Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose.

Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107-164 µg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10-40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17-0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03-0.10%) and 0.05% (0.01-0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5-2.3 h, tmax2 = 3.8-6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1-3.8 h. The majority (98-100%) of metabolites was excreted within 24 h. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 µg/kg bw/day). The highest daily intake (114 µg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.

Di-(2-ethylhexyl) adipate in selected total diet food composite samples.

Polyvinyl chloride (PVC) food-wrapping films plasticized with di-(2-ethylhexyl) adipate (DEHA) are commonly used by grocery stores in Canada to rewrap meat, poultry, fish, cheese, and other foods. DEHA was assessed as part of the Government of Canada's Chemicals Management Plan. The main source of exposure for most age groups was expected to be food. Although the margin of exposure from food and beverages is considered to be adequately protective, the Government of Canada committed to performing targeted surveys of DEHA in foods and food packaging materials to better define Canadian exposure to DEHA through dietary intake. In order to determine whether more-comprehensive targeted surveys on DEHA in foods should be conducted, 26 food composite samples from the 2011 Canadian total diet study were selected and analyzed for DEHA using a method based on solvent and dispersive solid-phase extraction and gas chromatography-mass spectrometry. These 26 food composites include cheese, meat, poultry, fish, and fast foods, and PVC films were likely used in packaging the individual foods used to make the composites. DEHA was detected in most of the meat, poultry, and fish composite samples, with the highest concentration found in ground beef (11 µg/g), followed by beef steak (9.9 µg/g), freshwater fish (7.8 µg/g), poultry liver pâté (7.4 µg/g), fresh pork (6.9 µg/g), cold cuts and luncheon meats (2.8 µg/g), veal cutlets (2.1 µg/g), roast beef (1.3 µg/g), lamb (1.2 µg/g), and organ meats (0.20 µg/g). Targeted surveys should be conducted to investigate the presence of DEHA in various foods packaged with PVC films in more detail and provide updated occurrence data for accurate human exposure assessment.

Effectiveness of various drug carriers in controlled release formulations of raloxifene HCl prepared by melt mixing.

In the present study solid dispersions of Raloxifene HCl were prepared by melt mixing. As drug carriers, biodegradable/biocompatible aliphatic polyesters were used. These formulations were compared to those based on extensively used drug carriers such as PEG and Gelucire 50/13. The used aliphatic polyesters namely poly(propylene succinate) (PPSu) and poly(propylene adipate) (PPAd) were prepared by melt polycondensation. The polyesters have melting points close to human body temperature and were used for first time as drug carries. Polymer cytocompatibility based on HUVEC cells viability in the presence of increasing concentrations of polymer was investigated and it was found that PPSu and PPAd exhibit comparable cytocompatibility with poly(dl-lactide). The physical state of solid dispersions was evaluated by FTIR, SEM and XRD techniques. In all cases the interactions between drug and carriers are limited and thus the dispersed drug was mainly in the crystalline state. SEM revealed that the particles size of the dispersed drug increases with increasing the drug amount. The release behavior of the drug is affected from both the drug amount and the kind of the used carrier. The drug is released almost immediately from PEG formulations while Gelucire results in sustained release. In formulations that polyesters were used as drug carriers the release is slower.

Amended final report of the safety assessment of dibutyl adipate as used in cosmetics.

Dibutyl Adipate, the diester of butyl alcohol and adipic acid, functions as a plasticizer, skin-conditioning agent, and solvent in cosmetic formulations. It is reportedly used at a concentration of 5% in nail polish and 8% in suntan gels, creams, and liquids. Dibutyl Adipate is soluble in organic solvents, but practically insoluble in water. Dibutyl Adipate does not absorb radiation in the ultraviolet (UV) region of the spectrum. Dibutyl Adipate is not toxic in acute oral or dermal animal toxicity tests. In a subchronic dermal toxicity study, 1.0 ml/kg day-1 caused a significant reduction in body weight gain in rabbits, but 0.5 ml/kg/day1 was without effect. In a study with dogs, no adverse effects were observed when an emulsion containing 6.25% Dibutyl Adipate was applied to the entire body twice a week for 3 months. Dibutyl Adipate was tested for dermal irritation using rabbits and mice and a none to minimal irritation was observed. Dibutyl Adipate at a concentration of 25% was not a sensitizer in a guinea pig maximization study. Undiluted Dibutyl Adipate was minimally irritating to the eyes of rabbits and 0.1% was nonirritating. A significant increase in fetal gross abnormalities was observed in rats given intraperitoneal injections of Dibutyl Adipate at 1.75 ml/kg on 3 separate days during gestation, but no effect was seen in animals given 1.05 ml/kg. Dibutyl Adipate was not genotoxic in either bacterial or mammalian test systems. Clinical patch tests confirmed the absence of skin irritation found in animal tests. Clinical phototoxicity tests were negative. Dibutyl Adipate at 0.1% was not an ocular irritant in two male volunteers. In a clinical test of comedogenicity, Dibutyl Adipate produced no effect. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that use of Dibutyl Adipate in suntan cosmetic products will result in repeated, frequent exposure in a leave-on product. The available data demonstrate no skin sensitization or cumulative skin irritation, no comedogenicity, and no genotoxicity. Combined with the data demonstrating little acute toxicity, no skin or ocular irritation, and no reproductive or developmental toxicity, these data form an adequate basis for reaching a conclusion that Dibutyl Adipate is safe as a cosmetic ingredient in the practices of use and concentrations as reflected in this safety assessment.

Effects of perinatal exposure to phthalate/adipate esters on hypothalamic gene expression and sexual behavior in rats.

Our previous research has identified the granulin (grn) and p130 genes as sex steroid-regulated genes in the neonatal rat hypothalamus that might be involved in sexual differentiation of the brain. Since phthalate/adipate esters such as di-n-butyl phthalate (DBP), diisononyl phthalate (DINP), and di-2-ethylhexyl adipate (DEHA) are suspected to interfere with the endocrine system as environmental endocrine disruptors having estrogenic or antiandrogenic properties, these chemicals may affect sexual differentiation of the brain. The present study assessed the effects of perinatal exposure to DBP, DINP, and DEHA on grn and p130 mRNA expressions in the hypothalamus on postnatal day (PND) 7 and sexual behaviors after maturation in rats. Maternal rats were given a phytoestrogen-free diet containing different doses of DBP (20, 200, 2,000, and 10,000 ppm), DINP (40, 400, 4,000, and 20,000 ppm) and DEHA (480, 2,400, and 12,000 ppm) from gestational day 15 to the day of weaning (PND 21). DBP and DINP exposure during the perinatal period resulted in an increase in hypothalamic grn and p130 mRNA levels in females and males, respectively, but DEHA exposure decreased expression levels of grn in males and p130 in females, although the effects were not dose-dependent. After maturation, male rats that were exposed to several doses of DBP, DINP, and DEHA displayed decreased copulatory behavior. The lordosis quotient was decreased in females perinatally exposed to DBP, DINP, and DEHA at all the doses used. On the other hand, serum levels of LH and FSH in both sexes and the estrous cycles in females were not affected by the treatments. These results suggest that inappropriate expression of grn and/or p130 genes in the brains of male and female neonatal rats by perinatal exposure to these chemicals may exert permanent effects on the hypothalamus, thereby decreasing sexual behavior after maturation.

The phytotoxicity to tobacco plants of short-chain carboxylic acids at atmospheric concentration levels in urban areas.

In this paper, we describe the influence of monocarboxylic acids (formic acid and acetic acid) and dicarboxylic acids (succinic acid and adipic acid), which are usually contained in aerosol particles and fog water, on the growth of tobacco plant. Their influence was examined by spraying the acid solutions on intact plants and by administering them in a culture medium for suspension-cultured cells. Their growth rates suggest that the influence of short-chain monocarboxylic acids was not significant in both the intact plant experiment and the cell culture experiment. In contrast, dicarboxylic acids exhibited significant influence on the growth of intact plants and no influence on culture cells, indicating that their toxicity is exerted mainly on the tissue of leaf surface. Phytotoxicity of dicarboxylic acids is higher than that of monocarboxylic acids.

Final report on the safety assessment of Stearamide DIBA-Stearate.

Stearamide DIBA-Stearate is a substituted dihydroxyisobutylamine (DIBA) that functions in cosmetic formulations as an opacifying agent, a surfactant-foam booster, and a viscosity increasing agent. Stearamide DIBA-Stearate was reportedly used in four cosmetic formulations, at concentrations of 1% to 3%. Few data on this ingredient were available. Data on related ingredients, including Dibutyl Adipate, Diisopropyl Adipate, Stearamide DEA, and Stearamide MEA, were considered in the assessment of safety. A formulation containing 1.3% Stearamide DIBA-Stearate (further diluted to 4% of the formulation) was mildly irritating but nonsensitizing in an repeated-insult patch test (RIPT). The same dilution was noncomedogenic. At a concentration of 20%, Dibutyl Adipate had an oral LD50 of 2 g/kg. Subchronic dermal exposure of rabbits (1.0 ml/kg/day) caused a reduction in weight gain that was not observed at a dose of 0.5 ml/kg/day. In studies using rabbits, undiluted Dibutyl Adipate caused mild to moderate skin irritation and minimal ocular irritation. When pregnant rats were treated intraperitoneally with approximately 1.75 ml/kg Dibutyl Adipate during gestation, the incidence of fetal gross abnormalities was increased. No effect was observed at smaller doses. Diisopropyl Adipate had low acute oral and percutaneous toxicity, and was only a very mild ocular irritant. In skin irritation studies using rabbits, 5.0% to 100% Diisopropyl Adipate caused minimal to mild irritation; these results were also seen in clinical testing with only moderate cumulative irritation, and no sensitization or photosensitization. A formulation containing 5.27% Stearamide MEA was not toxic to rats when applied topically daily for 13 weeks. In studies using rabbits, Stearamide DEA (35% to 40%) was not a skin or ocular irritant, and Stearamide MEA (5.27%) was not an ocular irritant. At 17%, Stearamide MEA was not irritating to the skin, but caused minimal to moderate irritation to the eyes of rabbits. Stearamide MEA (5.27%) did not cause sensitization during a clinical study. It was not possible, however, to determine the relevance of these data on related ingredients. Therefore, it was concluded that the available data are insufficient. Additional data needs are (1) method of manufacture; (2) chemical characterization, including impurities; (3) dermal absorption; if significantly absorbed, then a 28-day dermal toxicity study and a reproductive and developmental toxicity study may be needed; (4) two genotoxicity assays, at least one in a mammalian system; if positive, then a 2-year dermal carcinogenesis study using National Toxicology Program (NTP) methods may be needed; (5) ultraviolet (UV) absorption data; if significant absorption occurs in the UVA or UVB range, photosensitization data are needed. Absent these data, it was concluded that the available data are insufficient to support the safety of Stearamide DIBA-Stearate as used in cosmetic products.

[The concept of the clinical use of serotonin adipinate in treating surgical patients]. / Kontseptsiia klinicheskogo primeneniia serotonina adipinata pri lechenii khirurgicheskikh bol'nykh.

The influence of serotonin adipinate on the mechanisms of development of tissue hypoxia, disturbances of the microcirculatory bed and smooth muscles before, during and after operative interventions was studied in experiments and clinical practice. The syndrome of serotonin insufficiency is described including smooth muscle insufficiency which can be abolished by serotonin adipinate administered at the early postoperative period irrespective of the cause of surgery, age and sex of the patient. Good results were obtained in treatment of patients after operations on the liver, pancrease, heart, in patients with the diabetic foot and in other diseases. No complications or lethal outcomes resulting from using serotonin adipinate were noted.

Organizing pneumonia in textile printing workers: a clinical description.

In April 1992 an outbreak of severe respiratory illness occurred among aerographic textile workers in the area of Alcoi, Autonomous Community of Valencia, Spain. An epidemiological study linked this outbreak to the use of a reformulated aerosolized product, Acramin-FWN. We analyzed clinical, laboratory, and pathological data of the first 14 patients with confirmed organizing pneumonia (OP) secondary to this newly recognized occupational toxicant. The mean age of the patients was 30 yrs. The most common clinical findings were cough (86%), epistaxis (71%), dyspnoea (64%), oppressive chest pain (57%), and crackles (50%). A restrictive functional pattern was evident in 64%. Radiographic findings consisted predominantly of patchy infiltrates in 65% and a micronodular pattern in 35%. Treatment with corticosteroids did not prevent initial progression in 11 of the 14 patients and development of irreversible respiratory failure in five patients. At necropsy, besides features of OP, interstitial fibrosis and diffuse alveolar damage were evident. A low total lung capacity, the presence of crackles at admission, and increases in the alveolar-arterial oxygen difference were predictive of death. The organizing pneumonia caused by the inhalation of Acramin-FWN is characterized by a tendency to evolve into progressive interstitial fibrosis despite the use of corticosteroids. The illness is restricted to the respiratory system and once respiratory failure has developed the prognosis is poor.

Outbreak of organising pneumonia in textile printing sprayers. Collaborative Group for the Study of Toxicity in Textile Aerographic Factories.

Eight textile printing factories in Valencia, Spain, with a total workforce of 257 using spraying techniques were investigated as a result of severe interstitial lung disease occurring in three employees, one of whom died. Clinical and radiological data together with biopsy specimens from 71 (27.6%) workers with abnormal respiratory features indicated the occurrence of an outbreak of organising pneumonia resulting in 6 deaths. Epidemiological analysis included the 22 workers who fulfilled the radiological case definition based on chest radiograph and computed tomographic scan showing widespread nodular opacities or confluent patchy consolidation with a lung biopsy corresponding to organising pneumonia. The overall attack rate was 8.9%. Only 2 of the 22 cases never worked in factories A or B. Those who had only worked in factory A had the highest risk of being a case (RR = 24.3; 95% CI = 5.7-104.4). The relationship of case status to period of employment suggested an abrupt change in exposure conditions in the period when Acramin FWR was substituted by Acramin FWN. Although the precise toxicological mechanism is unknown, it is proposed that the lung disease was caused by spraying procedures delivered a respirable aerosol of Acramin FWN to distal airways and pulmonary parenchyma.

Safety evaluation of a barrier cream.

A barrier cream containing propylene glycol, silica, xylene, dioctyl adipate and amyl acetate was applied topically for 3 months in 3 species of animal. Patch tests were carried out in human volunteers up to 72 h. The cream produced slight erythema in rats, guinea pigs and rabbits, but the irritation indices remained within safe limits. Histologically, mild focal thickening and moderate thickening of stratum corneum were observed in rats and guinea pigs, respectively, after 3 months of daily application. Patch testing in human volunteers indicated that the barrier cream is reasonably safe for human use.