FINAL DRAFT
United States ECAO-CIN-P218
Environmental Protection
Agency
&EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS PROFILE
FOR NIAGARA BLUE 4B
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Profiles (HEEPs) are prepared for the
Office of Solid Waste and Emergency Response by the Office of Health and
Environmental Assessment. The HEEPs are Intended to support listings of
hazardous constituents of a wide range of waste streams under Section 3001
of the Resource Conservation and Recovery Act (RCRA), as well as to provide
health-related limits for emergency actions under Section 101 of the Compre-
hensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and Information obtained from Agency program
office files are evaluated as they pertain to potential human health,
aquatic life and environmental effects of hazardous waste constituents. The
literature searched and the dates of the searches are Included In the
section titled "Appendix: Literature Searched.' The literature search
material 1s current through November, 1985.
Quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these Include Reference doses (RfDs) for
chronic exposures. An RfD Is defined as the amount of a chemical to which
humans can be exposed on a dally basis over an extended period of time
(usually a lifetime) without suffering a deleterious effect. In the case of
suspected carcinogens. RfDs are not estimated 1n this document series.
Instead, a carcinogenic potency factor of q-|* Is provided. These potency
estimates are derived for both oral and Inhalation exposures where possible.
In addition, unit risk estimates for air and drinking water are presented
based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under CERCLA. These two RQs (chronic toxlclty and carclnogen-
Iclty) represent two of six scores developed (the remaining four reflect
IgnltabllUy, reactivity, aquatic toxlclty and acute mammalian toxlclty).
The first draft of this document was prepared by Syracuse Research
Corporation under EPA Contract No. 68-03-3228. The document was subse-
quently revised after reviews by staff within the Office of Health and
Environmental Assessment: Carcinogen Assessment Group, Reproductive Effects
Assessment Group. Exposure Assessment Group, and the Environmental Criteria
and Assessment Office In Cincinnati.
The HEEPs will become part of the EPA RCRA and CERCLA dockets.
111
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EXECUTIVE SUMMARY
Niagara Blue 4B 1s a common name for the commercial azo dye Direct Blue
15, which Is produced by the coupling of o-d1an1s1d1ne with l-am1no-8-
naphthol-3.6-d1sulfon1c acid under alkaline conditions. It Is soluble 1n
water, but 1s Insoluble In most organic solvents (Society of Dyers and
ColouMsts, 1971a). It can be used to dye or stain cellulose, leather,
paper, cotton, silk, wool and biological materials, and tint cinematograph
films (Society of Dyers and Colourlsts, 1971b). Four U.S. manufacturers
produced 0.270 million pounds of Niagara Blue 4B 1n 1982 (USITC, 1983).
Five U.S. companies currently market the dye under various tradenames
(AATCC, 1985). Importation of this dye through principal U.S. customs
districts was 8810 pounds 1n 1983 (USITC, 1984).
Experimental environmental fate data specific to Niagara Blue 4B are
very limited. Brown and Laboureur (1983) found that Niagara Blue 4B can be
substantially blodegraded under anaerobic conditions. If released to water,
Niagara Blue 4B may be susceptible to significant adsorption because
dyestuffs by their substantive nature (ability to be exhaustively deposited
from aqueous baths to fibers) are likely to be adsorbed onto both silts and
sediment of rivers and lakes (Brown and Laboureur, 1983). Removal of
adsorbed Niagara Blue 4B may occur by anaerobic blodegradatlon. In general,
direct dyes are expected to be relatively stable to direct photolysis 1n
natural waters (Porter, 1973). But humlc materials 1n natural water have
been found to strongly accelerate the Indirect photodecomposltlon of azo
dyes (Haag and Mill, 1985). Hydrolysis, volatilization and bloconcentratlon
are not expected to be significant. Apparently, Indirect photolysis,
1v
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mlcroblal degradation and adsorption are the Important fate processes In
water. In the atmosphere. Niagara Blue 4B will probably be present as
participate matter and dusts and may be removed from the atmosphere by wet
and dry deposition. In soil, Niagara Blue 4B may not leach significantly
since dyestuffs are susceptible to significant adsorption. It Is suscep-
tible to anaerobic blodegradatlon in soils (Brown and Laboureur, 1983).
Photodegradatlon In soil may not be significant beyond the surface layer.
The role of chemical oxidation/reduction In soils remains unknown.
Occupational exposure to Niagara Blue 4B occurs during Us production
and Us use In dyeing. Hastewater effluents are probably the major source
of release to the environment. Ambient monitoring data could not be located
In the available literature.
Pertinent data regarding the effects of Niagara Blue 4B on aquatic biota
could not be located 1n the available literature as cited In the Appendix.
As Indicated by excretion studies, at least 18X of an oral dose of
Niagara Blue 4B was absorbed from the gastrointestinal tract of rats and was
widely distributed throughout the body (Bowman et al., 1982). 3,3'-D1-
methoxybenzldlne has been Identified 1n the urine of workers occupatlonally
exposed to the dyes (Lowry et al., 1980; Genln, 1977) and In the urine of
rats and dogs treated orally with Niagara Blue 4B (Bowman et al.. 1982; Lynn
et al.. 1980). Alkaline hydrolyzable conjugates monoacetyl 3,3'-d1methoxy-
benzldlne and d1acetyl-3,3'-d1methoxybenz1d1ne were also found 1n the urine
of the rats (Bowman et al.. 1982; Lynn et al.. 1980). Peak excretion of
radioactivity occurred 8-16 hours after oral exposure to Niagara Blue 4B 1n
rats (Bowman et al., 1982). Approximately 75 and 19X was excreted 1n the
feces and urine, respectively.
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Specific Niagara Blue 4B bloassay data could not be located 1n the
available literature as cited 1n the Appendix. It 1s clear, however, that
Niagara Blue Is metabolized In part to 3,3-d1methoxybenz1d1ne which has been
Implicated as a carcinogen 1n animal test systems and exposed humans. IARC
considers^ 3,3-d1methoxybenz1d1ne to have sufficient evidence for animal
carclnogenldty. Group 2B. Based upon the evidence reviewed by IARC and
preliminary results of an NTP bloassay which suggest positive results,
3,3-d1methoxybenz1d1ne would be placed 1n EPA Group B2. In view of the data
Indicating that 3,3-d1methoxybenz1d1ne Is a metabolate of Niagara Blue 4B,
Niagara Blue should also be considered to fall In EPA weight of the evidence
category B2.
The mutagenlclty of Niagara Blue 4B In frameshlft sensitive tester
strains of Salmonella typhlmurlum was greatly enhanced when flavin
mononucleotlde (a reducing agent) or gut flora reduction was Included In the
testing (Reid et al., 1984; Prlval et al.. 1982, 1984). This finding
Indicates that reduction of the azo bond 1s one Important step 1n activating
Niagara Blue 4B to a mutagen. In an abstract, no Increases In unscheduled
DNA systhesls were reported In rat hepatocytes after hi vivo or ^ vitro
exposures to Niagara Blue 4B (Hlrsalls et al., 1983). In another abstract
Increased mutant colonies were reported In L51784 mouse lymphoma cells with
S9 metabolic activation (Rudd et al., 1983).
No data regarding teratogenlc effects after oral or Inhalation exposure
to Niagara Blue 4B were available. Niagara Blue 4B caused a dose-related
Increase 1n resorptlon and malformed fetuses In rats following 1ntraper1to-
neal Injection (Beaudoln, 1968) and Increased resorptlons 1n rats following
subcutaneous Injection (Lloyd and Beck, 1966). Pertinent data regarding the
reproductive effects of Niagara Blue 4B could not be located 1n the avail-
able literature as cited 1n the Appendix.
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The chronic and subchronlc toxUHy of Niagara Blue 4B has not been
adequately described. The only study found was a 30-day study 1n which the
only effects observed In rats dosed with 1000 mg/kg/day, 5 days/week were
blue coloration, Increased kidney weight and decreased adrenal weight
(Lelst, 1982). These effects were not observed 1n rats after a 2-week
recovery period.
Data were Insufficient to derive an RfD, RQ, q * or F factor. Because
Niagara Blue 4B 1s metabolized to 3.3'-d1methoxybenz1d1ne. an EPA Group B2
chemical and IARC Group 2B, the dye 1s placed 1n EPA Group B2, probable
human carcinogen.
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TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. .PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 4
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 5
2.1. WATER. : 5
2.1.1. Hydrolysis. 5
2.1.2. Oxidation/Reduction 5
2.1.3. Photolysis 5
2.1.4. Mlcroblal Degradation 6
2.1.5. Volatilization 6
2.1.6. Adsorption 6
2.1.7. Bloconcentratlon 7
2.2. AIR 7
2.3. SOIL 7
2.4. SUMMARY 8
3. EXPOSURE - 10
3.1. WATER 10
3.2. FOOD 11
3.3. INHALATION 11
3.4. DERMAL 11
3.5. SUMMARY 11
4. PHARMACOKINETCS 12
4.1. ABSORPTION 12
4.2. DISTRIBUTION 12
4.3. METABOLISM 13
4.4. EXCRETION 14
4.5. SUMMARY 14
5. EFFECTS 16
5.1. CARCINOGENICITY 16
5.1.1. Animal Studies 16
5.1.2. Human Studies 16
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TABLE OF CONTENTS (cont.)
5.2. MUTAGENICITY 16
5.3. TERATOGENICITY 18
5.4. OTHER REPRODUCTIVE EFFECTS 19
5.5. CHRONIC AND SUBCHRONIC TOXICITY 19
5.6. OTHER RELEVANT INFORMATION 20
5.7. SUMMARY 20
6. AQUATIC TOXICITY 22
7. EXISTING GUIDELINES AND STANDARDS 23
7.1. HUMAN 23
7.2. AQUATIC 23
8. RISK ASSESSMENT 24
9. REPORTABLE QUANTITIES 27
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 27
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED10)
FOR CARCINOGENICITY. 27
10. REFERENCES 30
APPENDIX: LITERATURE SEARCHED 36
1x
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
FUN Flavin mononucleotlde
GC Gas chromatography
Kow Octanol/water partition coefficient
LD50 Dose lethal to SOX of recipients
MS Mass spectrometry
RfO Reference dose
RQ Reportable Quantity
SD Standard deviation
UDS Unscheduled DNA synthesis
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUNBER
Niagara Blue 4B 1s commonly referred to as Direct Blue 15; the Colour
Index reference number 1s C.I. 24400 (Society of Dyers and Colourlsts,
1971a). The current CAS designation for Niagara Blue 4B Is 2,7-naphthlene-
dlsulfonlc add, S.a'-ta.a'-dlmethoxyfl.l'-b1phenyl]-4,4'-d1yl)b1s(azo))b1s
[5-am1no-4-hydroxy-], tetrasodlum salt. Direct Blue 15 1s currently
marketed In the United States under the following tradenames (AATCC, 1985):
Amldlne Sky Blue 5B Ex. (John Campbell & Co.). Atlantic Direct Sky Blue H
L1q. (Atlantic Industries), Pergasol Sky Blue H L1q. (C1ba-Ge1gy Corp.),
Phenamlne Sky Blue A L1q. (BASF Myandotte), Pontamlne Sky Blue MW L1q.
(Hobay Chem.).
The structure, molecular weight, empirical formula and CAS Registry
number for Niagara Blue 4B are as follows:
MaS
N-N
OH NH,
N-N
S03Na
OCHj
OCH,
SO.Na
Molecular weight: 996.9
Empirical formula: C-.H00N,0,,S.Na.
J4 ^b b Ib 4 4
CAS Registry number: 2429-74-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Niagara Blue 4B 1s soluble 1n water, forming a reddish-blue solution.
and Insoluble 1n most organic solvents (Society of Dyers and Colourlsts,
1971a). All direct dyes are water soluble and form anlons by dissociation
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(Kuehnl et al., 1979). In aqueous solution, the molecules of direct dye-
stuffs are linked by hydrogen bonds forming larger agglomerates or colloidal
solutions, which reduces their solubility and promotes disposition on
celluloslc fibers. The structure of these agglomerates allows firm linkage
to the cellulose molecule by multiple hydrogen bonds (Kuehnl et al., 1979).
Physical properties such as melting point, boiling point, vapor
pressure, density and log K could not be located In the available
literature. Lack of appropriate fragment values precluded the computer
calculation of log K (U.S. EPA, 1986a). The air conversion factor for
Niagara Blue 4B Is 1 ppm = 41.44 mg/m8.
The manufacture and testing of Niagara Blue 4B probably do not conform
to rigid chemical specifications, and Us composition may vary 1n order to
meet shade and Intensity requirements.
1.3. PRODUCTION DATA
Niagara Blue 4B 1s produced by coupling o-dlanlsldlne to 2 mol of H acid
(l-am1no-8-naphthol-3.6-d1sulfon1c acid) under alkaline conditions (Society
of Dyers and Colour1sts, 1971a).
In 1982, four U.S. manufacturers produced 6.270 million pounds of
Niagara Blue 4B (USITC, 1983), the most recent production figure available.
In 1984, Atlantic Industries, Sandoz Color & Chemical and Hobay Chemical
were listed as manufacturers (USITC, 1985). Five U.S. companies currently
market the dye under various tradenames (AATCC, 1985) (see Section 1.1.).
The production data available from the public portion of the U.S. EPA TSCA
Production File for 1977 are listed 1n Table 1-1.
Importation of Niagara Blue 4B through principal U.S. customs districts
was 8810 pounds In 1983 (USITC. 1984) and 7716 pounds 1n 1980 (USITC, 1981).
0852p -2- 12/31/86
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TABLE 1-1
Niagara Blue 4B Production Data for 1977*
Producer/Location
Manufacturer/Importer
Production Range
(pounds)
DuPont Puerto R1co
Manatl, PR
DuPont
Deepwater, NJ
Mobay Chemical
Bayonne, NJ
Atlantic Chemical
Nutley, N3
Toms River Chemical
Toms River. NJ
Hilton-Davis Chemical
Cincinnati. OH
GAP Corp.
Rensselaer, NY
American Hoechst
Brldgevater, NJ
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Importer
confidential
1-10 thousand
confidential
10-100 thousand
confidential
none
0.1-1 million
confidential
'Source: U.S. EPA. 1977
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1.4. USE DATA
Niagara Blue 4B Is a dye that can be used to dye cellulose, leather and
paper; stain cotton, silk, wool and biological materials; and tint cinemato-
graphic film (Society of Dyers and Colourlsts, 1971b).
1.5. SUMMARY
Niagara Blue 4B 1s a common name for the commercial azo dye Direct Blue
15, which 1s produced by the dlazotlzatlon of o-dlanlsldlne with l-amlno-8-
naphthol-3,6-d1sulfon1c acid under alkaline conditions. It 1s soluble In
water, but 1s Insoluble 1n most organic solvents (Society of Dyers and
Colourlsts, 1971a). It can be used to dye or stain cellulose, leather,
paper, cotton, silk, wool and biological materials, and tint cinematographic
films (Society of Dyers and Colourlsts, 1971b). Four U.S. manufacturers
produced 0.270 million pounds of Niagara Blue 4B In 1982 (USITC, 1983).
Five U.S. companies currently market the dye under various tradenames
(AATCC. 1985). Importation of this dye through principal U.S. customs
districts was 8810 pounds 1n 1983 (USITC. 1984).
0852p -4- 05/28/87
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
2.1. WATER
2.1.1. Hydrolysis. Experimental hydrolysis data could not be located In
the available literature as cited 1n the Appendix; however, since Niagara
Blue 4B does not contain functional groups that are readily susceptible to
environmental hydrolysis, hydrolysis 1s not expected to be environmentally
significant.
2.1.2. Oxidation/Reduction. Specific experimental data regarding Niagara
Blue 4B could not be located In the available literature. Takemura et al.
(1965) reported that bubbling H S through a pure azo-dye solution yields
aromatic amines, and suggested that azo dyes In wastewater may be reduced at
the azo linkage (by H.S or SO. 1n the water) to form Intermediates such
as benzldlne or naphthylamlne from which the dye 1s produced; however, a
water system receiving dyes would have to be very polluted so that H.S or
S0? (or a reducing environment) would significantly convert the dye.
2.1.3. Photolysis. Porter (1973) examined the photodegradatlon rate In
aqueous solution of 8 direct dyes and 12 other azo dyes In artificial light
and 1 direct dye and 1 basic dye 1n natural sunlight. Based on the experi-
mental results, the author concluded that direct dyes are relatively stable
to direct photolysis In natural waters. Although Niagara Blue 48 was not
studied, Us structure 1s similar to several dyes that were tested.
Haag and Hill (1985) examined the aqueous photodegradatlon rate of 15
azo dyes by simulated and natural sunlight. Significant direct photolysis
was observed for some dyes. In natural water, h-m1c -.ateMals were found to
strongly accelerate the photodecompos1t1on rate of all the dyes. Therefore,
Indirect photolysis may be an Important removal mechanism for azo dyes 1n
water.
0852p -5- 09/23/86
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2.1.4. Mlcroblal Degradation. Brown and Laboureur (1983) reported that a
number of azo dyes, Including Niagara Blue 4B, were substantially blodegrad-
ed under anaerobic test conditions. The average primary blodegradatlon
(loss of color) of Niagara Blue 4B was 83% by anaerobic sludge Inoculum
obtained either from a digester of a sewage treatment works or from a
laboratory digester operated under a specified protocol. Although the
blodegradatlon study was continued for 42 days. It Is not clear whether the
reported degradation for Niagara Blue 4B was attained In 42 days. The
authors suggested that the breakdown of dyestuffs 1n the environment may be
Initiated under anaerobic conditions.
Brown et al. (1981) measured the aerobic respiration rate of activated
sludge In the presence of Niagara Blue 4B and concluded that the dye 1s
unlikely to be significantly toxic to aerobic sewage treatment at concentra-
tions normally reaching these facilities.
2.1.5. Volatilization. Experimental data could not be located 1n the
available literature as cited In the Appendix; however, since Niagara Blue
4B Is soluble 1n water (Society of Dyers and ColouMsts, 1971a) and 1s
expected to have a relatively low vapor pressure based on Us chemical
structure, a relatively small Henry's Law constant 1s expected. Therefore,
volatilization from water Is not expected to be significant In the
environment.
2.1.6. Adsorption. Experimental data specific to Niagara Blue 4B could
not be located In the available literature as cited 1n the Appendix.
Because of their substantive nature (ability to be exhaustively deposited
from aqueous baths to fibers), dyestuffs are likely to be adsorbed onto both
sewage works sludge and onto silts and sediments of rivers and lakes (Brown
and Laboureur, 1983). In conventional biological waste treatment systems,
0852p -6- 12/31/86
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soluble dye removal usually occurs when the .dye Is adsorbed onto sludge
(Porter, 1973). Sewage works sludge 1s usually treated by anaerobic diges-
tion or landfill Ing; therefore, removal of the dye from the sludge may occur
by anaerobic blodegradatlon. Similar anaerobic conditions exist In many
lakes and rivers with respect to adsorbed material on silts and sediments
and, therefore, adsorbed dyes may be subject to anaerobic degradation 1n the
environment (Brown and Laboureur, 1963).
2.1.7. B1oconcentrat1on. Experimental data could not be located 1n the
available literature. Since Niagara Blue 4B 1s water soluble (Society of
Dyers and Colourlsts, 1971a), bloconcentratlon 1n aquatic organisms 1s not
expected to be significant.
2.2. AIR
Niagara Blue 4B In the atmosphere 1s most likely to be associated with
partlculate matter and dusts, especially from atmospheric effluents result-
Ing from production and use. These partlculate matter and dusts are subject
to wet and dry deposition. Since the compound contains amlne substltuents,
1t may also undergo heterogeneous oxidation reactions with HO radical
present In the atmosphere; however, none of the atmospheric fate processes
of this compound have been studied.
2.3. SOIL
Pertinent experimental data could not be located 1n the available
literature as cited In the Appendix. The role of chemical oxidation and
reduction In soil 1s not clear, although 1t 1s known that dyes, 1n general,
are resistant to oxidation by ozone, chlorine and oxides of nitrogen
(Porter, 1973). Hydrolysis may not be significant since this compound does
not contain hydrolyzable groups. Because of light attenuation and scatter-
ing, photolysis may not be significant beyond the surface layer of soil.
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Brown and Laboureur (1983) have shown that Niagara Blue 4B and other azo
dyes are susceptible to anaerobic blodegradatlon. The ability of Niagara
Blue 4B to undergo aerobic blodegradatlon Is not clear but appears to be
unlikely (Porter. 1973).
Since Niagara Blue 4B Is water soluble (Society of Dyers and Colourlsts,
1971a), leaching In soil might be expected; however, the substantive nature
of dyestuffs (Brown and Laboureur, 1983), Including the direct dyes (Kuehnl
et al., 1979), Indicates that significant adsorption to soil may occur.
Therefore, significant leaching In soil may not occur.
2.4. SUMMARY
Experimental environmental fate data specific to Niagara Blue 4B are
very limited. Brown and Laboureur (1983) found that Niagara Blue 48 can be
substantially blodegraded under anaerobic conditions. If released to water,
Niagara Blue 4B may be susceptible to significant adsorption because
dyestuffs by their substantive nature (ability to be exhaustively deposited
from aqueous baths to fibers) are likely to be adsorbed onto both silts and
sediment of rivers and lakes (Brown and Laboureur, 1983). Removal of
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It Is susceptible to anaerobic blodegradatlon 1n soils (Brown and Laboureur,
1983). Photodegradatlon 1n soil may not be significant beyond the surface
layer. The role of chemical oxidation/reduction In soils remains unknown.
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3. EXPOSURE
Niagara Blue 4B has not been reported to occur In nature; therefore,
exposure from natural sources Is not expected to occur. Occupational expo-
sure to Niagara Blue 4B occurs during Us production and use for the dyeing
of various products. Likely routes of exposure are Inhalation of partUu-
lates and dermal exposure. Based on a National Occupational Hazard Survey
conducted between 1972 and 1974, 1t 1s estimated that 70 U.S. workers are
potentially exposed to Niagara Blue 4B (NIOSH, 1984).
3.1. yATER
Pertinent monitoring data for Niagara Blue 4B In water could not be
located 1n the available literature as cited 1n the Appendix. For the
organic dye Industry, 1n general, It has been estimated that "90% of the dye
ends up on the fabric, while 10% 1s lost to wastewater effluents during
dyeing operations (Porter. 1973; Brown et al.. 1981). Losses of dyes to
wastewater effluents during manufacture have been estimated to be 1-2%
(Brown et al.. 1981). Waste streams from dye manufacture contain dissolved
«f
Inorganic salts and small amounts of dye and dye Intermediates (Steadman et
al., 1977). Hastewater effluents are, therefore, the major source of
release to the aquatic environment; the efficiency of wastewater treatment
operations determines the amount of dye that reaches natural waters.
Release of dye from textile fabrics may occur from commercial or
consumer washing; however, dyes In most finished products are considered to
be essentially 'fast* (they do not migrate or wash out) (Jones. 1979).
Various after-treatments are commonly applied to fabrics dyed with direct
dyes to Improve their colorfastness (Kuehnl et al., 1979).
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3.2. FOOD
Pertinent data regarding exposure to Niagara Blue 4B through food could
not be located In the available literature as cited In the Appendix.
3.3. INHALATION
Pertinent ambient or occupational air monitoring data specific to
Niagara Blue 4B could not be located In the available literature as cited 1n
the Appendix.
Ambient atmospheric emissions may occur from ventilation effluents at
production and use sites. In addition, air effluents from production opera-
tions such as spray drying may be sources of release. Partlculate emissions
from these sources are usually filtered at plant sites, which should reduce
significantly the amount of partlculate matter actually reaching the ambient
atmosphere.
3.4. DERMAL
Pertinent monitoring data regarding dermal exposure of Niagara Blue 4B
could not be located In the available literature as cited In the Appendix.
The general public Is exposed primarily to finished dyes after they have
been applied to products; however, there Is Uttle chance of dyes coming off
In perspiration, saliva or washings 1f label Instructions are followed
(Jones, 1979).
3.5. SUHHARY
Occupational exposure to Niagara Blue 4B ccurs during Us production and
Us use In dyeing. Wastewater effluents are probably the major source of
release to the environment. No ambient monitoring data were located 1n the
available literature.
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4. PHARMACOKINETICS
4.1. ABSORPTION
Bowman et al. (7982) found that male Fischer 344 rats excreted 18.8% of
a dose of radioactivity 1n the urine collected for 192 hours after a single
oral dose of 12 mg/kg of l4C-N1agara Blue 4B. Approximately 13.IX of the
dose was excreted 1n the first 24 hours and 17.6% of the dose was excreted
In the first 48 hours. Fecal excretion over 192 hours accounted for 74.4%
of the dose of radioactivity, with 61% of the dose excreted In the first 24
hours. Since biliary excretion was not measured, H 1s not known how much
of the fecal excretion was due to excretion In the bile. These results
Indicate that -18.8% of the dose was absorbed from the gastrointestinal
tract. No data were located that evaluated absorption by the Inhalation or
dermal route.
4.2. DISTRIBUTION
Beaudoln and Pickering (1960) looked for Niagara . Blue 4B 1n various
tissues after IntrapeMtoneal Injection of a 140 mg/kg dose In a 2% aqueous
solution was .given to pregnant Sherman rats on day 8 of gestation. Rats
were killed on gestation day 20 and tissues were examined. Dye granules
were detected In the macrophages of the lungs, liver, uterus, ovary, spleen
and lymph nodes. The dye was also found In the basal portion of the
proximal tubules of the kidneys and In the placenta and 1n the yolk sac.
which accumulated the most dye.
Bowman et al. (1982) administered 12 mg/kg 14C-labe1ed Niagara Blue 4B
In 1 mi distilled water to 18 male Fischer 344 rats by oral Intubation.
At 2, 4, 8, 12, 24 or 72 hours after dosing, three rats were killed and
samples from tissues, organs, fluids, carcass, and urine and feces were
collected for analysis by radlochemlcal assays. 14C was widely distribut-
ed throughout the body. Other than the gastrointestinal tract, the highest
0852p -12- 05/28/87
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levels of 14C were found In the liver, kidney, lung and carcass. The lung
level of 14C peaked at 4 hours, while 14C content of other tissues
peaked at 8 hours. Compared with other organs, the liver accumulated a
significant amount of radioactivity, with 1.14 v9 equivalents at 72 hours.
Tissue levels for other nonexcretory organs were <0.06 ng equivalents at
72 hours.
4.3. METABOLISM
Lowry et al. (1980) observed dlmethoxybenzldlne In the urine of workers
occupatlonally exposed to 3,3'-d1methoxybenz1d1ne-based dyes. Similar
results were reported by Genln (1977).
Bowman et al. (1982) gave 20 male Fischer 344 rats an oral dose of 12
mg/kg Niagara Blue 4B and, using GC and radlochemlcal assays, looked for the
metabolites 1n urine collected at varying Intervals until 192 hours after
dosing. Four control rats received water. Excretion of »*C peaked during
the 8- to 16-hour Interval; no metabolites were detected by GC after 25
hours. The metabolites found and the percentage of administered dose are as
follows: alkaline hydrolyzable conjugates, 0.48%; monoacetyl-3,3'-d1-
^
methoxybenzldlne. 0.27%; free 3,3'-dlmethoxybenzldlne, 0.22%; and dlacetyl-
3,3'-d1methoxybenz1d1ne, 0.22%. Much of the radioactivity from the dose
(17.6%) was not extractable Into benzene at alkaline pH. These water
soluble metabolites were not characterized.
Lynn et al. (1980) studied the metabolism of Niagara Blue 46 In rats and
dogs. Four male Sprague-Dawley rats were given a single dose (100 mg/kg) of
Niagara Blue 4B In water by gavage. Urine was collected at 24-hour
Intervals and analyzed for 3,3'-dlmethoxybenzldlne by GC/MS. Two female
mongrel dogs were given 100 mg/kg Niagara Blue 4B In food, and urine was
0852p -13- 12/31/86
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collected at 24-hour Intervals for 3 days and analyzed for 3,3'-d1methoxy-
benzldlne. The percentage of the administered dose excreted as 3,3'-d1-
methoxybenzldlne after 72 hours was variable 1n the rats: 0.17X+0.18
(mean+SD of four rats). In addition to 3,3'-d1methoxybenz1d1ne, monoacetyl-
3,3'-d1methoxybenz1d1ne was Identified 1n the rat urine. In dogs, 0.03%
(mean of two dogs) of the administered dose was excreted as 3,3'-d1methoxy-
benzldlne 48 hours after dosing.
4.4. EXCRETION
Bowman et al. (1982) studied the excretion l4C-N1agara Blue 4B 1n male
Fischer 344 rats that received a single oral dose of 12 mg/kg l4C-N1agara
Blue 4B by gavage. Urine and feces were collected at Intervals of 0-8,
8-16, 16-24, 24-48, 48-96, 96-144 and 144-192 hours after dosing. Peak
excretion of 14C In urine and feces occurred between 8 and 16 hours after
dosing. At 144-192 hours after dosing, detectable levels of **C were
still being excreted. Results showed that 74.4X of the administered dose
was excreted 1n the feces. with 12% of the dose being excreted as Intact dye
In the feces. Radioactivity In the urine accounted for 18.8* of the
administered dose.
4.5. SUMMARY
As Indicated by excretion studies, at least 18% of an oral dose of
Niagara Blue 4B was absorbed from the gastrointestinal tract of rats and was
widely distributed throughout the body (Bowman et al., 1982). 3,3'-D1-
methoxybenzldlne has been Identified 1n the urine of workers occupatlonally
exposed to the dyes (Lowry et al., 1980; Genln, 1977) and 1n the urine of
rats and dogs treated orally with Niagara Blue 46 (Bowman et al.. 1982; Lynn
et al., 1980). Alkaline hydrolyzable conjugates, monoacetyl-3,3'-d1methoxy-
benzldlne and d1acetyl-3t3'-d1methoxybenz1d1ne were also found 1n the urine
0852p -14- 09/23/86
-------
of the rats (Bowman et al., 1982; Lynn et al., 1980). Peak excretion of
radioactivity occurred 8-16 hours after oral exposure to Niagara Blue 4B 1n
rats (Bowman et al., 1982). Approximately 75 and 19X was excreted 1n the
feces and urine, respectively.
0852p -15- 09/23/86
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5. EFFECTS
5.1. CARCINOGENICITY
5.1.1. Animal Studies. Pertinent data regarding the carclnogenlclty of
Niagara Blue 4B In animals could not be located In the available literature
as cited 1ri the Appendix. NTP (1986) has performed a chronic drinking water
study on 3.3-d1methoxybenz1d1ne (a metabolite of Niagara Blue) using rats;
hlstopathology 1s 1n progress. IARC (1982) concluded that evidence 1s
sufficient to classify 3,3'-d1meth- oxybenzldlne, a metabolite of Niagara
Blue 4B, as an animal carcinogen.
5.1.2. Human Studies. Genln (1977) found benzldlne 1n the urine of 8/22
workers and 3,3'-d1methoxybenz1d1ne 1n the urine of 3/22 workers exposed to
benzldlne-based dyes. The urinary levels ranged from trace amounts to 0.3
vg/ml. Upon examination of company records of an unspecified number of
workers, Genln (1977) found five cases of bladder tumors. Three of the
bladder tumors occurred In workers who dried and ground direct azo dyes.
These workers were exposed for 3-24 years and had latent periods of 18-43
years. The Intensity of exposure to dyes was not measured.
5.2. MUTAGENICITY
The mutagenlclty testing of Niagara Blue 4B 1s summarized In Table
5-1. Reid et al. (1984) and PMval et al. (1982 abstract; 1984) found that
Niagara Blue 4B was mutagenlc 1n frameshlft-sensHlve tester strains
(TA1538, TA98) of Salmonella typhlmurlum using a prelncubatlon protocol.
Both of these Investigators found that the mutagenlclty of Niagara Blue 4B
was greatly enhanced when hamster S9 mix plus the reducing agent flavin
mononucleotlde (FHN) or rat S9 mix plus rat fecal bacteria extract was
Included In the testing. This finding Indicates that the reduction of the
0852p -16- 05/28/87
-------
CO
en
ro
•o
TABLE 5-1
Hutagenlclty Testing of Niagara Blue 4B
Assay
Reverse
notation
Reverse
nutation
UDS
LS178V/TK*/-
Gene nutation
Assay
Indicator
Organ 1 so)
Salmonella
typhlnurlum
TA1S38
S. typhlmurlun
TA98
male F344 rat
hepatocytes
mouse
lynphoma cells
Conpound
and/or
Purity
at least 7
tnpurltles
comnerclal
grade
MR
NR
Application Concentration
or Dose
20-nlnutes at 0.2S-1.0
37*C preln- t«M>les/p1ate
cubatlon step
followed by
plate Incorp-
oration
30-nlnutes at 0.1-1.0
30*C prelncu- p«oles/plate
ballon step
followed by
plate Incorp-
oration
Ifl »l»o. gavage NR
\n vitro
liquid NR
suspension
Activating
System
»S-9 rat
»S-9 rat and
rat cecal
bacterial
eitract
»S-9 hamster
» FUN
»S-9 hamster
»S-9 and FHN
none
»S-9
Response Comments
» reduction by
» glulflora reducing
systen and FHN
greatly enhanced
» mutagenlc response;
the compound was
not tested In the
absence of S-9
FNN greatly In-
» creased nutagenlc
activity; not
tested In the
absence of S-9
- NC
i more small
colonies than
large colonies
Reference
Reid et al..
19B4
Prlval et al..
198? Abstract.
1984
Hlrsalls
et al.. 1983
Abstract
Rudd et al..
1983 Abstract
were reported
Indicating both
mutagenlc and
clastogenlc acti-
vity
NR • Mot reported; NC = no connent
00
CD
-------
azo bond to release free o-d1an1s1d1ne appears to be one Important step 1n
activating Niagara Blue 4B to a mutagen.
Mlrsalls et al. (1983) reported In an abstract that no Increases 1n
unscheduled DNA synthesis (UDS) were found In male F344 rat hepatocytes
either 1n \n vitro or in vivo tests. In another abstract, H was reported
that Niagara Blue 4B produced an Increased In tr1fluorothym1d1ne resistant
(TK~) colonies 1n L5178Y mouse lymphona cells when 59 was present 1n the
assay. The authors Indicated that more small colonies were Induced than
larger colonies. This finding would Indicate that Niagara 4B may be both
mutagenlc and clastogenlc. It should be stressed that the studies of
Mlrsalls et al. (1983) and Rudd et al. (1983) are reported In abstract form,
and thus cannot be critically reviewed.
5.3. TERATOGENICITY
Pertinent data regarding the teratogenlc effects after oral or Inhala-
tion exposure to Niagara Blue 48 could not be located 1n the available
literature as cited In the Appendix.
A study by Beaudoln (1968) showed Niagara Blue 4B to be teratogenlc In
Wlstar rats after Intraperltoneal Injection. Groups of 9-35 rats were
Injected 1ntraper1toneally with a 2% aqueous dye solution on day 8 of gesta-
tion at doses of 70, 140 or 200 mg/kg. At the same time, 5 control rats
were Injected with distilled water and 15 controls were left untreated.
Dams were killed on day 20, uteri were removed and the number of resorptlon
sites and live fetuses were counted. Fetuses were fixed 1n Bouln's fluid or
95X alcohol for later examination. Results showed a dose-related Increase
1n the number of resorptlons. A dose-related Increase 1n the number of
malformed survivors was also observed. Anomalies found Included anoph-
thalmla, hydrocephalus, exencephaly, mlcrophthalmla, vertebral defects,
0852p -18- 05/28/87
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encephalomenlngocele, megalophthalmla and tailless fetuses. Exposure to the
highest dose caused the deaths of 10/35 dams. Thirteen dams receiving
unspecified doses of Niagara Blue 4B showed a decrease 1n weight gain, which
was most significant during days 8-13.
In a study by Lloyd and Beck (1966), pregnant Wlstar rats were Injected
subcutaneously on gestation day 8.5 with a IX aqueous solution of Niagara
Blue 4B (91% pure). Four groups of 11-13 dams each were Injected with 50,
75, 100 or 150 mg/kg. No control group data were provided. Dams were
killed on day 20.5, uteri were removed and the number of resorptlon sites
and live fetuses were counted. Live fetuses were then examined for external
malformations. A dose-related Increase 1n the number of resorptlons
occurred, with 100% of 50 Implantations being resorbed at the 150 mg/kg dose
level. Malformations were found In 3/91 live fetuses 1n the lowest dose
group. No other malformations were observed. Deaths of dams occurred at
Incidences of 1/12 at 75 mg/kg. 2/13 at 100 mg/kg and 6/11 at 150 mg/kg.
Lloyd and Beck (1966) also tested the hypothesis that the resorptlons
occurring before 20.S days represented fetal toxlclty rather than the
nonv1ab1!1ty of malformed fetuses. Groups of 8-13 dams were Injected
subcutaneously with 100 mg/kg of Niagara Blue 4B on day 8.5 of gestation and
killed on day 11.5, 14.5 or 20.5. The percentages of resorptlons were 47.8,
61.7 and 56.6% In dams killed on days 11.5, 14.5 and 20.5. respectively.
The results Indicate that most resorptlons seen at term were due to deaths
of fetuses within 3 days of treatment and that the deaths represented a
direct toxic effect rather than a consequence of malformation.
5.4. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the reproductive effects of Niagara Blue 4B
could not be located In the available literature as cited 1n the Appendix.
0852p -19- 05/28/87
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5.5. CHRONIC AND SUBCHRONIC TOXICITY
Chronic oral or Inhalation studies of Niagara Blue 4B were not avail-
able. In a subchronlc study, groups of 20 male and 20 female rats of
unspecified strain were administered 1000 mg/kg of commercial grade Niagara
Blue 4B by gavage, 5 days/week for 30 days for a total of 22 doses (Lelst,
1982). Controls were given an "appropriate" vehicle not containing the dye.
Unspecified numbers of rats were killed following treatment and some were
killed after a 2-week recovery period. The following Indicators of toxlclty
were unaffected: clinical signs, mortality, food consumption, urlnalysls,
hematology and clinical chemistry. The skin and organs of the test rats
turned blue. Upon hlstologlcal examination of liver, kidneys, adrenals and
spleen a reversible Infiltration of blue color 1n the kidney tubules was
noted. Reversible Increased kidney weight and decreased weight of the
adrenals was observed.
5.6. OTHER RELEVANT INFORMATION
Lelst (1982) reported that the acute oral LDrQ of Niagara Blue 4B 1n
rats was >5000 mg/kg. a dose that produced no toxic effects.
5.7. SUMMARY
Pertinent data regarding the cardnogenldty of Niagara Blue 4B In
animals could not be located 1n the available literature as cited 1n the
Appendix. NTP (1986) has performed a chronic drinking water study of
3,3-d1methoxybenz1d1ne using rats; hlstopathology Is In progress.
D1methoxybenz1d1ne 1s a metabolite of Niagara Blue and has been observed 1n
the urine of exposed animals and humans. Bladder cancer has been reported
1n workers occupatlonally exposed to azo-dyes (Genln, 1977).
Niagara Blue 4B gave positive results 1n Salmonella typhlmurlum strains
TA1538 and TA98 with rat or hamster S-9 activation, and mutagenlc activity
0852p -20- 05/28/87
-------
was enhanced when FHN or bacterial reduction was Included In the system
(Reid et al.. 1984; Prlval et al.. 1982. 1984). No Increase In UDS was
observed 1n rat hepatocytes either \f± vivo or \n_ vitro (Hlrsalls et al.,
1983). Increased chromosomal aberrations were found 1n L51784 mouse
lymphoma cells with metabolic activation (Rudd et al., 1983).
No data regarding teratogenlc effects after oral or Inhalation exposure
to Niagara Blue 48 were available. Niagara Blue 4B caused a dose-related
Increase In resorptlon and malformed fetuses 1n rats following 1ntraper1to-
neal Injection (Beaudoln, 1968) and Increased resorptlons 1n rats following
subcutaneous Injection (Lloyd and Beck, 1966). Pertinent data regarding the
reproductive effects of Niagara Blue 4B could not be located 1n the avail-
able literature as cited In the Appendix.
The chronic and subchronlc toxlclty of Niagara Blue 4B has not been
adequately described. The only study found was a 30-day study In which the
only effects observed 1n rats dosed with 1000 mg/kg/day, 5 days/week were
blue coloration, Increased kidney weight and decreased adrenal weight
(Lelst, 1982). These effects were not observed In rats after a 2-week
recovery period.
0852p -21- 05/28/87
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6. AQUATIC TOXICITY
Pertinent data regarding the effects of Niagara Blue 4B on aquatic biota
could not be located In the available literature as cited 1n the Appendix.
0852p -22- 09/23/86
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
OSHA/NIOSH (1980) concluded that 3,3'-d1methoxybenz1d1ne dyes may
present a cancer risk to humans and recommended that they be handled with
caution and that exposure be minimized. U.S. EPA (1981) did not require
testing of 3,3'-d1methoxybenz1d1ne-based dyes.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic biota from the
effects of Niagara Blue 48 could not be located In the available literature
as cited 1n the Appendix.
0852p -23- 09/23/86
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8. RISK ASSESSMENT
Pertinent data regarding the cardnogenlcHy of Niagara Blue 4B 1n
animals could not be located 1n the available literature as cited In the
Appendix. NTP (1986) has performed a chronic drinking water study of
3,3-d1methoxybenz1d1ne using rats; Mstopathology 1s 1n progress.
D1methoxybenz1d1ne 1s a metabolite of Niagara Blue and has been observed In
the urine of exposed animals and humans. Bladder cancer has been reported
In workers occupatlonally exposed to dyes (Genln, 1977).
The mutagenlclty of Niagara Blue 4B In frameshlft sensitive tester
strains of Salmonella typhlmurlum was greatly enhanced when flavin
mononucleotlde (a reducing agent) or gut flora reduction was Included In the
testing (Reid et al., 1984; PMval et al., 1982, 1984). This finding
Indicates that reduction of the azo bond 1s one Important step 1n activating
Niagara Blue 4B to a mutagen. In an abstract, no Increases In unscheduled
DNA systhesls were reported In rat hepatocytes after j£ vivo or ^r) vitro
exposures to Niagara Blue 4B (M1rsal1s et al., 1983). In another abstract
Increased mutant colonies were reported In L51784 mouse lymphoma cells with
S9 metabolic activation (Rudd et al., 1983).
No data regarding teratogenlc effects after oral or Inhalation exposure
to Niagara Blue 4B were available. Niagara Blue 4B caused a dose-related
Increase In resorptlons and malformed fetuses 1n rats following 1ntraper1to-
neal Injection (Beaudoln, 1968) and Increased resorptlons In rats following
subcutaneous Injection (Lloyd and Beck, 1966). Pertinent data regarding the
reproductive effects of Niagara Blue 4B could not be located In the avail-
able literature as cited In the Appendix.
0852p -24- 05/28/87
-------
The chronk and subchronlc toxldty of Niagara Blue 4B has not been
adequately described. The only study found was a 30-day study In which the
only effects observed 1n rats dosed with 1000 mg/kg/day, 5 days/week for 30
days were blue coloration. Increased kidney weight and decreased adrenal
weight (Lelst, 1982). These effects were not observed after a 2-week
recovery period. This study Is Inadequate for RfO derivation.
'Niagara Blue 4B 1s a 3,3'-d1methoxybenz1d1ne-based dye. 3,3'-D1methoxy-
benzldlne has been Identified In the urine of rats and dogs treated orally
and 1n the urine of workers occupatlonally exposed to dyes (Bowman et al.,
1982; Lynn et al., 1980; Lowry et al., 1980). From company records, Genln
(1977) found several bladder cancer cases 1n workers occupatlonally exposed
to dyes and Identified 3,3'-d1methoxybenz1d1ne In the urine of dye-exposed
workers. Although workers were exposed to mixtures of benzldlne- and
3,3'-d1methoxybenz1d1ne-based dyes, the limited ep1dem1olog1cal evidence as
well as the finding of 3,3'-d1methoxybenz1d1ne, a known animal carcinogen
(IARC, 1982), 1n the urine leads to the conclusion that Niagara Blue 4B may
present a risk to man (OSHA/NIOSH. 1980). No cardnogenlclty studies of
Niagara Blue 1n animals were available at the time this report was written;
however, an NTP (1986) chronic drinking water study of 3,3-d1methoxy-
benzldlne using rats Is In progress and reported by personal communication
with the CAG to be positive at several tumor sites.
Taken together, the presence of a carcinogenic metabolite (3,3-dl-
methoxybenzldlne) of Niagara Blue 1n test animals and exposed workers raises
a serious concern about the human cancer potential. IARC considers dl-
methoxybenzldlne to have sufficient animal evidence (IARC Group 2B), and
that EPA would likely come to the same conclusion regarding
3,3-d1methoxybenz1d1ne. NTP 1s reported to have a tumorlgenlc response with
0852p -25- 05/28/87
-------
drinking water exposure of rats to 3,3-d1methoxybenz1d1ne. Based on these
data, U 1s appropriate to provisionally give 3,3-d1methoxybenz1d1ne an EPA
Group B2 we1ght-of-evidence classification. By virtue of this metabolite
being Identified with exposure to Niagara Blue. It Is similarly appropriate
to place Niagara Blue In a provisional EPA Group B2 classification as well.
A cancer potency derivation for Niagara Blue will have to await a further
analysis of the d1methoxybenz1d1ne data and/or the testing of Niagara Blue
Itself 1n a bloassay.
0852p -26- 05/28/87
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9. REPORTABLE QUANTITIES
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
The only study available concerning the subchronU toxlclty of Niagara
Blue 4B was a 30-day study 1n which reversible Increased kidney weight and
decreased adrenal weight were observed In rats given a 1000 mg/kg/day dose
of Niagara Blue 4B by gavage 5 days/week for 30 days. Since these effects
were not observed 1n rats killed after a 2-week recovery period, they were
reversible. The short duration of the study and the failure of the study to
demonstrate definitive toxic effects precluded gathering of sufficient data
to derive an RQ (Table 9-1).
9.2. HEIGHT OF EVIDENCE AND POTENCY FACTOR (F-=1/ED1()) FOR CARCINOGENICITY
Pertinent data describing the cardnogenlcUy of Niagara Blue 48 In
animals were not available. NTP (1986) Is testing a metabolite of Niagara
Blue, 3,3-d1methoxybenz1d1ne, 1n rats 1n a chronic drinking water study and
hlstopathology 1s 1n progress. Genln (1977) found cases of bladder tumors
In workers occupatlonally exposed to dyes and also detected 3,3'-d1methoxy-
benzldlne 1n the urine of dye-exposed workers. Lowry et al. (1980) also
detected 3.3'-d1methoxybenz1d1ne In the urine of workers occupatlonally
exposed to dyes. The limited ep1dem1olog1cal evidence and the finding of
3,3'-d1methoxybenz1d1ne, a known animal carcinogen (IARC, 1982). 1n the
urine of exposed workers leads to the conclusion that Niagara Blue 4B may
present a risk to humans.
Taken together the presence of a carcinogenic metabolite (3,3-dl-
methoxybenzldlne) of Niagara Blue In test animals and exposed workers raises
a serious concern about the human cancer potential. IAKC considers
dlmethoxybenzldlne to have sufficient animal evidence (IARC Group 2B), and
EPA would likely come to the same conclusion regarding 3,3-d1methoxy-
benzldlne. NTP Is reported to have a tumoMgenlc response with drinking
0852p -27- 05/28/87
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TABLE.9-1
Niagara Blue 4B
Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are not sufficient for deriving an RQ.
0852p -28- 05/28/87
-------
water exposure of rats to 3,3-d1methoxybenz1d1ne. Based on these data, H
Is appropriate to provisionally give 3,3-d1methoxybenz1d1ne an EPA Group B2
welght-of-evldence classification. By virtue of the metabolite being
Identified with exposure to Niagara Blue, H 1s similarly appropriate to
place Niagara Blue 1n a provisional EPA Group B2 classification as well. A
cancer potency derivation for Niagara Blue will have to await a further
analysis of the d1methoxybenz1d1ne data and/or the* testing of Niagara Blue
Itself in a bloassay.
0852p -29- 05/28/87
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AATCC Buyers' Guide. Textile Chemist and ColoMst. 17: 80.
Beaudoln, A.R. 1968. Teratogenlc activity of six dlsazo dyes 1n the Ulstar
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Beaudoln A.R. and H.J. Pickering. 1960. Teratogenlc activity of several
synthetic compounds structurally related to Trypan Blue. Anat. Rec. 137:
297-305.
Bowman, M.C., U.L. Oiler, C.R. Nony, K.L. Rowland, S.H. Bllledeau and L.K.
Lowry. 1982. Metabolism and distribution of 2 carbon-14-labeled benzldlne-
congener-based dyes In rats as determined by gas chromatography, high
pressure liquid chromatography and radloassays. J. Anal. Toxlcol. 6(4):
164-174.
Brown, D. and P. Laboureur. 1983. The degradation of dyestuffs: Part I.
Primary blodegradatlon under anaerobic conditions. Chemosphere. 12:
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Brown, D., H.R. Hltz and L. Schaefer. 1981. The assessment of the possible
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with a screening test. Chemosphere. 10(3): 245-261.
0852p -30- 05/28/87
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Genln, V.A. 1977. Formation of blastomogenlc dlphenylamlno derivatives as
a result of the metabolism of direct azo dyes. Vopr. Onkol. 23(9): 50-52.
(Rus.) (Cited 1n NIOSH, 1980)
Haag, W.R7 and T. Hill. 1985. Direct and Indirect photolysis of azo dyes.
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IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. WHO,
IARC, Lyons, France. Supplement 4, p. 116-118.
Jones, T.C. 1979. Preliminary Risk Assessment Phase 1. Benzldlne, Its
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Lelst, K.H. 1982. Subacute toxlclty studies of selected organic colorants.
Ecotoxlcol. Environ. Saf. 6(5): 457-463.
Lloyd, J.B. and F. Beck. 1966. Relation of chemical structure to terato-
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0852p -31- 05/28/87
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Lowry, L.K., W.P. Tolos, M.F. Boenlger, C.R. Nony and H.C. Bowman. 1980.
Chemical monitoring of urine from workers potentially exposed to benzldlne-
derlved azo dyes. Toxlcol. Lett. 7: 29-36.
Lynn, R.K.. D.W. Danlelson, A.M. IHas, 3.M. Kennlsh, K. Wong and H.B.
Matthews. 1980. Metabolism of blsazoblphenyl dyes derived from benzldlne,
3,3'-d1methylbenz1d1ne or 3,3'-d1methoxybenz1d1ne to carcinogenic aromatic
amines 1n the dog and rat. Toxlcol. Appl. Pharmacol. 56(2): 248-258.
M1rsal1s, J., K. Tyson, J. Beck, et al. 1983. Induction of unscheduled DNA
synthesis (UOS) 1n hepatocytes following |ri vitro and Iji vivo treatment.
Environ. Mutagen. 5: 482.
NIOSH (National Institute for Occupational Safety and Health). 1984.
Current Awareness File. Registry of Toxic Effects of Chemical Substance
(RTECS). NIOSH, Cincinnati. OH.
NTP (National Toxicology Program). 1986. Management Status Report. Dated
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OSHA/NIOSH (Occupational Safety and Health Administration/National Institute
for Occupational Safety and Health). 1980. Health Hazard Alert: Benzldlne,
0-Tol1d1ne and 0-D1an1s1d1ne-Based Dyes. DHHS(NIOSH) Publ. No. 81-106.
Porter, J.J. 1973. Stability of add, basic and direct dyes to light and
water. Text. Res. J. 43(12): 735-744.
0852p -32- 05/28/87
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PMval, M.J., V.D. HHchcll, H. Pelperl, V. Vaughan-Dellarco and S.3. Bell.
1982. Evaluation and application of a protocol for testing azo dyes for
mutagenlclty 1n Salmonella typhlmurlum. Environ. Mutagen. 4: 414.
PMval. H.J., S.J. Bell, V.C. Mitchell, H.D. Pelperl and V.L. Vaughan.
1984. Mutagenlclty of benzldlne and benzldlne-congener dyes and selected
monoazo dyes 1n a modified Salmonella assay. Mutat. Res. 136(1): 33-47.
Reid, T.M., K.C. Morton. C.Y. Wang and C.M. King. 1984. Mutagenlclty of
azo dyes following metabolism by different reduct1ve/ox1dat1ve systems.
Environ. Mutagen. 6: 705-717.
Rudd, C.J., A.D. Mitchell and J. Spaldlng. 1983. L5178Y mouse lymphoma
cell mutagenesls assay of coded chemicals Incorporating analyses of the
colony size distributions. Environ. Mutagen. 5: 419.
Society of Dyers and ColouMsts. 1971a. Colour Index, Vol. 3, 3rd ed.
Lund Humphries, Bradford, U.K. p. 4208.
Society of Dyers and ColouMsts. 1971b. Colour Index. Vol. 2, 3rd ed.
Lund Humphries. Bradford, U.K. p. 2226.
Steadman. T.R., E.M. Helper. T. Parsons. G.E. Wlltdns and N.P. Phillips.
1977. Industrial Process Profiles for Environmental Use: Chapter 7.
Organic Dyes and Pigments Industry. EPA-600/2-77-023g. NTIS PB281479.
p. 69.
0852p -33- 05/28/87
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Takemura, N.. T. Aklyama and C. Nakahama. 1965. A survey of the pollution
of the Sumlda River, especially on the aromatic amines 1n the water. Inter.
J. Air Pollut. 9(10): 665-670.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1981. Benzldlne, 0-Tol1d1ne and 0-D1an1s1d1ne-Based Dyes
Response to the Interagency Testing Committee. Federal Register. 46(214):
55004-55006.
U.S. EPA. 1986a. Graphical Exposure Modeling System (GEMS). Octanol Water
Partition Coefficient (CLOGP) data base. U.S. EPA, Washington. DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
USITC (U.S. International Trade Commission). 1981. Imports of Benzenold
Chemicals and Products 1980. USITC Publ. 1163, Washington. DC. p. 57.
USITC (U.S. International Trade Commission). 1983. Synthetic Organic
Chemicals.. U.S. Production and Sales, 1982. USITC Publ. 1422, Washington,
DC. p. 60.
USITC (U.S. International Trade Commission). 1984. Imports of Benzenold
Chemicals and Products 1983. USITC Publ. 1548, Washington. DC. p. 51.
0852p -34- 05/28/87
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USITC (U.S. International Trade Commission). 1985. Synthetic Organic
Chemicals. U.S. Production and Sales, 1984. USITC Publ. 1745, Washington,
DC. p. 66.
0852p -35- 05/28/87
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APPENDIX
LITERATURE SEARCHED
This profile 1s based on data Identified by computerized literature
searches of the following:
GLOBAL
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n April, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985-1986. TLVs: Threshold Limit Values for Chemical Substances
and Physical Agents In the Workroom Environment with Intended
Changes for 1985-1986. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed., Vol. 2A. John U1ley and
Sons. NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John U11ey and
Sons. NY. p. 2879-3816.
0852p -36- 05/28/87
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John WHey and
Sons, NY. p.. 3817-5112.
Grayson. H. and 0. Eckroth, Ed. 1978-1983. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
ITII (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Hanual for Handling and
Disposal with Toxldty and Hazard Data. ITII, Tokyo, Japan. 700 p.
Jaber, H.H., W.R. Habey, S.T. L1u, T.W. Chow and H.L. Johnson.
1984. Data aqu1s1t1on for environmental transport and fate screen-
Ing for compounds of Interest 1n the Office of Solid Waste. EPA
600/6-84-010. NTIS PB84-243906. SRI International, Menlo Park, CA.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical. Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1984. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call 1n Programs. Office of Pesticide Programs,
Washington. DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales, 1982, USITC Publ.
1422, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
0852p -37- 05/28/87
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Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson. W.W. and M.T. Mnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee. J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Hater
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA. Washington, DC.. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington. DC. EPA 540/9-79-003. NTIS PB 80-196876.
0852p -38- 05/28/87
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