National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Linoleic acid
• (Z,Z)-9,12-OCTADECADIENOIC ACID (9CI)

Human Toxicity Excerpts

• ...SEEMS TO BE RELATIVELY FREE OF SKIN IRRITANT EFFECTS IN ITS USE IN PAINTS & VARNISHES. [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1792]**PEER REVIEWED**
  
• The fat in the normal diet of 19 apparently well men was partly replaced by linoleic acid. Linoleic acid exposure resulted in changes in many platelet function tests that were ascribed to decreased platelet activation. Based on in vitro studies linoleic acid may alter platelet metabolism inhibiting platelet cyclooxygenase and either reducing or increasing (depending on dose level) the formation of prostaglandins. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. ]**PEER REVIEWED**
  
• The effects of linoleic acid on the motility of human spermatozoa in whole semen were examined using 21 semen samples obtained from 11 normal volunteers. The motility of the spermatozoa in 15 of 21 (71%) of the semen samples was inhibited by added linoleic acid concentrations that were less than or close to the physiological concentration ranges of free fatty acids in blood plasma (1 to 30 mg/dl). Preliminary studies indicated that oleic acid inhibited mobility less than linoleic acid and that linolenic acid was more inhibitory than linoleic acid. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3622]**PEER REVIEWED**
  
• Mild local irritant. Ingestion can cause nausea and vomiting. [Prager, J.C. Environmental Contaminant Reference Databook Volume 2. New York, NY: Van Nostrand Reinhold, 1996., p. 667]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• WHEN GIVEN IN LARGE DOSES TO RATS, WEIGHT LOSS, PROGRESSIVE SECONDARY ANEMIA, LEUCOPENIA & PEDICULOSIS WERE OBSERVED. [Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. II-134]**PEER REVIEWED**
  
• Skin irritation was slight when the compound was applied to the depilated abdominal skin of guinea pigs under an occlusive wrap for 24 hr. Arterial infusion of linoleic acid at 4 mM had no damaging ultrastructural effects on the arterial endothelium of rats. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3620]**PEER REVIEWED**
  
• Increased dietary levels of linoleic acid produced damage to erythrocyte membranes of dogs, platelet membranes of rabbits and platelet activity of rats were also observed. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3620]**PEER REVIEWED**
  
• Linoleic acid was administered intraperitoneally at dose levels of 40 or 200 mg/kg/day every second day for 4 weeks to male Wistar rats fed a fat-free diet. Both dose levels resulted in decreased liver microsomal activity, which may affect metabolic activity of the liver. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3622]**PEER REVIEWED**
  
• The addition of linoleic acid to baby hamster kidney cells reduced cell-to-substrate adhesion, caused morphological changes, and altered cellular growth properties. The data indicate that the effects were probably due to changes in the content of surface membrane lipids. The cytotoxicity of autoxidized polyunsaturated fatty acids toward human umbilical vein endothelial cells was examined in vitro. Autoxidized linolenic acid is more toxic than linolenic acid. Autoxidized arachidonic acid is as toxic as linolenic or arachidonic acid. The major toxic components in autoxidized linoleic acid are linoleic acid hydroperoxides, and a major component in autoxidized arachidonic acid is (E)-4-hydroxy-2-nonenal. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3622]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• None found

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Absorption, Distribution and Excretion

• None found

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Metabolism/Metabolites

• The oral administration of secondary autoxidation products of linoleic acid to rats led to two toxic effects on hepatic carbohydrate metabolism, as compared to the administration of saline or linoleic acid, which were used as controls. One effect was depletion of glucose 6-phosphate and fructose 6-phosphate caused by the reduction of glycolysis and glycogenolysis, accompanied by a decrease in glycogen synthesis and pentose phosphate cyclic activity. Another effect was the depletion of oxaloacetate and isocitrate caused by the reduction in enzyme activity of the mitochondrial citrate cycle. These effects on hepatic carbohydrate metabolism are explained by the authors as follows: the incorporated secondary products impaired the activities of hexokinase and phosphoglucomutase in the liver. The reduction in these enzyme activities resulted in the depletion of glucose 6-phosphate and fructose 6-phosphate, which led ultimately to decreases in the activities of phosphofructokinase, the pentose phosphate cycle, and glycogen synthesis. Moreover, the secondary products disturbed the mitochondrial membrane, resulting in a decrease in the activity of the citrate cycle, which was accompanied by depletion of its metabolites. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3623]**PEER REVIEWED**
  
• The hepatotoxicity of orally administered secondary autoxidation products of linoleic acid in rats was investigated and compared to the effects following administration of a saline solution and linoleic acid as controls. The de novo synthesis of fatty acids was strongly reduced in the secondary products group. The level of nicotine adenine dinucleotide phosphate (NADPH) in the liver significantly decreased whereas that of nicotine adenine dinucleotide (NADH) did not. The activities of glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase apparently decreased. The activities of NAD + kinase and NAD + synthetase decreased and that of NAD + nucleosidase increased in the secondary products group. Therefore the depletion of nicotine adenine dinucleotide phosphate can be attributed to the inhibition of two metabolic systems (an nicotine adenine dinucleotide phosphate-supplemental system and a synthetic system of NADP and NAD), and resulted in the reduction of lipogenesis in the liver. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3623]**PEER REVIEWED**
  
• The effects of unsaturated fatty acids on glycine and glutamate uptake in cultured glial or C6 glioma cells were compared for several cis and trans fatty acids. Elaidic acid and linolelaidic acid were much less effective inhibitors than arachidonic acid or their cis-unsaturated analogues oleic acid and linoleic acid, respectively. Non-esterified unsaturated fatty acids, especially arachidonic acid, readily enter fluid domains of the membrane and produce significant changes in the packing of the lipid molecules. During anoxia, release of arachidonic acid could compromise glutamate uptake and contribute to neuronal death. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 3620]**PEER REVIEWED**
  

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TSCA Test Submissions

• Linoleic acid (CAS # 60-33-3) was evaluated for dermal permeability in in vitro study with human and rat skin (protocol and data not reported). Following 95 hours in contact with human skin in in vitro study, 9% of the applied dose had diffused into the sample. Debilitated rat skin, 56% of an applied dose diffused into the sample under identical study conditions.[AKZO CHEMIE AMERICA; Letter from Akzo Chemie America to USEPA Containing Risk Evaluation of Oleylamine; 4/17/84; EPA Doc No. 40-8484004; Fiche No. OTS0526843]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.