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Chapter 10 p-CRESIDINE NH2 ~ OCH3 ~ 1 CH3~ E=Cresidine (2-methoxy-5-methylanaline) is a white crystalline solid that melts at 51°C. It is sparingly soluble in water, but volatilizes in the presence of steam. ~Cresidine is also known as 2-methoxy-5-methylben zeneamine, 5-me thyl-o-an is id ine and, m-amino- ~-cresol methyl ether. ~:Cresidine is obtained from the methylation and reduction by hydrogen of p-cresol, which is derived from the action of nitrous acid and excess nitric acid on E:toluidine. PRODUCTION - Currently, the sole U.S. producer of E:cresidine is the Sherwin-Williams Company in St. Bernard, Ohio (Stanford Research Institute International, 1979~. There is no record of plant capacity. The production of ~-cresidine was reported by the U.S. International Trade Commission in 1976-1977, implying that commercial production was greater than 2 ,300 kg/year {U.S. International Trade Commiss ion, 1978 ~ . At least 450 kg/year 274
was produced commercially in the United States in 1978-1979 {Stanford Research Institute International, 1979~. Imports {in thousands of kilograms) through principal U.S. customs districts for 1976 to 1979 are as follows: 1976, 262. 3; 1977, 40. 2; and 1978, 125.7 (U.S. International Trade Commission, 1977, 1978, 1979) . USES p-Cresidine appears to be used solely as a chemical intermediate in the production of dyes. file mast commercially important of these dyes is the food, drug, and cosmetic dye (FD&C) Red No. 40, (of which 864 metric tons were produced in the United States dur ing 1978 by the following companies: Buffalo Color Corp., Buffalo, N. Y.; Crompton & Knowles Corp., Gibraltar, Pa. H. Kohnstamm & Co., Tnc., Brooklyn, N. Y.; Hilton Davis Chemical Co., Division of Sterling Drug, Inc., Cincinnati, Ohio; and Warner-Jenkinson Co., St. Louis, Mo. (U.S. International Trade Commission, 1979~. E~Cresidine can alto be used to manufacture six other dyes produced commercially in the United States, although no separate production figures were reported: C. I. Direct Blue 67, produced by Crompton & Knowles Corp., Fairlawn, N. J.; Direct Blue 126, produced by Harshaw Chemical Co., subsidiary of Gulf Oil Corp., Louisville Ky.; Direct Green 26, produced by Toms River Chemical Corp., Toms River, N. J.; Direct Orange 34, produced by Cro~qpton ~ Knowles Corp., Fairlawn, N. J. and E. I. du Pont de Nemours & Co., Inc., Deep~ster, N. J.; and Direct Red 79 and Direct Violet 9, produced by 275
Crompton & Knowles Corp, Fairlawn, N. J., and Toms River Chemical Corp., Tome River, N. J. (Colour Index, 1971; U.S. International Trade Commission, 1979~. EXPOSURE .. There are few data to support an estimation of human exposure to p-cresidine. Small quantities of the chemical appear to be produced and imported and most exposures probably occur during the synthesis of dyes that use E~cresidine as an intermediate. Some E~cresidine may appear as an impurity in I7D&C Red No. 40. There are no Food and Drug Administration (FDA) regulations for spares idine; however, the FDA regulations for Red No. 40 allow for the presence of up to 1% each of sulfonated subsidiary dyes used in its production (21 CER 741. The subsidiary dyes may result from the presence of impur ities, such as ~cresidine, in the FD&C Red No. 40 intermediates, one of which is diazotized cresidine-~=ulfonic acid (Bell, 1976). 276
ANAL1PrIC HE:TlIODS Although ~cresidine should respond to many of the procedures for primary aromatic amines, no information was available concern ins analytic chemical methods for the compound. Sherwin Williams Company k indly provided the following information in the ensuing paragraphs (private communication, 1980~. Assays for Pur ity Analysis is accomplished by using a gas cbromatograph equipped with 1.5 m long column (0 .32 cm inner diameter) packed with 20% SE-30 on Chromosorb W AW DMCS (80-100 mesh) and a flame ionization detector. The column oven is operated at 180°C and the injector and detector at 300°C; the nitrogen carrier flows at 20 ml/minute. Under these conditions, a methanol solution (0.4 ~1) containing 400 p9 of the confound is in jec ted into the instrument for analysis; quantification is based on the area under the ~cre~idine peak. Although the retention time (tR, cannot be determined from the available information, it appear'; to be approximately 6 minutes or less. the peak is symmetr ical. me sensitivity of the assay can easily be enhanced by a factor of approximately 1,000 by in jecting a larger volume and using less attenuation; however, this technique offers no particular advantage to the purity analysis. 277
Analysis of Atmosphere in the Workroom. Atmosphere in a Sherwin-Williams workroom is sampled by using an apparatus consisting of . a midget bubbler charged with 10 ml of acetic anhydride followed by an activated carbon impinger and a membrane filter to protect the vacuum pump. Air samples are collected at a rate of approximately 1 1/minute for 1 to 2 hours. Any E~cresidine in the air reacts with the acetic anhydr ide to form the corresponding acetamide, which is analyzed by high-pressure liquid chromatography (HPLC). The acetic anhydride from the bubbler is diluted to 2S ml with the same solvent, and 10 pi is in jected into an HPLC equipped with a column of Partisil 1025 ODS (0.46 X 25 cm) and a W absorption detector set at 280 nm. The mobile phase consists of 55% methanol-45% water containing 0.59 acetic acid; the flow rate is 1.0 ml/minute. Under these conditions the tR of ~cresidine acetamide is approximately 7.0 minutes. Quantitation is accomplished by relating the areas under the peaks from samples of unknown E-cresidine content to those of standards of acetylamino-p-cresidine. The minimum detectable level of the compound in the diluted solution from the bubbler is 0.5 ~g/ml. 278
HEALTH EFFECTS Data on the toxicity of ~cresidine in animals and humans are virtually nonexistent. the National Institute for Occupational Safety and Health (1976) has reported an oral LD50 in rats of 1, 450 mg/kg. In dose range-f inding studies conducted by the National Cancer Institute (NCI) Biossesy Program (Natione1 Cancer Institute, 1979) groups of f ire male and female F-344 rats and f ive male and female B6C3F1 mice were placed on diets containing 0, 1 and 31 ~cresidine for 8 weeks. Deathe (number unspecified) occurred in male and female mice and in female rats receiving the 31 diet. No deaths occurred in the male rats receiving 3% ~cresidine in any of the groups receiving the 1% diet or in the control group. Ch ron ic Tox ic i ty Ca rc inogen to ity . In the NCI Bioassay Program, E~-cresidine was administered to male and female F-344 rats at concentrations of 0. at and 1.01 in the diet for 104 weeks. The chemical was also administered for 104 weeks at tin we ighted concentrations of O. .221 and 0 . 44% to female B6C3~1 mice for 104 weeks at a time-weighted concentration of 0. 22% to ma le mice of the came stra in and for 92 weeks at a tiae-weighted concentration of 0.461 to a separate group of male B6C3~1 mice. 279
Bladder carcinomas and olfactory neuroblastomas were observed in dosed rats of both sexes. A statistically significant incidence of neoplastic nodules of the liver, hepatocellular carcinomas, or mixed hepatocholangiocarcino~s also occurred in the low-dose male rate. ~ . A statistically significant number of bladder carcinomas were also observed in both high- and low-dose male and female mice. In addition, both high- and low-dose female mice had a significant incidence rate of hepatocellular carcinoma. Comparisons Of E~cresidine to other single-ring aromatic amines and to 2-FAA (N-2-fluorenylacetamide} for potency in producing urinary bladder tumors in rats and mice are shown in Figures 10-1 and 10-2. . 280
Figure 10-1 ~ comparison of the potency of single-ring aromatic amines and 2-FM in producing bladder tumors in rats. in Ct in C: o Ct en m _ _ 1 iL - O _ Z a: a 0 o IL ~ To 0 ~ ' 0 =- - _ . _ \ _\ - C~ Sz~o O 0 . . 0. 0 i, C J: o - ~ ! ~ '3ON301ONI 281 O ~O - - · c, o z - · · o cn y 3 0 o o) c 0 I ~ _ 0` Z~ o ~ ~ o <l Z~O ~ao I \ =¢o ~ mO . ~ O = O _ ° 2 ° l O_4 c~ J
. . In lo en o ~ - ~ J . r Figure 10-2 A comparison of the potency of single-ring aromatic amines and 2-FAA i n product ng b] adder tumors ~ n mi ce . . ~ . Ct · - Ct - - \\ \\ S . Hi: LO ~ ~ ~ m ~ ~ ~ . - - o - ~ _ Hi r ~ ~ ~ ! . o - - o - ~o - o -o o o o lo co ~ ~ do ~ ~ 3ON3OlONI 282 . -~°~1 Cal Go LL ILL O ,0 Us y 3 TIC ~ C]
Mutagen ic ity The only data on the mutagenicity of p-cresidine were obtained f ram the FDA Bureau of Foods . The results were frown tests conducted by Stanford Research Institute Interna~clonal and Inveresk Research International (IRI) in the NCI collaborative study evaluating the reproducibility of results obtained in the Salmonella microsome and Escherichia colt, WP2 u~rA assays. The data from four Salmonella strains and one E. cold strain WP2 u~rA show that there are differences among the responses obtained by the two laboratories. For example, at IRI, ~-cresidine induced mutations in TA 1537, TA 1538, TA 98, and TA 100 strains without metabolic activation. Similar differences for other chemicals were also obtained in this collaborative study. Overall, however, a positive response was reported by both laboratories for ~-cresidine, with mutagenic dose-responses in TA 1538, TA 98, and TA 100. Teratogen ic ity No data were available to evaluate the teratogenicity or reproduct ive tax ic i ty of p-c res id ine . CONCLUS IONS ED "C~NDATI AS Other than the cancer bioassay conducted by NCI, there is virtually no other biologic data on ~cresidine. The lack of data makes it difficult to assess the potential health effects of this compound. Because of the positive carcinogenicity demonstrated 283
in rats and mice, Et-cresidine must also be considered potentially care inogen ic in humans . The preliminary mutagenicity data appear to show a positive response for E~cresidine, but conf Oration is needed. Additional data are also needed on metabolism, metabolic activation, mutagenicity and genetic toxicity in path animal and human in vitro test systems. - 284 \
REE1 :RE:NCES Production, Uses, Exposure Bell, S. J. 1976. Preparation and spectral compilation of FD`C Red No. 40 intermediates and subsidiary dyes. J. Assoc. Off. Anal. Chem. 59: 1294-1311. Code of Federal Regulations. 1980 e Title 21, Part 24 . Listing of Color additives subject to certif ication. Off ice of the Federal Register, National Archives and Records Service, General Services Administration, Washington, D.C . SR! International. 1979. 1979 Directory of Chemical Producers: Un ited States of Amer ice . Stanford Research Institute International, Menio Park, Calif . 1122 pp. The Society of Dyers and Colourists. -1971. Colour Index, Volume 4, Lund Humphr ies Pr inters, London. U. S. International Trade Commission. 1977. Synthetic Organic Chemicals. United States Production and Sales, 1976. USITC Publication 833 . U. S. Government Pr inting Off ice, Washington, D.C. 357 pp. U. S. International Trade Commission. 1978. Synthetic Organic Chemicals. United States Production and Sales, 1977. USITC Publication 920. U.S. Government Printing Office, Washington, D.C. 417 pp. 285
U.S. International Trade Commission. 1979. Synthetic Organic Chemicals . United States Production and Sales, 1978. USING Publication 1001. U.S. Government Printing Office, Washington, D.C. 369 pp. 286 .
Health Effects National Cancer Institute. 1979. Bioassay of ~cresidine for possible carcinogenicity. Tech. Report Series 142, NCI-CG-TR-142. U. S. Department of Health, Education, and Welfare, Bethe sda, Md . National Institute for Occupational Safety and Health. 1976 Reg i stry of Tox ic Ef f eats of Chemical Substances . H . E . , . Chr istensen, ed. U. S . Department of Health, Education, and Welfare, Bethesda, Md. 287
