Toxicity Studies of Ethylene Glycol Ethers 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol (CAS Nos. 109-86-4, 110-80-5, 111-76-2) Administered in Drinking Water to F344/N Rats and B6C3F1 Mice
Glycol alkyl ethers represent a class of high-production-volume chemicalswith widespread industrial applications as solvents and chemicalintermediates. Comparative toxicity studies with three glycol ethers,2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol, were conducted inF344/N rats and B6C3F1 mice in both 2-week and 13-week drinking waterstudies. Toxicologic endpoints evaluated in animals includedhistopathology, hematology, clinical chemistry, urinalysis, andreproductive system parameters. Genetic toxicity was also evaluated foreach glycol ether in several in vitro and in vivo assays.
In the 2-week studies, groups of five male and five female rats and micereceived 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in thedrinking water. Estimates of compound consumption based on waterconsumption by male and female rats ranged from 100 to 400 mg/kg for2-methoxyethanol, 200 to 1600 mg/kg for 2-ethoxyethanol, and 70 to300 mg/kg for 2-butoxyethanol. For mice, consumption values ranged from200 to 1300 mg/kg for 2-methoxyethanol, 400 to 2800 mg/kg for2-ethoxyethanol, and 90 to 1400 mg/kg for 2-butoxyethanol.There were no chemical-related effects on survival for rats or mice in the2-week studies. Decreased body weight gains were noted for both male andfemale rats treated with 2-methoxyethanol or 2-ethoxyethanol for 2 weeks,and there were dose-related decreases in water consumption for rats of eachsex treated with the ethylene glycol ethers. Most of the changes in organweights for rats and mice treated with the glycol ethers were sporadic(mice) or related to low final mean body weights (rats), except for thymicatrophy in male and female rats and testicular atrophy in males of bothspecies receiving 2-methoxyethanol or 2-ethoxyethanol.
In the 13-week studies in rats, groups of 10 males and 10 females received2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking waterat concentrations ranging from 750 to 6000 ppm, 1250 to 20,000 ppm, or 750to 6000 ppm, respectively. In the 13-week studies in mice, groups of 10males and 10 females received 2-methoxyethanol, 2-ethoxyethanol, or2-butoxyethanol in the drinking water at concentrations ranging from 2000to 10,000 ppm, 2500 to 40,000 ppm, or 750 to 6000 ppm, respectively.Estimates of compound consumption based on water consumption by male andfemale rats ranged from 70 to 800 mg/kg for 2-methoxyethanol, 100 to 2200-mg/kg for 2-ethoxyethanol, and 70 to 500 mg/kg for 2-butoxyethanol.For-mice, consumption values ranged from 300 to 1800 mg/kg for 2-methoxyethanol, 600 to 11,000 mg/kg for 2-ethoxyethanol, and 100 to1300 mg/kg for 2-butoxyethanol.
Chemical-related mortality occurred in male and female rats administered4500 or 6000 ppm 2-methoxyethanol and in male and female rats administered20,000 ppm 2-ethoxyethanol. No deaths occurred in rats administered2-butoxyethanol or in mice administered 2-methoxyethanol, 2-ethoxyethanol,or 2-butoxyethanol. Decreased body weight gains occurred in dosed ratsand mice in all three studies; the greatest reductions in body weight gainwere seen with 2-methoxyethanol.
In rats administered 2-methoxyethanol or 2-ethoxyethanol, treatment-relatedhistopathologic changes were observed in the testes, thymus, andhematopoietic tissues (spleen, bone marrow, and liver). A dose-relateddegeneration of the germinal epithelium in the seminiferous tubules of thetestes was more severe in 2-methoxyethanol-treated rats than in ratstreated with 2-ethoxyethanol. In special stop-exposure studies in malerats in which administration of the glycol ethers was stopped after 60days, marked degeneration of the seminiferous tubules was present in ratstreated with 3000 ppm 2-methoxyethanol, and mild to moderate degenerationwas observed in rats treated with 1500 ppm. Moderate to marked testiculardegeneration was present in rats treated with 10,000 or 20,000 ppm2-ethoxyethanol but not in rats treated with 5000 ppm. After 30 and 56days of recovery from treatment with these chemicals, only partial recoveryfrom testicular degeneration was observed. There was no testiculardegeneration after 60 days of treatment with 1500 to 6000 ppm 2-butoxyethanol.
2-Methoxyethanol treatment for 13 weeks resulted in a progressive anemiaassociated with a cellular depletion of bone marrow and fibrosis of thesplenic capsule. Anemia was also seen with 2-ethoxyethanol, but evidenceof an adaptive response was indicated by increased hematopoiesis in thebone marrow, spleen, and liver. Toxicity with 2-butoxyethanol was limitedto the liver and hematopoietic system. Cytoplasmic alteration and aminimal hepatocellular degeneration were present in the liver of male andfemale rats. A minimal anemia was present, and a hematopoietic responsewas evident in the bone marrow and spleen.
In mice, 2-methoxyethanol and 2-ethoxyethanol had similar effects on thetestes, spleen, and adrenal gland (females only). A dose-relateddegeneration of the germinal epithelium in seminiferous tubules of thetestes was more severe with 2-methoxyethanol than with 2-ethoxyethanol. Adose-related increase in splenic hematopoiesis was also more prominent with2-methoxyethanol. Both 2-methoxyethanol and 2-ethoxyethanol caused aprominent lipid vacuolization of the X-zone of the adrenal gland in femalemice. There were no chemical-related lesions attributed to 2-butoxyethanol administration in mice.
All three of the glycol ethers were negative in Salmonella typhimuriummutation tests conducted with and without induced hamster and rat liver S9.In the mouse lymphoma L5178Y cell mutation assay, 2-ethoxyethanol wasnegative without S9 but was weakly positive in the presence of induced ratliver S9; 2-methoxyethanol and 2-butoxyethanol were not tested in thisassay. At high concentrations, 2-ethoxyethanol induced sister chromatidexchanges (SCEs) in Chinese hamster ovary cells with and without S9.Chromosomal aberrations (Abs) were also induced by 2-ethoxyethanol, butonly in the absence of S9 and without a delay in cell cycle. In contrast,2-butoxyethanol induced cell cycle delay but did not induce SCEs or Abswith or without S9. 2-Ethoxyethanol was the only glycol ether tested forinduction of sex-linked recessive lethal mutations in germ cells ofDrosophila melanogaster; both feeding and injection trials were negative.
In summary, based on survival, decreased body weight gains, andhistopathologic effects, the rank order of toxicity for the three glycolalkyl ethers was 2-methoxyethanol>2-ethoxyethanol>2-butoxyethanol; thetoxic effects were more severe in rats than in mice. In the 13-week studyof 2-methoxyethanol in rats, a no-observed-adverse-effect level (NOAEL)was not reached, since testicular degeneration in males and decreasedthymus weights in males and females occurred at the lowest concentrationadministered (750 ppm). In the 13-week study of 2-ethoxyethanol in rats,the NOAEL for decreased thymus weights in males was 1250 ppm; for femalerats treated with 2-ethoxyethanol for 13 weeks, the NOAEL for allhistopathologic and hematologic effects was 5000 ppm. In rats treated with2-butoxyethanol for 13 weeks, the NOAEL for liver degeneration was 1500 ppmin males and females.
For male mice treated with 2-methoxyethanol for 13 weeks, the NOAEL fortesticular degeneration and increased hematopoiesis in the spleen was 2000ppm. A NOAEL was not reached for female mice treated with2-methoxyethanol, since adrenal gland hypertrophy and increasedhematopoiesis in the spleen occurred at the lowest concentrationadministered (2000 ppm). For male mice treated with 2-ethoxyethanol for 13weeks, the NOAEL for testicular degeneration and increased hematopoiesis inthe spleen was 20,000 ppm. For female mice in the 13-week study of2-ethoxyethanol, the NOAEL for adrenal gland hypertrophy and increasedhematopoiesis in the spleen was 5000 ppm. No clear chemical-relatedeffects were seen in male or female mice administered 2-butoxyethanol for13 weeks at concentrations as high as 6000 ppm.
2-Methoxyethanol: Ethylene glycol monomethyl ether; methyl cellosolve
2-Ethoxyethanol: Ethylene glycol monoethyl ether; cellosolve
2-Butoxyethanol: Ethylene glycol monobutyl ether; butyl cellosolve
Report Date: July 1993