Comparison of the short-term effects of di(2-ethylhexyl) phthalate, di(n-hexyl) phthalate, and di(n-octyl) phthalate in rats
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Cited by 88 publications
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The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P450 isoenzyme(s) catalyzing w oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fall to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid.The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.
The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P450 isoenzyme(s) catalyzing w oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fall to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid.The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.
Phthalate esters are used as plasticizers for a variety of plastic materials; those of C8 and above are used to add flexibility to polyvinyl chloride (PVC). They also are used with vinyl and cellulose resins to lend toughness and flexibility. They are commonly used in wire and cable coverings, moldings, vinyl consumer products, and medical devices. Some low‐molecular‐weight phthalate esters (e.g., methyl, ethyl, and butyl) are preferentially used as industrial solvents and in consumer products, such as ink and lacquer. Phthalates occur mainly in liquid form with high boiling ranges and very low vapor pressures, both contributing to the high stability of these materials. The critical health effects of phthalate esters like DEHP, butylbenzyl phthalate (BBP), di‐ iso ‐butyl phthalate (DIBP), di‐ n ‐butyl phthalate (DNBP), and dipentyl phthalate (DPP) are their interaction with the endogenous production of fetal testicular testosterone in rats. This impairs the reproduction of rodents by decreasing sperm production so that ECHA has labeled this group as toxic for reproduction (1B), whereas high molecular phthalates (HMP) such as DINP do not warrant classification for effects on sexual function, fertility, and developmental toxicity. Currently, di‐isononylphthalate (DINP) is replacing di(2‐ethylhexyl) phthalate (DEHP) widely in industrial and consumer products. Photodegradation half‐lives of dimethyl‐ and diethylphthalate are about 14 and 3 days, respectively, those of the other esters below 1 day. Half‐lives of aerobic degradation differ largely. The acute aquatic EC or LD50 values determined in algae, daphnids, and minnows mostly did not show effects at the solubility limits. Legal limits of European Commission (EC) for phthalates in plastic layer in direct contact with food are as follows: DBP up to 0.3 mg/kg, BBP, up to 30 mg/kg, DEHP, up to 1.5 mg/kg, sum of DINP and DIDP up to 9 mg/kg.
Esters of Aromatic Mono‐, Di‐, and Tricarboxylic Acids, Aromatic Diacids and Di‐, Tri‐, Or Polyalcohols
The simple aliphatic esters of benzoic acid are liquids used as solvents, flavors, or perfumes. The arylbenzoate benzyl is used as a miticide or plasticizer. In general, these compounds have a low order of toxicity. The primary effect expected from ingestion of moderate amounts of benzoates is gastrointestinal irritation, gastric pain, nausea, and vomiting. Available data indicate a low order of skin absorbability, and the undiluted materials may be either slight or moderate skin irritants. In rabbits, the degree of skin irritation caused by alkyl benzoates increases with an increase in molecular weight. The salicylates are used as flavorants, perfumes, or analgesics. The most commonly used member of this class of compounds is methyl salicylate. Ingestion of relatively small quantities of methyl salicylate may cause severe, rapid‐onset salicylate poisoning. The lower alkyl esters of p ‐ or 4‐hydroxybenzoic acid (C1 to C4), also named the methyl‐, ethyl‐, propyl‐, and butyl parabens, are high‐boiling liquids that decompose on heating. They are widely used in the food, cosmetic, and pharmaceutical industries as preservatives, bacteristats, and fungistats. Parabens also have been used therapeutically for the treatment of moniliasis, a Candida albicans infection. By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The lower paraben homologues have low potential for acute or chronic systemic toxicity and are therefore approved as human food additives. The cinnamates (phenyl acrylates, phenylpropenoic acid esters) are mainly used as fragrances in the perfume industry. The cinnamates appear to have low to moderate toxicity in mammals. In humans, dermal exposure to allyl cinnamate may cause skin irritation. Some p ‐aminobenzoic acid (PABA) esters occur naturally, since the free compound, PABA, is an intricate part of the vitamin B complex and is utilized for its synthesis. PABA esters exhibit a low order of acute toxicity in experimental animals. In humans, cases of methemoglobinemia after topical benzocaine or procaine use have been reported. Sunscreen agents containing PABA esters may occasionally produce allergic photosensitization. The ortho‐aminobenzoates (anthranilates) are less irritating and less likely to cause sensitization than the para‐aminobenzoates, but have less therapeutic usefulness. They are used in some sunscreen lotions. Anthranilates have low toxicity potential. Long‐chain fatty acids of glycerides may be replaced by one or more acetyl groups to produce mono‐, di‐, or triacetin. Acetins, propionates, and butyrates serve as food additives, solvents or plasticizers, and surface‐active agents. Available evidence indicates that these agents exhibit a low order of toxicity. Normally, no irritant effects occur upon inhalation or direct dermal contact. The higher glycerides of fatty acids with odd‐numbered carbon chains (C 5 to C 11 ) are found naturally in very small quantities in diverse organisms, and the even‐numbered (C 12 to C 24 ) esters are common nutritional constituents. They are used as emulsifiers for foods, industrial raw materials, or nonacid detergent components. Some toxicity data are available for the C 5 and C 8 compounds. The even‐numbered C 12 to C 18 glycerides are nontoxic. Little toxicological information is known about resorcinol esters compounds. Gallates are chemically trihydroxybenzoic acid esters. They serve generally as antioxidants, and the propyl, octyl, and dodecyl gallates have been approved as food additives. The gallates exhibit low acute and chronic toxicity in experimental animals. The bulk of evidence suggests that they are not carcinogenic or teratogenic. Oxalates, malonates, glutarates, and succinates are high‐flash, high‐boiling fluids. Oxalates and malonates are mainly used as solvents for resins or as chemical intermediates. The general industrial use of these materials has not been associated with any particular toxicity problem. Diethyl oxalate, which can exert typical local solvent and systemic effects, may present an exception. In humans, diethyl oxalate may cause irritation to skin and mucous membranes. Chemical and physical property data for alkyl and alkoxy adipates, azelates, and sebacates are summarized. These compounds are important chemical intermediates and are used extensively as plasticizers. Some of these agents are used in food packaging materials. They possess low acute toxicities, and their irritant effects on the skin and eye are very slight. Available evidence suggests that the lower alkyl adipates (dimethyl, diethyl, dibutyl) are reproductive and/or fetal toxicants. Maleic acid esters ( cis ‐2‐butenoates), fumarates ( trans ‐2‐butenoates), and itaconates have been utilized as plasticizers, raw materials for chemical syntheses, or preservatives for fats and oils. The esters of alkenyl dicarboxylic acids are of low acute toxicity. They have a tendency to cause skin or eye irritation in rabbits. Allergic dermatitis has occurred in humans exposed to dibutyl maleate. Subacute and chronic toxicity data for these compounds are limited. The aromatic ortho ‐dicarboxylic acid (phthalate) esters are among the most important industrial chemicals. They are used as plasticizers for a variety of plastics; those of C8 and above are used to add flexibility to PVC. They also are used with vinyl and cellulose resins to lend toughness and flexibility. They are commonly used in wire and cable coverings, moldings, vinyl consumer products, and medical devices. Some low‐molecular‐weight phthalate esters (e.g., methyl, ethyl, and butyl) are used as industrial solvents rather than as plasticizers. Occasionally, these low‐molecular‐weight phthalates have applications for consumer products such as ink and lacquer. Physically, phthalates occur mainly in liquid form with high boiling ranges and very low vapor pressures, with both contributing to the high stability of these materials. The biological responses to phthalate esters vary based on the alcohol side chain and the animal species tested. In general, phthalate esters have low potential for acute toxicity following oral, dermal, or inhalation exposure. They are nonirritating or slightly irritating to the skin and eyes, and they are not sensitizers.
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