F-344 rats showed significant diuresis at 6 and 12 h after both 5 and 10 g/kg DEG, with animals in the 10 g/kg dose group having significant diuresis until 24 h (Fig. [Na++K+]-[Cl-+HCO3-]). The method comprises steps of: adding by weight 66.5-68.5 parts of benzoic acid and 31.5-33.5 parts of diethylene glycol in a reaction kettle . Overall this study has concluded that both strains would be appropriate models to conduct DEG mechanistic studies or risk assessments. Diethylene glycol is an organic liquid compound with the chemical structure: CH 2 OHCH 2 OCH 2 CH 2 OH. Magnification 100 for all images. Urine was collected in iced tubes at timed intervals up to 48 h. Metabolic cages were rinsed with water between collections. Articles of Ethylene Glycol Dibenzoate are included as well. http://dx.doi.org/10.1016/j.annemergmed.2013.12.011. You may switch to Article in classic view. Hinson J, Mays J, Cameron A. Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice. Heilmar R, Lenk W, Lohr D. Toxicokinetics of diethylene glycol (DEG) in the rat. In addition, the study provides key mechanistic insight by relating the magnitude of DGA tissue retention to the presence of toxic effects. The aim of this review is to summarize all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, toxicity of DEG, diagnosis, and management. If patients are stabilized, they may then enter the final phase with various delayed neuropathies and other neurological effects, sometimes fatal. Conclusions: Immediately after collection, the urine samples were vortexed and the volume and pH were recorded. As one important and related example, male Wistar rats have been shown to have increased sensitivity to ethylene glycol (EG)-induced nephrotoxicity, about double that of male F-344 rats (Cruzan et al., 2004). Careers. Both strains receiving 10 g/kg DEG were oliguric by 36 h (significantly lower urine volumes than controls) and had become an-uric by 48 h. Additionally at the high dose only, DEG-treated F-344 and Wistar rat kidneys appeared large, swollen, and weighed substantially more than the control kidneys. In addition, these results add to existing mechanistic information regarding DEG toxicity by showing that metabolism to and target organ accumulation of DGA is required to produce toxicityDGA was detected in the kidneys of 10 g/kg-treated animals and only these animals showed significant renal toxicity in terms of metabolic parameters and histology. The Skin Deep scoring system was designed to help the public understand whether a product is safe to use or whether it contains ingredients of concern. If poisoning is pronounced, patients can progress to a second phase with more severe metabolic acidosis and evidence of emerging renal injury, which, in the absence of appropriate supportive care, can lead to death. Toxicity. was blinded as to the animal treatment. )@il=O +@ tXQNsTuC`WY _m`P+/aEPR-#! Share Profile . Mechanisms of toxicity: For more information about the substance, you may click one of the links below to take you to the relevant section: Program and regulatory information about this substance, including links to EPA applications/systems, statues/regulations, or . The NOAEL for the developing offspring is considered to be 3300 ppm. The mean estimated fatal dose in an adult has been defined as approximately 1 mL/kg of pure DEG. 4, Table 3). Methods: However, both rat strains treated with 10 g/kg DEG showed marked hepatocellular changes characterized as substantial vacuolization and edema with centrilobular necrosis (Table 3). Toxic and Nutritional Optic Neuropathies-An Updated Mini-Review. Lenk W, Lohr D, Sonnenbichler J. Pharmacokinetics and biotransformation of diethylene glycol and ethylene glycol in the rat. Both strains had undetectable DGA tissue concentrations in the 2 and 5 g/kg DEG dose groups. Exposure to DGB was also found to affect lipid metabolism leading to increased lipid production and mobilization in a non-monotonic dose-related fashion. To a 190 L aliquot of homogenate, 10 L of sodium citrate (80 mmol/L in water) was added as internal standard. What's New; Design; Help; Glossary; References; About; Work-Related. Related Pages. Landry G, Martin S, McMartin K. Diglycolic acid is the nephrotoxic metabolite in diethylene glycol poisoning inducing necrosis in human proximal tubule cells in vitro. DIETHYLENE BENZYL BENZOATE: ICSC: 0447 (August 1997) 2,2'-Oxybisethanol dibenzoate Diethylene glycol dibenzoate: CAS #: 120-55-8 EC Number: 204-407-6 ACUTE HAZARDS PREVENTION FIRE FIGHTING; FIRE & EXPLOSION: Combustible. In our studies, both strains exhibited similarly increased urine volumes after DEG administration at the 5 and 10 g/kg doses with diuresis in both strains peaking at roughly 3-fold higher than controls at 612 h; urine volume was not increased at 2 g/kg in either strain. DEG for gavage was provided by Shell Chemical LP (Houston TX) and analyzed for purity by gas chromatography (GC). In the Panama epidemic, the ingested dose to produce renal failure was estimated as 0.36 g/kg (Sosa et al., 2014). Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. The observer (F.A.) 314.36 Molecular Formula. From 6 to 24 h, there was no difference in urine pH between strains. Cruzan G, Corley R, Hard G, Mertens J, McMartin K, Snellings W, Gingell R, Deyo J. Subchronic toxicity of ethylene glycol in Wistar and F-344 rats related to metabolism and clearance of metabolites. Epub 2014 May 9. MeSH Data are represented as number of rats from each strain assigned to 1 of 2 following categories: (++++) normal glycogen staining or (0) no glycogen staining with n = 3 for Wistar (2 g/kg) and n = 4 for all other groups. Clipboard, Search History, and several other advanced features are temporarily unavailable. INTRODUCTION . The limit of quantitation of DGA by this method was 1.05 mol/g. Urine volume is increased in both F-344 and Wistar rat strains at 5 and 10 g/kg DEG doses (A and B). Toxicokinetics: eCollection 2020. Domestic Substances List Categorization. 2 DEG is . already built in. The OPPT assessment concluded that diethylene glycol abietate is poorly absorbed via all routes of exposure and is of low-moderate concern for human health effects, with the only identified health concerns being dermal and respiratory sensitization. This site needs JavaScript to work properly. Besenhofer LM, Adegboyega PA, Bartels M, Filary MJ, Perala AW, McLaren MC, McMartin KE. EG-treated Wistar rats have increased renal calcium oxalate crystal retention, as well as higher plasma oxalate levels (Li and McMartin, 2009; Corley et al., 2008; Li et al., 2010). Li Y, McMartin K. Strain differences in urinary factors that promote calcium oxalate crystal formation in the kidneys of ethylene glycol-treated rats. Kidney tissue was analyzed for DGA content by HPLC by adapting a method initially developed for plasma citric acid levels (Gu et al., 2008). Please enable it to take advantage of the complete set of features! Additionally, 4 m sections of formalin-fixed liver tissue were cut and stained with periodic acid-Schiff (PAS), and examined with light microscopy to detect for glycogen depletion (Myers et al., 2008). . In addition, DGA is the only metabolite causing necrotic cell death in human proximal tubule cells in vitro (Landry et al., 2011), with no effects being seen with the parent DEG or with 2-HEAA. In: Bancroft J, Gamble M, editors. Ethanol, 2,2'-oxybis- . Most of the documented cases of DEG poisoning have been epidemics (numbering over a dozen) where DEG was substituted in pharmaceutical preparations. Oral/Parenteral Toxicity: oral-rat LD50 2830 mg/kg American Industrial Hygiene Association Journal. FOIA 6). RTECS # ID5950000 CAS # 111-46-6 See: NMAM or OSHA Methods. Clin Toxicol (Phila). No adverse effects noted in 90-day study of dogs at 1,000 ppm in the diet; Low frequency of developmental toxicity (increased cervical ribs) observed in rats at doses not maternally . Clinical, laboratory, diagnostic, and histopathologic features of diethylene glycol poisoning-Panama, 2006. HWK,E)w XYZH4H%#! _Zedg>{7xna(W^9smq5,!=766?i9:?9? Besenhofer LM, McLaren MC, Latimer B, Bartels M, Filary MJ, Perala AW, McMartin KE. Data are represented as means SEM (n = 3 for Wistar (2 g/kg); n = 4 for all other groups). Inhibition of metabolism of diethylene glycol prevents target organ toxicity in rats. Urine pH in DEG-treated Wistar and F-344 rats was significantly lower from 6 to 36 h (Fig. Ethanol, 2,2'-oxybis-, dibenzoate; Oxydiethylene dibenzoate; Category. However, glycogenolysis-induced increases in blood glucose levels peak at approximately 2.5 h, and regress back to normal levels by 4 h, when maximum glycogen depletion is observed histologically (Hinson et al., 1983). An estimated BCF value of 120 was calculated for diethylene glycol dibenzoate (SRC), using an estimated log Kow of 3.04 (1,SRC) and a recommended regression-derived equation (2). 2015 Feb 1; 282(3): 244251. 2020 Dec 15;2:586674. doi: 10.3389/ftox.2020.586674. DEG ingestion can lead to serious complications that may prove fatal. At 48 h, blood pH, bicarbonate, and CO2 in the 10 g/kg dose groups were significantly decreased from 0 g/kg controls without a difference between the strains. 23, Pg. Diethylene glycol poisoning can also result in hepatic disease, pancreatitis, and neurologic abnormalities, which appear up to a few days after exposure [8,12]. We claim: 1.A nasal insert comprising a wall in the shape of a tube, the wall including a first end defining a first orifice and a second end defining a second orifice, and wherein: the first end has a diameter, diagonal measurement, or cross-sectional area larger than that of the second end; the first end further defines at least one break in the wall, so that the first end incompletely . Contact. Updated. Clin Toxicol (Phila). Metabolic acidosis was assessed using the parameters of blood pH, bicarbonate, CO2 and the calculated anion gap (Table 1). Glycogen depletion occurred initially in the centrilobular region and progressed outward, results similar to that observed in high dose DEG intoxication in our studies. Blood lactate concentrations were not measured in that study, but there was no increase in lactate in the present study indicating the minimal role of lactic acidosis in the overall acidosis. !,t2Y O d DEG is metabolized by alcohol and aldehyde dehydrogenases to two primary metabolites, 2-hydroxyethoxyacetic acid (2-HEAA) and diglycolic acid (DGA). 0 studies in PubMed science library may include information on the toxicity of this chemical: NLM PubMed: EC (Environment Canada). These results would appear to indicate a somewhat greater excretion of 2-HEAA at the lower doses and for longer periods in Wistar rats, but this would need to be confirmed analytically. 95, 1962. Diethylene glycol (DEG) is a clear, colorless, practically odorless, viscous, hygroscopic liquid with a sweetish taste. Role of tissue metabolite accumulation in the renal toxicity of diethylene glycol. Use water spray, alcohol-resistant foam, powder, carbon dioxide. Reports in the literature suggest a difference between the minimal toxic dose of DEG in humans and the apparent toxic dose in rats. Myers R, Fredenburgh J, Grizzle W. Carbohydrates. The evidence from this study suggested that a dietary concentration of diethylene glycol dibenzoate at 10000 ppm should be considered as the No Observed Adverse Effect Level (NOAEL) for P (F0) and F1 parent animals. HHS Vulnerability Disclosure. Prognosis may be improved, however, with prompt supportive care and timely use of fomepizole or ethanol. 173, 1939. The second column was washed once with distilled water, and then DGA and citrate were eluted in 1 mL of 8 mmol/L sulfuric acid. Laboratory findings in clinical assessment of diethylene glycol can include an elevated osmolar gap, elevated anion gap, elevated creatinine, and acidosis [8,11,12]. The ACC had no role in study design, in the collection, analysis and interpretation of data and in the writing of the report. 2021 Aug 3;9:709495. doi: 10.3389/fchem.2021.709495. 2830mg/kg [1] Ecology may be hazardous to environment. Diethylene glycol. Clinical features: 8600 Rockville Pike, Bethesda, MD, 20894 USA. Generating an ePub file may take a long time, please be patient. "x]AHsI@.Qn].z'?-o}'m^o/_T_.9jx%wRWZm>M[a7_~H ToKj o4jCT^_%>kK7?mK' [Myy5!\{%C;?.or xop}$TyTh%[r\>4rTq8rv'7'TIJ=zZ=VB$itM4vi%2@^-jXyiVgv4$mZ>cdxdJPrln'U#Cq!.P%(fi q. Kwi2I ]Co+\~DAV|{?@M}M{RP4v]oV%h,pxY-@ey`\xxwi@E_,&|,mR[o-y/+"rVHP >6vX?\*}^R0Cn44r The present study provides convincing evidence that the key step in the mechanism of toxicity of DEG is the formation of DGA and its retention in tissues. NO open flames. Calvery and Klumpp calculated that the smallest lethal dose in adults who ingested the DEG-containing elixir of sulfanilamide during the 1937 Elixir of Sulfanilamide disaster to be approximately 1.1 mL DEG/kg (1.2 g/kg body weight) (Calvery and Klumpp, 1939). TOXICITY OF DEG: Doses of DEG necessary to cause human morbidity and mortality are not well established. Also, this study has shown that 10 g/kg DEG-induced liver damage manifested as severe glycogen depletion and centrilobular necrosis, and that it also followed a threshold response, much like the kidney toxicity, regardless of rat strain. Diethylene glycol dibenzoate | C18H18O5 | CID 8437 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological . Disclaimer, National Library of Medicine The invention relates to a preparation method of a plasticizer, particularly a preparation method of a plasticizer diethylene glycol dibenzoate, which comprises the following steps: heating benzoic acid and diethylene glycol until the benzoic acid is dissolved, adding a catalyst to carry out reflux reaction, starting a vacuum pump, heating to 200-220 DEG C, keeping the temperature to react . Route/Organism Dose Effect Accessibility The results showed little to no glycogen depletion in either rat strain at the lower doses of DEG (2 and 5 g/kg) (Fig. This contrasts to the F-344 rat urine pH, whereby the only significant decrease was in the 10 g/kg treated animals (Fig. Data are represented as means SEM (n = 3 for Wistar (2 g/kg); n = 4 for all other groups). Therefore, estimates on the DEG dose associated with lethality in humans vary widely with the minimum value being 0.014 g/kg and the maximum being 1.8 g/kg (Schier et al., 2011). Alfred S, Coleman P, Harris D, Wigmore T, Stachowski E, Graudins A. SAFETY DATA SHEET Creation Date 08-Jul-2014 Revision Date 24-Dec-2021 Revision Number 5 1. Haz-Map. The remaining blood was transferred to separator tubes (BD, Franklin Lakes, NJ) to isolate plasma. More often, these epidemics have occurred in developing and impoverished nations where there is limited access to intensive medical care and quality control procedures are substandard. Analysis of BPA and DGB by FT-IR revealed that exposure to both compounds lead to changes in the biochemical composition of liver. Vol. Periodic acid-Schiff staining for liver glycogen detection in DEG treated rats. At the lower DEG doses, there was no strain difference and no necrosis noted. Before Treatment with DEG at 10 g/kg, but not at 2 or 5 g/kg, produces kidney injury at 48 h in both Wistar and F-344 rats as assessed by blood urea nitrogen (BUN) (A), plasma creatinine (B), and kidney to body weight ratios (C). Therefore, increases in blood glucose likely could have peaked early after DEG administration, but were undetectable at 4 h and 48 h, even with severe glycogen depletion being detectable histologically at 48 h post-termination. Policies. 1A and B). Recommendation for diethylene glycol dibenzoate usage levels up to: not for fragrance use. At the 2 and 5 g/kg doses, no changes in renal function were noted and only minor increases in vacuolization were present in both strains; the minor pathology noted in these groups did not approach the magnitude of vacuolar degeneration observed in the 10 g/kg DEG animals. 1C). AD4Z27s"#)A@T l z,8km( c*?v;&v'l&kL76;3Y21j30-f{SL#U33T;s1 U6Bv%@#t D.e`YlsT/{$,x @Du 0 YE The DEG contained DEG (99.78%), EG (0.05%), and triethylene glycol (0.08%). FOIA. Most recent studies have used the Wistar strain because of the known strain difference in ethylene glycol (EG) toxicity (Cruzan et al., 2004), and the historical idea that the renal damage from DEG might result from the metabolism to EG, which then would produce the renal damage. It is a colorless, odorless, hygroscopic liquid with a sweet taste. For example, Wistar rats showed significant decreases in urine pH up to 24 h at the 2 and 5 g/kg doses, with recovery by 48 h, whereas in F-344 rats, urine pH values in the 2 and 5 g/kg dose groups were not statistically different from controls. Uses advised against Food, drug, pesticide or biocidal product use. See how this product scores for common concerns. n=R#'N;mX6G#e[OL 86Il_q8>5) mUl@s 7*3itq"H4w{\c$u9Ey/,\f[Ost.o=>H: Our results show that Wistar and F-344 rat strains had similarly decreased blood pH and bicarbonate as well as similar anion gaps, only at the 10 g/kg dose, indicating the same degree of metabolic acidosis in both strains. There were no significant differences between strains. They are based predominantly on reports following some epidemics of mass poisonings, which may underestimate toxicity. DEG produced marked renal necrotic damage only at the 10 g/kg dose regardless of rat strain, with only minor, non-necrotic effects at 2 and 5 g/kg, indicating a threshold dose effect as opposed to a linear, no threshold increase in DEG-induced renal injury (Table 3). The importance of DGA in the toxicity of DEG has recently been confirmed in human cases in the Panama epidemic, where the presence of elevated DGA concentrations in the serum and urine had the strongest association with case status (odds ratio > 999), compared to DEG and its other possible metabolites (2-HEAA, oxalate, glycolate, EG); also, the absolute concentrations of DGA in the serum and urine were markedly higher than any other metabolite (Schier et al., 2013). For each tissue, a 1 mm slice was fixed in 10% neutral buffered formalin. government site. Four micrometer sections were cut, embedded, and stained (hematoxylin and eosin) by the LSUHSC-S Department of Cell Biology and Anatomy. These data support the hypothesis of a threshold between the 5 and 10 g/kg doses for hepatotoxicity. The ePub format is best viewed in the iBooks reader. 2B) were significantly increased in 10 g/kg DEG-treated rats compared to controls, with no difference between strains. Dose and strain-dependent decreases in urine pH in DEG-treated Wistar and F-344 rats (C and D). Urine pH in the 2 and 5 g/kg dose groups returned to normal by 48 h. Urine pH was not measureable at 48 h in the 10 g/kg DEG-treated rats due to the oliguria or anuria. Water body should be given special attention. [0039] The stripping compositions may have a favorable aquatic toxicity profile.
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