2,2'-Dihydroxy-4,4'-dimethoxybenzophenon

2,2'-Dihydroxy-4,4'-dimethoxybenzophenone was present at a mean concentration of 0.11 ng/mL in 2 of 34 urine samples from Tunisian women, collected from May to October 2012(1). The compound was tested for but not detected in urine samples from the general population in Seoul and Gyeonggi province, Korea; sampling was conducted between July and August, 2014(2).

Biomonitoring of human exposure to bisphenol A diglycidyl ethers (BADGEs; resin coating for food cans), p-hydroxybenzoic acid esters (parabens; preservatives), benzophenone-type UV filters (BP-UV filters; sunscreen agents), triclosan (TCS; antimicrobials), and triclocarban (TCC; antimicrobials) has been investigated in western European countries and North America. Nevertheless, little is known about the exposure of Greek populations to these environmental chemicals. In this study, 100 urine samples collected from Athens, Greece, were analyzed by liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of total concentrations of five derivatives of BADGEs, six parabens and their metabolite (ethyl-protocatechuate), five derivatives of BP-UV filters, TCS, and TCC. Urinary concentrations of BADGEs, parabens, ethyl-protocatechuate, BP-UV filters, TCS and TCC (on a volume basis) ranged 0.3-20.9 (geometric mean: 0.9), 1.6-1010 (24.2), <2-71.0 (2.1), 0.5-1120 (4.4), <0.5-2580 (8.0) and <0.5-1.9 (0.6) ng/mL, respectively. All 19 target chemicals were found in urine, and the highest detection rates were observed for methyl paraben (100%), bisphenol A bis (2,3-dihydroxypropyl) ether (90%), ethyl paraben (87%), 2,4-dihydroxybenzophenone (78%), propyl paraben (72%), and TCS (71%). Estimated daily intakes (EDIurine), calculated on the basis of the measured urinary concentrations, ranged from 0.023 ug/kg bw/day for sum5BADGEs to 31.4 ug/kg bw/day for sum6Parabens. /Benzophenones/

LC50; Species: Dugesia japonica (Flatworm); Conditions: freshwater, static; Concentration: 35 mg/L for 24 hr />99% purity/

LC50; Species: Dugesia japonica (Flatworm); Conditions: freshwater, static; Concentration: 14 mg/L for 48 hr (95% confidence interval: 10.9-17.9 mg/L) />99% purity/

LC50; Species: Dugesia japonica (Flatworm); Conditions: freshwater, static; Concentration: 2.1 mg/L for 96 hr (95% confidence interval: 1.7-2.7 mg/L) />99% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 800(SRC), determined from a structure estimation method(2), indicates that 2,2'-dihydroxy-4,4'-dimethoxybenzophenone is expected to have low mobility in soil(SRC). Volatilization of 2,2'-dihydroxy-4,4'-dimethoxybenzophenone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.4X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Utilizing the Modified MITI test, 0% of the Theoretical BOD was reached in 4 weeks(3) indicating that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 800(SRC), determined from a structure estimation method(2), indicates that 2,2'-dihydroxy-4,4'-dimethoxybenzophenone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 45(SRC), from an estimated log Kow of 3.90(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Utilizing the Modified MITI test, 0% of the Theoretical BOD was reached in 4 weeks(5) indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, which has an estimated vapor pressure of 7.4X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 2,2'-dihydroxy-4,4'-dimethoxybenzophenone may be removed from the air by wet and dry deposition(SRC). 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone absorbs UV light at wavelengths of 284 and 340 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Safe in the present practices of use and concentration. Ingredient, concentration, and use information are available in documents discoverable at https://cir-reports.cir-safety.org

IDENTIFICATION AND USE: 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone (Benzophenone-6) is used as a cosmetic ingredient in a range of cosmetic products. HUMAN STUDIES: There are no data available. ANIMAL STUDIES: Benzophenone-6 was hepatotoxic in guinea pigs when given i.p. for 15 days at 5 mg/kg. Benzophenone-6 was nonmutagenic when assayed directly and was mutagenic with metabolic activation in Salmonella strain TA1537. Benzophenone-6 did not induce sister chromatid exchanges in vivo in the bone marrow of Chinese hamsters.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 2,2'-dihydroxy-4,4'-dimethoxybenzophenone can be estimated to be 800(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2,2'-dihydroxy-4,4'-dimethoxybenzophenone is expected to have low mobility in soil(SRC).

2,2'-Dihydroxy-4,4'-dimethoxybenzophenone's production and use as a ultraviolet light absorber with special applications in paints and plastics(1) and limited use as a cosmetic ingredient(2) may result in its release to the environment through various waste streams(SRC).

An estimated BCF of 45 was calculated in fish for 2,2'-dihydroxy-4,4'-dimethoxybenzophenone(SRC), using an estimated log Kow of 3.90(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for 2,2'-dihydroxy-4,4'-dimethoxybenzophenone is estimated as 1.2X10-10 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that 2,2'-dihydroxy-4,4'-dimethoxybenzophenone is expected to be essentially nonvolatile from water and moist soil surfaces(2). 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.4X10-9 mm Hg(SRC), determined from a fragment constant method(1).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The hepatotoxicity of benzophenone /-6/ was studied in guinea-pigs. Male guinea-pigs were injected intraperitoneally with 5 mg/kg benzophenone every day for 15 days and were killed 24 hours after the last injection. Liver sections were examined for histopathological changes. Hepatic glycogen and DNA concentrations were determined by histochemical techniques. Changes in hepatocellular DNA content were used as a marker of mitotic activity. Benzophenone /-6/ induced slight hepatomegaly and nodular cirrhotic lesions. The lobular architecture and hepatic cords were disrupted. The cirrhotic lesions which occurred in the perilobular and centrilobular regions consisted of hepatocellular degeneration, mild fatty changes, and replacement of hepatocytes with connective tissue. Hepatocellular necrosis, seen primarily in the periportal region, also contained areas of regeneration. Proliferation of bile duct epithelial cells was observed. Fibrinous thrombi with significant amounts of leukocyte infiltration were seen in the blood vessels. Macrophages and Kupffer cells containing bile pigments were observed frequently in the sinusoids. Significant depletion of glycogen stores occurred. Biliary epithelial cells showed significantly increased mitotic activity. The authors conclude that benzophenone /-6/ causes unequivocal hepatotoxicity. The increased mitotic activity seen in biliary epithelial cells could indicate incipient hepatocarcinogenesis. Since benzophenone /-6/ is widely used in the perfume industry, long term toxicity studies are needed.

/GENOTOXICITY/ The mutagenicity of Benzophenones-2, -6, and -8 was investigated with the Ames mammalian-microsomal assay. Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were used; all tests were performed. in the presence and absence of Aroclor-induced rat liver microsomal S-9 cell fraction to observe the mutagenic effect of each compound following metabolic activation. Preliminary cytotoxicity studies determined the dose range of each compound to be used. Benzophenones-2, -6, and -8 were nonmutagenic when assayed directly and were mutagenic with metabolic activation in Salmonella strain TA1537. Benzophenone-8 was weakly mutagenic in Salmonella strain TA1537, whereas Benzophenone-6 was determined to be mutagenic at three doses in the same strain.

/GENOTOXICITY/ Female Chinese hamsters were orally administered 62.5-500 mg/kg Benzophenones-2 and -6 in a 10% aqueous acacia solution. The animals were sacrificed, and the frequency of bone marrow SCE exchange was determined. Benzophenones-2 and -6 did not induce SCE in vivo in the bone marrow of Chinese hamsters. Cytotoxicity was not observed with either chemical.

/GENOTOXICITY/ The gradient plate test of McMahon et al., a modification of the Ames test, was used to investigate the effects of Benzophenone-2 and -6 on bacterial mutation. The chemicals were dissolved in DMSO and tested at concentrations of 0.1-1000 ug/mL with and without rat liver S-9 metabolic activation. Benzophenones-2 and -6 were tested with Salmonella typhimurium strains G46, TA1535, TAlOO, C3076, TA1537, D3052, TA1538, and TA98 (histidine auxotrophs) and Escherichia co/i strains WP2 and WP2 uvrA-(tryptophan auxotrophs). Benzophenone-2 inhibited the growth of all the bacterial strains but did not induce mutations with or without metabolic activation. Benzophenone-6 did not inhibit bacterial growth and did not produce mutations in any of the bacterial strains with or without metabolic activation. The induction of unscheduled DNA synthesis (repair synthesis) in primary cultures of adult rat hepatocytes was studied after exposure of the cultures to Benzophenones-2 and -6 dissolved in DMSO and at concentrations of 0.5-1000 nmoles/mL. Cytotoxicity was observed at the 500 and 100 nmoles/mL concentrations of both chemicals. Benzophenones-2 and -6 did not induce DNA repair synthesis.

2,2'-Dihydroxy-4,4'-dimethoxybenzophenone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone absorbs UV light at wavelengths of 284 and 340 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).