjusting for body weight. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg body weight to males and 35, 70, and 150 mg/kg to females) for 105 weeks. Survival of all exposed groups of mice was generally similar to that of the control groups. Mean body weights of exposed females were less than vehicle controls. Feed consumption by exposed males and females was similar to that by the controls. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups, and these incidences exceeded the historical control range. All hepatocellular neoplasms combined occurred with a positive trend. In female mice, the incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. Incidences of centrilobular hepatocyte hypertrophy were significantly increased in all exposed groups of males and females. All exposed groups of male mice had significant increases in the incidences of multinucleated hepatocytes and chronic active inflammation. The incidences of cystic degeneration of hepatocytes in 625 and 1,250 ppm males were significantly increased. The incidence of histiocytic sarcoma in 625 ppm females was significantly increased and exceeded the historical control range. The incidences of kidney nephropathy and mineralization in exposed groups of females and the severity of nephropathy in exposed groups of males were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1,250 ppm males and females. The incidences of hyperplasia of lymphoid follicles in the spleen were significantly increased in all exposed groups of males and in 312 and 625 ppm females. GENETIC TOXICOLOGY: Benzophenone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without hamster or rat liver activation enzymes. No significant increases in the frequencies of micronucleated polychromatic erythrocytes were seen in bone marrow samples from male mice administered benzophenone three times by intraperitoneal injection. In addition, no increases in micronucleated normochromatic erythrocytes were noted in peripheral blood of male or female mice administered benzophenone for 14 weeks in dosed feed. CONCLUSIONS: Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma; mononuclear cell leukemia in male F344/N rats may have been related to benzophenone exposure. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginally increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F1 mice may have been related to benzophenone exposure. Administration of benzophenone in feed resulted in increased incidences and/or severities of nonneoplastic lesions in the kidney and liver of male and female rats and in the liver, kidney, nose, and spleen of male and female mice. Decreased incidences of mammary gland fibroadenoma in female rats were related to benzophenone exposure.

Animals↗
PubMed2000

NTP technical report on the toxicity studies of benzophenone (CAS No. 119-61-9). Administered in feed to F344/N rats and B6C3F mice.

Benzophenone is used as a photoinitiator, a fragrance enhancer, an ultraviolet curing agent, and, occasionally, as a flavor ingredient; it is also used in the manufacture of insecticides, agricultural chemicals, and pharmaceuticals and is an additive for plastics, coatings, and adhesives. In 14-week studies conducted to determine the toxicity of benzophenone, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm benzophenone in feed. These exposure concentrations resulted in the following average daily doses: 75, 150, 300, 700, or 850 mg benzophenone per kilogram body weight for male rats; 80, 160, 300, 700, or 1,000 mg/kg for female rats; 200, 400, 800, 1,600, or 3,300 mg/kg for male mice; and 270, 540, 1,000, 1,900, or 4,200 mg/kg for female mice. Animals were evaluated for clinical pathology, reproductive system effects, liver cytochrome P450 effects, and histopathology. Genetic toxicity studies were conducted in Salmonella typhimurium and mouse bone marrow polychromatic erythrocytes. Benzophenone was unpalatable at 20,000 ppm. All 20,000 ppm rats had significant body weight loss and were terminated for humane reasons before the end of studies. All male mice and four female mice in the 20,000 ppm group died. There was no exposure-related mortality in the remaining groups. Significantly decreased body weights relative to the controls were observed in all exposed groups of female rats and all exposed groups of male rats except the 1,250 ppm group. Lower body weights were apparent in 10,000 ppm male mice and in 5,000 ppm or greater female mice. In rats, the liver and kidney were identified as target organs of benzophenone toxicity. Treatment-related increases in liver weights were attributed to hypertrophy and/or cytoplasmic vacuolization of hepatocytes. Increased kidney weights were associated with a spectrum of renal changes in exposed males and females. Unique lesions observed in animals that died early as well as in survivors were well demarcated, wedge-shaped areas of prominent tubule dilatation. The lesion occurred in 2,500 ppm or greater males and in 10,000 and 20,000 ppm females. Foci of tubule regeneration were increased relative to the controls in exposed males and females. In exposed mice, significant microscopic findings were limited to centrilobular hypertrophy in the liver that corresponded to increased liver weights. The severity of hepatocyte hypertrophy was exposure-concentration dependent, with marked severity in all 20,000 ppm animals. Clinical chemistry analyses confirmed liver toxicity. In rats, increases in serum bile salt concentrations indicated cholestatic liver disease. On day 22, a 15-fold increase was evident in the 20,000 ppm groups, and at week 14, a twofold increase was seen in the 10,000 ppm groups. Increases in alanine aminotransferase and sorbitol dehydrogenase activities were mild in mice; however, more convincing of liver damage were increased alkaline phosphatase activities and serum bile salt concentrations, especially in 20,000 ppm females. Biochemical data indicated that benzophenone was a relatively potent inducer of the phenobarbital-type (2B) cytochrome P450 enzymes. Overall, induction was greater in rats than in mice. The gross (increased organ weights) and microscopic (hepatocellular hypertrophy) liver changes associated with benzophenone administration in rats and mice accompanied benzophenone-induced increases in pentoxyresorufin dealkylase activity. Benzophenone was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537, with or without S9 activation, and it did not induce micronuclei in bone marrow erythrocytes of male mice administered benzophenone by intraperitoneal injection. In conclusion, the liver is the primary target organ of benzophenone toxicity in rats and mice based on increases in liver weights, hepatocellular hypertrophy, clinical chemistry changes, and induction of liver microsomal cytochrome P450 2B isomer. The kidney was also identified as a target organ of benzophenone toxicity in rats only, based on exposure concentration-related increases in kidney weights and microscopic changes. The no-observed-adverse-effect level for benzophenone was not achieved in these studies.

Animals↗
PubMed2002

Experimental study on phototoxicity and the photosensitization potential of ketoprofen, suprofen, tiaprofenic acid and benzophenone and the photocross-reactivity in guinea pigs.

BACKGROUND: Ketoprofen, suprofen and tiaprofenic acid are arylpropionic anti-inflammatories. Their chemical structures share the same elements as the benzoyl radical and the tiophene ring. We experienced nine cases of ketoprofen photoallergy, seven cases of suprofen photoallergy and three cases of tiaprofenic photoallergy. PURPOSE: To find the key structure of photosensitivity and photocross-reactivity to ketoprofen, suprofen and tiaprofenic acid. METHODS: : Three animals were tested for phototoxicity and six animals for the photosensitization potentials of ketoprofen, suprofen, tiaprofenic acid and benzophenone, and the photocross-reactivity of the above chemicals. Test substances were applied symmetrically on both sides of the animals' backs. The animals were irradiated with 180 mJ/cm2 UVB ((1/2) MED) and 10 J/cm2 UVA on the left side. The reactions were read on days 2, 3 and 4. The photosensitization potentials of ketoprofen, suprofen, tiaprofenic acid and benzophenone were determined using the Adjuvant-Strip method. Six animals were assigned to each test group and to a control group. RESULTS: Ketoprofen, suprofen, tiaprofenic acid and propionic acid showed negative reactions with the phototoxic test. Benzophenone showed phototoxic reactions to 40% acetone (ac.), 20% ac. and 10% ac. Therefore, we used 5% aq. benzophenone with the photosensitization test. Ketoprofen was the strongest photosensitizer (6/6) and showed photocross-reactivities to suprofen (2/6), tiaprofenic acid (3/6) and benzophenone (6/6). Suprofen was a strong photosensitizer (4/6) and showed photocross-reactivities to ketoprofen (1/4) and tiaprofenic acid (2/4), but not to benzophenone. Tiaprofenic acid was also a photosensitizer (2/6) but showed a photocross-reactivity only to benzophenone (2/2). Benzophenone was also the strongest photosensitizer (6/6), but did not photocross-react to the above three chemicals. CONCLUSION: From the test results, it appears that benzoyl radical is the key structure for photosensitivity and the photocross-reactivity of ketoprofen, suprofen and tiaprofenic acid. The whole structure of benzophenone was needed to induce photosensitization of benzophenone. The animals that were photosensitized from the entire structure of benzophenone did not photocross-react to ketoprofen, suprofen or tiaprofenic acid.

Animals↗
PubMed2006

Surface photochemistry: benzophenone as a probe for the study of silica and reversed-phase silica surfaces.

This work reports the use of benzophenone, a very well characterized probe, to study new hosts: two reversed-phase silicas. Laser-induced room temperature luminescence of argon purged solid powdered samples of benzophenone adsorbed onto the two different reversed-phase silicas, RP-18 and RP-8, revealed the existence of a low energy emission band in contrast with the benzophenone adsorbed on 60 A pore silica, where only triplet benzophenone emits. This low energy emission band was identified as the fluorescence of the ketyl radical of benzophenone, which is formed as the result of a hydrogen atom abstraction reaction of the triplet excited benzophenone from the alkyl groups of the surface of the reversed silicas. Such emission does not exist for benzophenone adsorbed onto 60 A pore silica. Room temperature phosphorescence was obtained in argon purged samples for all the surfaces under use. The decay times of the benzophenone emission vary greatly with the alkylation of the silica surface when compared with "normal" silica surface. A lifetime distributions analysis has shown that the shortest lifetimes for the benzophenone emission exist in the former case. Triplet-triplet absorption of benzophenone was detected in all cases and is the predominant absorption in the case of 60 A pore silica, while benzophenone ketyl radical formation occurs in the case of the reversed silicas. Diffuse reflectance laser flash photolysis and gas chromatography-mass spectrometry techniques provided complementary information, the former about transient species and the latter regarding the final products formed after laser irradiation, both at 266 nm or 355 nm. Product analysis and identification show that the degradation photoproducts are dependent on the excitation wavelength, the photochemistry being much more rich and complex in the 266 nm excitation case, where an alpha-cleavage reaction occurs. A detailed mechanistic analysis is proposed.

Journal Article↗
PubMed2006

Carcinogenesis studies of benzophenone in rats and mice.

Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and B6C3 F1 mice were fed diets containing 0, 312, 625, and 1250 ppm benzophenone for 105 weeks. Survival of males exposed to 1250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1250 ppm groups. Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F(1) mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F(1) mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F(1) mice may have been related to benzophenone exposure.

Adenoma↗
PubMed2003

Benzophenone in cartonboard packaging materials and the factors that influence its migration into food.

Benzophenone may be present in cartonboard food-packaging materials as a residue from UV-cured inks and lacquers used to print on the packaging. It may also be present if the cartonboard is made from recycled fibres recovered from printed materials. A method has been devised to test for benzophenone in cartonboard packaging materials and to test for migration levels in foodstuffs. Packaging is extracted with solvent containing d10-benzophenone as the internal standard. Foods are extracted with solvent containing d10-benzophenone and the extract defatted using hexane. The extracts are analysed by GC-MS. For analysis of food, the limit of detection was 0.01 mg x kg(-1) and the limit of quantification was 0.05 mg x kg(-1). The calibration was linear from 0.05 to 20 mg x kg(-1). The method for food analysis was validated in-house and it also returned satisfactory results in a blind check-sample exercise organized by an independent laboratory. The methods were applied to the analysis of 350 retail samples that used printed cartonboard packaging. A total of 207 (59%) packaging samples had no significant benzophenone (<0.05 mg x dm(-2)). Seven (2%) were in the range 0.05- 0.2 mg x dm(-2), 60 (17%) were from 0.2 to 0.8 mg x dm(-2) and 76 (22%) were from 0.8 to 3.3 mg x dm(-2). A total of 71 samples were then selected at random from the 143 packaging samples that contained benzophenone, and the food itself was analysed. Benzophenone was detected in 51 (72%) of the foods. Two food samples (3%) were in the range 0.01-0.05 mg kg(-1). A total of 29 (41%) were from 0.05 to 0.5 mg kg(-1), 17 (24%) were from 0.5 to 5 mg x kg(-1) and three (4%) food samples exceeded 5 mg x kg(-1). The highest level of benzophenone in food was 7.3 mg x kg(-1) for a high-fat chocolate confectionery product packaged in direct contact with cartonboard, with room temperature storage conditions and with a high contact area:food mass ratio. When the mass fraction of benzophenone migration was calculated for the different contact and storage regimes involved, the attenuation effects of indirect contact and of low temperature storage were cumulative. Thus, there was a sixfold reduction in migration for indirect contact compared with direct contact, a sixfold reduction for chilled/frozen storage compared with ambient storage, and 40-fold reduction for the two contact conditions combined.

Benzophenones↗
PubMed2002

Genotoxic activation of benzophenone and its two metabolites by human cytochrome P450s in SOS/umu assay.

The genotoxic potential of benzophenone and its metabolically related compounds, benzhydrol and p-benzoylphenol, was investigated using human cytochrome P450 (P450) enzymes. Benzophenone and its two metabolites (0.1-1mM) showed a suppression of bacterial growth without any P450 system, but no induction of umu gene expression was observed in Salmonella typhimurium TA1535/pSK1002. Human liver microsomes induced the bacterial cytotoxicity of these compounds without any umu gene expression. On the other hand, with the addition of Escherichia coli membranes expressing recombinant human P450 2A6 and NADPH-cytochrome P450 reductase (NPR), benzophenone showed umu gene expression (64 umu units/min/nmol) P450 2A6). Moderate activation of benzophenone by P450 1A1/NPR membranes, 1A2/NPR membranes, or 1B1/NPR membranes was also observed. Activation of benzhydrol and p-benzoylphenol by the P450/NPR system was similar to that of benzophenone. These results suggest that benzophenone and its metabolically related benzhydrol and p-benzoylphenol can be bioactivated by P450 2A6 and P450 family 1 enzymes. Until now, benzophenone has been investigated mainly in terms of estrogenic activity and cytotoxicity, however, the genotoxic activation of benzophenone by human cytochrome P450s should be examined in terms of the risks to humans.

Animals↗
PubMed2002

Benzophenone-induced estrogenic potency in ovariectomized rats.

To assess the estrogenic potency of benzophenone by in-vivo uterotrophic assay, we gave orally either the compound (100 or 400 mg/kg) or 17beta-estradiol (0.2 mg/kg) as a positive control, once per day for 3 days, to ovariectomized Sprague-Dawley (SD) rats, and all rats were killed 24 h after being given the last dose. The high dose of benzophenone elicited an approximately 1.9-fold increase in absolute and relative uterine weight, and 17beta-estradiol increased uterine weight approximately fivefold relative to the control. The uterine response caused by both compounds was accompanied by an increase in luminal epithelium height and stromal cell numbers in the uterus and an increase in the thickness of vaginal epithelium cell layers with cornification. At 24 h after the last dose, the mean serum concentrations of benzophenone, benzhydrol and p-hydroxybenzophenone in the high-dosed rats were 10.4+/-1.0, 1.5+/-0.3, and 0.7+/-0.2 (mean +/- SE) micro mol/l, respectively, whereas in the serum of low-dosed rats these compounds were not detected. When a single oral administration of benzophenone (100 or 400 mg/kg) was given to intact female rats, serum concentrations of benzophenone, benzhydrol and p-hydroxybenzophenone increased in a dose-dependent manner 6 h later. Previously, Nakagawa et al. (2000) and Nakagawa and Tayama (2001) reported that the subcutaneous injection of p-hydroxybenzophenone into juvenile female rats elicited estrogenic activity in reproductive organs, whereas neither benzophenone nor benzhydrol had such an effect. In addition, p-hydroxybenzophenone itself rather than the parent compound caused a proliferation of estrogen receptor-positive MCF-7 cells in vitro. Based on these findings, it is apparent that the pro-estrogenic compound benzophenone requires biotransformation to p-hydroxybenzophenone, a metabolite with intrinsic hormonal activity.

Administration, Oral↗
PubMed2000

Metabolism and toxicity of benzophenone in isolated rat hepatocytes and estrogenic activity of its metabolites in MCF-7 cells.

The metabolism and cytotoxicity of benzophenone and estrogenic activity of its metabolites have been studied in freshly isolated rat hepatocytes and cultured MCF-7 human breast cancer cells, respectively. The incubation of hepatocytes with benzophenone (0.25-1.0 mM) elicited a concentration- and time-dependent cell death, accompanied by loss of intracellular ATP and depletion of adenine nucleotide pools. Benzophenone at a low-toxic level (0.25 mM) in the hepatocyte suspensions was converted to benzhydrol, p-hydroxybenzophenone and its sulfate conjugate, without marked loss of cell viability. The amounts of benzhydrol and sulfate conjugate increased with time. In contrast, addition of 2,6-dichloro-4-nitrophenol (an inhibitor of sulfotransferase; 0.1 mM), nontoxic to hepatocytes during the incubation period, enhanced benzophenone-induced cytotoxicity, and this effect was accompanied by a decrease in the formation of sulfate conjugate and increase in the amount of free p-hydroxybenzophenone. In another experiment, MCF-7 cells, estrogen-responsible breast cancer cells were cultured in estradiol free medium and then exposed to 10 nM-500 microM benzophenone or its metabolites for 6 days. Although at higher concentrations all the compounds were toxic, except for benzophenone and benzhydrol, 10-100 microM p-hydroxybenzophenone significantly increased cell proliferation. These results indicate that benzophenone is enzymaticaly converted to benzhydrol, p-hydroxybenzophenone and its sulphate conjugate in rat hepatocytes. Even if there is less free p-hydroxybenzophenone than benzhydrol and sulfate conjugate in hepatocyte suspensions, p-hydroxybenzophenone itself acts as a weak xeno-estrogen on MCF-7 cells.

Animals↗