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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
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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
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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).
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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
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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.
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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
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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
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Representative terms from entire chapter:
trade commission
Figure 10-1 ~ comparison of the potency of single-ring aromatic amines
and 2-FM in producing bladder tumors in rats.
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281
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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 .
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282
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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
