Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.
Boner H. and Erslew AJ (1994). The blood and lymphoid organs. In: Pathology, 2nd ed., E Rubin and JL Farber (eds). J. B. Lippincott Company, Philadelphia, pp. 994-1097.
2.
Boor PJ, Gotlieb AI, Joseph EC, Kerns WD, Roth RA, and Tomaszewski KE (1995). Contemporary issues in toxicology. Chemical-induced vasculature injury. Toxicol. Appl. Pharmacol.132: 177-195.
3.
Chabra RS, Huff JE, Schwetz BS, and Selkirk J. (1990). An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program . Environ. Health Perspect.86: 313-321.
4.
Chanas B., Ward S., Healy R., Nyska A., and Ghanayem BI (1999). Effect of Gender on the Hematotoxicity of 2-Butoxyethanol (BE) in F344 Rats. 38th Annual Meeting of The Society of Toxicology, March 14-18, 1999, in New Orleans , Louisiana (abstract).
5.
Chien S., Usami S., and Bertles JF (1970). Abnormal rheology of oxygenated blood in sickle cell anemia. J. Clin. Invest.49: 623-634.
6.
Cotran RS, Kumar V., and Robbins S. (1994). Diseases of red cells and bleeding disorders. In: Pathologic Basis of Disease, 5th ed., RS Cotran, V Kumar, and S Robbins (eds). W. B. Saunders Company, Philadelphia, pp. 583-628.
7.
Dill AJ, Lee KM, Bates DJ, Anderson DJ, Johnson RE, Chou BJ, Burka LT, and Roycroft JH (1998). Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice. Toxicol. Appl. Pharmacol.153: 211-226.
8.
Garza JA (1990). Massive fat and necrotic bone marrow embolization in a previously undiagnosed patient with sickle cell disease. Am. J. Forensic Med. Pathol.11: 83-88.
9.
Ghanayem B. (1996). An overview of the hematoxicity of ethylene glycol ethers. Occup. Med.2: 253-268.
10.
Ghanayem BI , Blair PC, Thompson HB, Maronpot RR, and Matthews HB (1987). Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. Toxicol. Appl. Pharmacol.91: 222-234.
11.
Ghanayem BI , Burka LT, and Matthews HB (1987). Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: Role of alcohol and aldehyde dehydrogenases. J. Pharmacol. Exp. Ther.242: 222-231.
12.
Ghanayem BI , Sanchez IM, and Matthews HB (1992). Development of tolerance to 2-butoxyethanol-induced hemolytic anemia and studies to elucidate the underlying mechanisms. Toxicol. Appl. Pharmacol.112: 198-206.
13.
Ghanayem BI and Sullivan CA (1993). Assessment of the hemolytic activity of 2-butoxyethanol and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum. Exp. Toxicol.12: 305-311.
14.
Gibson T. (March 23, 1984). A Market Analysis of 2-Butoxyethanol and 2-Butoxyethylacetate. Regulatory Impacts Branch, U.S. Environmental Protection Agency under subcontract EPA 36-5 of ICF Inc., contract 68-02-4055.
15.
Grossblatt N (ed) (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
16.
Hayashi Y., Hasegawa H., Tanaka G., and Ohmae S. (1996). A 13-week oral repeated dose toxicity study of a new antineoplastic agent S-1 in rats. J. Toxicol. Sci.21(suppl. 3): 505-526.
17.
Horton DP, Ferriero DM, and Mentzer WC (1995). Nontraumatic fat embolism syndrome in sickle cell anemia. Pediatr. Neurol.12: 77-80.
18.
Huo MH, Friedlander GE, and Marsh JS (1996). Orthopaedic manifestations of sickle-cell disease . Pediatr. Infect. Dis. J.15: 725.
19.
Jay WL and Rowlands S. (1975). The stages of osmotic hemolysis. J. Physiol.252: 817-832.
20.
Jones TC, Hunt RD, and King NW (1996). Disturbances of circulation. In: Veterinary Pathology, 6th ed., TC Jones, RD Hunt, and NW King (eds). Williams & Wilkins, Baltimore, pp. 159-176.
21.
Kaysser TM, Wandersee NJ, Bronson RT, and Barker JE (1997). Thrombosis and secondary hemochromatosis play a major role in the pathogenesis of jaundiced and spherocytic mice, murine models for hereditary spherocytosis. Blood90: 4610-4619.
22.
Mandell GA and Meek RS (1993). Infarctions of the ilia in young patients with sickle hemoglobinopathies. Clin. Nucl. Med.18: 558-560.
23.
Mariscal I. , Moffat C., Huebner B., and Seaman AC (1973). A mechanism of thrombosis requiring neither platelets nor thrombin. Scand. J. Haematol.10: 390-400.
24.
National Toxicology Program ( 1993). Toxicity Studies of Ethylene Glycol Ethers—2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Technical Report Series No. 26, NIH publication 93-3349 , Public Health Service, U.S. Department of Health and Human Services, Bethesda, Maryland.
25.
National Toxicology Program ( 1998). Toxicology and Carcinogenesis Studies of 2-Butoxyethanol (CAS No. 11-76-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NIH publication No. 98-3974, Public Health Service, U.S. Department of Health and Human Services, Bethesda, Maryland.
26.
Nelson BK, Setzer JV, Brightwell WS, Mathinos PR, Kuczik MH, Weaver TE, and Goad PT (1984). Comparative inhalation teratogenicity of four glycol ether solvents and amino derivatives in rats. Environ. Health Perspect.57: 261-271.
27.
Onuba O. (1993). Bone disorders in sickle-cell disease. Int. Orthop.17: 397-399.
28.
Palmer N. (1993). Bones and joints. In: Pathology of Domestic Animals, 4th ed., KVF Jubb, PC Kennedy , and N Palmer (eds). Academic Press, Inc., Baltimore, pp. 1-181.
29.
Reed W. and Vichinsky EP (1998). New considerations in the treatment of sickle cell disease. Annu. Rev. Med.49: 461-474.
30.
Resar LM, Oliva MM, and Casella JF (1996). Skull infarction and epidural hematomas in a patient with sickle cell anemia. J. Pediatr. Hematol. Oncol.18: 413-415.
31.
Rodgers GP, Schechter AN, Noguchi CT, Klein HG, Nienhuis AW, and Bonner RF (1984). Periodic microcirculatory flow in patients with sickle-cell disease. N. Engl. J. Med.311: 1534-1538.
32.
Rosenberg AE (1994). Skeletal system and soft tissue tumors. In: Pathologic Basis of Disease, 5th ed., RS Cotran, V Kumar, and S Robbins (eds). W. B. Saunders Company , Philadelphia, pp. 1213-1271.
33.
Schultze AE and Roth RA (1993). Fibrinolytic activity in blood and lungs of rats treated with monocrotaline pyrrole. Toxicol. Appl. Pharmacol.121: 129-137.
34.
Smith JA (1996). Bone disorders in sickle cell disease. Hematol. Oncol. Clin. North Am.10: 1345-1356.
35.
Sokoloff L. (1958). Idiopathic necrosis of bone in small laboratory animals. Arch. Pathol.65: 323-326.
36.
Tucker MJ (1986). A survey of bone disease in the Alpk/AP Rat. J. Comp. Pathol.96: 197-203.
37.
Udden MM and Paton CS (1994). Hemolysis and deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2-butoxyethanol. I. Sensitivity in rats and resistance in normal humans. J. Appl. Toxicol.14: 91-96.
38.
Van Hoeven KH , Wanner JL, and Ballas SK (1997). Cytologic diagnosis of fat emboli in peripheral blood during sickle cell infarctive crisis. Diagn. Cytopathol.17: 54-56.
39.
Ward S., Blair PC, and Ghanayem BI (1989). Hematologic effects of 2-butoxyethanol (BE) in vivo and its effect on the morphology of rat erythrocytes. Toxicologist9: 1155.
40.
Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Foerster J., Athens JW, and Lukens JN (1981). Acquired coagulation disorders. In: Clinical Hematology, 8th ed., MM Wintrobe (ed). Lea & Febiger, Philadelphia, pp. 1206-1246.
41.
Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Foerster J.Athens JW, and Lukens JN (1981). Paroxysmal nocturnal hemoglobinuria (PNH). In: Clinical Hematology , 8th ed., MM Wintrobe (ed). Lea & Febiger, Philadelphia , pp. 978-990.
42.
Woodard JC and Montgomery CA (1978). Musculoskeletal system. In: Pathology of Laboratory Animals, K Benirschke, FM Garner, and TC Jones (eds). Springer-Verlag Inc., New York, pp. 663-880.
43.
Woodard JC and Webster Jss (1991). Skeletal system. In: Handbook of Toxicologic Pathology, WM Haschek and CG Rousseaux (eds). Academic Press Inc., San Diego, pp. 489-534.
44.
Zbinden G. and Grimm L. (1985). Thrombosis effects of xenobiotics. Arch. Toxicol.8(suppl.): 131-141.
