SCREENING LEVEL HAZARD CHARACTERIZATION
FOR HIGH PRODUCTION VOLUME CHEMICALS
CHEMICAL CATEGORY NAME
Monocyclic Aromatic Amines
SPONSORED CHEMICALS
N,N-Diethylaniline
[9th CI Name: Benzeneamine, N,N-diethyl-]
N,N-Dimethyl-/Moluidine
[9th CI Name: Benzeneamine, N,N, 4-trimethyl-]
N-Ethyl-m-toluidine
[9th CI Name: Benezeneamine, N-ethyl-3-methyl-]
N-Ethylaniline
[9th CI Name: Benzeneamine, N-ethyl-]
SUPPORTING CHEMICALS
Aniline
[9th CI Name: Benzeneamine]
N,N-Dimethylaniline
[9th CI Name: Benzeneamine, N,N-dimethyl-]
o-Toluidine
[9th CI Name: Benzeneamine, 2-methyl-]
m-Toluidine
[9th CI Name: Benzeneamine, 3-methyl-]
/>-Toluidine
[9th CI Name: Benzeneamine, 4-methyl-]
March 2008
INTERIM
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001
CAS No. 91-66-7
CAS No. 99-97-8
CAS No. 102-27-2
CAS No. 103-69-5
CAS No. 62-53-3
CAS No. 121-69-7
CAS No. 95-53-4
CAS No. 108-44-1
CAS No. 106-49-0

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SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1	U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2	U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3	U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4	U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5	OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6	U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
2

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SCREENING LEVEL HAZARD CHARACTERIZATION
Monocyclic Aromatic Amines Category
Introduction
The sponsor, American Chemistry Council, Monocyclic Aromatic Amines and Nitroaromatics Panel, submitted a
Test Plan and Robust Summaries to EPA for the Monocyclic Aromatic Amines Category on November 21, 2001.
EPA posted the submission on the ChemRTK HPV Challenge website on January 11, 2002
(http://www.epa.gov/chemrtk/pubs/summaries/aroamin/cl3310tc.htm'). EPA comments on the original submission
were posted to the website on April 4, 2002. Public comments were also received and posted to the website. The
sponsor submitted updated/revised documents on July 3, 2002 which were posted to the ChemRTK website on July
24, 2002. The monocyclic aromatic amines category consists of the following chemicals:
Sponsored Chemicals
N,N-Diethylaniline	CAS No. 91-66-7
N,N-Dimethyl-p-toluidine	CAS No. 99-97-8
N-Ethyl-m-toluidine	CAS No. 102-27-2
N-Ethylaniline	CAS No. 103-69-5
Supporting Chemicals
Aniline	CAS No. 62-53-3
N,N-Dimethylaniline	CAS No. 121-69-7
o-Toluidine	CAS No. 95-53-4
/w-Toluidine	CAS No. 108-44-1
/?-Toluidine	CAS No. 106-49-0
This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor under the HPV Challenge Program. In preparing the hazard characterization,
EPA considered its own comments and public comments on the original submission as well as the sponsor's
responses to comments and revisions made to the submission. Structures of the sponsored and supporting chemicals
are included in the appendix. The screening-level hazard characterization for environmental and human health
toxicity is based largely on SIDS endpoints and is described according to established EPA or OECD effect level
definitions and hazard assessment practices.
Category Justification
The four members of the monocyclic aromatic amines category are N-alkyl substituted aromatic amines having a
single amino group with methyl or ethyl substituents on the nitrogen atom. Two of the category members also have
a methyl substituent on the aromatic ring, i.e., the toluidines. The category members are typically manufactured by
reaction of an aniline or a toluidine isomer with either methanol or formaldehyde for the N-methyl derivatives or
ethanol or acetaldehyde for N-ethyl derivatives. The category members are used as chemical intermediates in the
synthesis of a variety of organic chemicals. The sponsor grouped the chemicals based on the similarities in structure
and available supporting data. Based on similarities in structure, physical-chemical properties and toxicological
properties, EPA considers the grouping of the four substances into one category appropriate.
Supporting Chemicals Justification
Supporting chemicals	CAS No.	Endpoints supporting
Aniline	62-53-3	repeated-dose, reproductive and developmental toxicity, chromosomal aberrations
N,N-Dimethylaniline	121-69-7 repeated-dose toxicity
o-Toluidine	636-21-5	plant toxicity
/w-Toluidine	108-44-1	repeated-dose, reproductive and developmental toxicity, chromosomal aberrations
/?-Toluidinc	106-49-0 chromosomal aberrations
3

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The sponsor submitted data for supporting chemicals to address data gaps for plant toxicity, the repeated-dose,
reproductive and developmental toxicity and chromosomal aberrations endpoints. The supporting chemicals are
similar in structure and exhibit toxicity similar to the sponsored substances. EPA considered them appropriate to
use as supporting chemicals. Furthermore, the supporting chemicals, aniline, o-toluidine, w/-toluidinc and
/Moluidinc have been evaluated in the OECD HPV chemicals program and the data are available from the OECD
website at htto://cs3 -hq .oecd.org/scripts/hpv/. These data have been used, where appropriate, to characterize the
toxicity of the sponsored substances.
Sum m an-Conclusion
The lou K \ allies of llie monomelic am malic amines caleuor\ members indicate dial llicir potential lo
bioaccuniulale is km. The monomelic aromatic amines caleuor\ members are noi readils biodegradable, uidicaliim
dial lliev li;i\ e llie potential lo persist m ilie eiin irounieui
The e\ alualiou of ;i\ ailable loxicils dala lor lisli. aquatic 11in eriebrales and aquatic plains lor 11le niouocsclic
aromatic aniines caleuor\ members mdicales ilial llie acnie lia/ard lo lisli is km. lo ai|iialic in\eriebrales is km (\-
e 111 n l;i 111111 ic) lo moderate i\.\-dielh\ laiiilinei and lia/ard lo ;u|ii;ilie plains is low (\ -el I in lamlinei lo moderate
(Wdielhs laiiilmei.
\cnie oral and dermal lo.xicils of caleuor\ nienibers is km and acnie inhalation lo.xicils of caleuor\ nienibers is
limli. The caleuoix nienibers are sIiu1111\ iiriialniu lo llie skin and e\es of rabbits. bin are noi seiisiii/nm Repealed
oral exposure lo \.\-dielh\ I aniline resulted in decreased red cell counts and henioulobiu concentrations and
hisiopalholomcal chaimes in the li\erand spleen (chaimes in rclali\e and absolute wemlils. hemosiderosis and
hcmalopoicsis) Repeated iiihalalion exposure lo \-elh\ l-w-iohudiue resulted in methemoglobinemia in rats at all
exposure concentrations I inlarued spleens, increased production of red cells in the spleen, bone marrow and other
hematological chanues uere seen that were coiisisteiit with the induction of lienioK lie anemia Repealed oral
iiihalalion studies w itli the supportnm chemicals. /jMoliudiue and aniline, rcspecli\ el>. corroborated these liudiims.
Rats and mice w itli the chrouicalK exposed lo the supporting chemical, aniline, had decreased o\ ar\ weights In a
combined repeated-dose rcprodiicli\ e de\ elopniental loxicils scrceuiim test w itli the supporting chemical,
w-lohudiuc. effects tin reprodiiction were implantation losses I Tl'ecls obser\ ed in de\ elopniental loxicils studies in
rats exposed lo \.\-dielh\ lamline and llie supportiim chemicals, aniline and />Mohiidiue. include decreased lelal
weiuhis. hematopoietic acli\ its. increased h\er weiuhts and pnp nioriahts The caleuors memheiv \-elh\ lamline.
Y\-dielh\ laiiihue and \.\-dinielh\ l-/'-ioliiidine. were not niuiaueuic in viim. \-elh\ l-w-ioliudiue induced uene
mutations in the presence of metabolic acli\ alion I !ased on dala from the supporium chemicals. \-l jh\ \-ni-
loliiidine is noi expected lo induce chromosomal aberrations and other caleuoix members ha\e potential lo induce
chromosomal aberrations w itli or w iilioui metabolic acti\ aliou lu VI P chrome loxicils carciuouemcils studies in
I"-'44 rals and I ><>(' 'I'I mice w itli llie supporiiuu chemicals aniline. Wdinielhv lamline and "-toliudiiie posiii\ e
e\ ideuce for carciuoueuicils was seen (see studs suniniaries lor details | hup. utp-apps uichs.iiih uo\ nip io\ |.
l lie poteuiial health lia/ard of the mouocschc aromatic amines caleuors is moderate \ la the oral exposure route and
liiuli \ la the iiihalalion exposure mule based on repealed-dose and de\ elopmeiilal loxicils Related chemicals
supporting the cateuors nienibers show e\ ideuce of carcuioucuicils
No dala naps ha\ e been identified under llie I ll'V ( lialleime I'rourani
1. Physical-Chemical Properties and Environmental Fate
A summary of physical-chemical properties and environmental fate data submitted is provided in Table 1. For the
purpose of the screening-level hazard characterization, the review and summary of these data was limited to the
octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence,
respectively.
4

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Octanol-Water Partition Coefficient
N,N-Diethyl aniline (CAS No. 91-66-7)
Log Kow = 3.17 (measured)
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
Log Kow = 2.81 (measured)
N-Ethyl-m-toluidine (CAS No. 102-27-2)
Log Kow = 2.66 (estimated)
N-Ethyl aniline (CAS No. 103-69-5)
Log Kow =1.92 (measured)
Biodegradation
N,N-Diethylaniline (CAS No. 91-66-7)
In two separate modified MITI tests using activated sludge as inoculum, no degradation was observed after 28 days.
N,N-diethyl aniline is not readily biodegradable.
N-Ethyl-m-toluidine (CAS No. 102-27-2)
In a closed-bottle test using adapted activated sludge as inoculum, no degradation occurred after 28 days.
N-ethyl-i-toluidine is not readily biodegradable.
N-Ethyl aniline (CAS No. 103-69-5)
In a closed-bottle test, no biodegradation was observed after 28 days.
N-ethyl aniline is not readily biodegradable.
Conclusion: The log Kow values of the monocyclic aromatic amines category members indicate that their potential
to bioaccumulate is low. The monocyclic aromatic amines category members are not readily biodegradable,
indicating that they have the potential to persist in the environment.
Table 1. Summary of Physical-Chemical Properties and Environmental Fate Data
Endpoints
N-Ethylaniline
(103-69-5)
N-Ethyl-//i-toluidine
(102-27-2)
N,N-Dimethyl-/;-
toluidine
(99-97-8)
N,N-Diethylaniline
(91-66-7)
Melting Point (C)
-64 (m)
8.7 (e)
-6.6 (e)
-38.8 (m)
Boiling Point (C)
203 - 207 (m)
221 (m)
190.2-211 (m)
215.5-217.1 (m)
Vapor Pressure
(hPa at 25C)
0.4 (m)
(at 20 C)
0.33 (e)
0.78 (m)
0.18 (m)
Log Kw
1.92 (m)
2.66 (e)
2.81 (m)
3.17 (m)
Water Solubility
(mg/L at 25C)
2700(m)
(at 20 C; pHll)
1131 (m)
349.1 (m)
130 (m)
(at 20 C)
Direct Photodegradation
(cm3/molecule-sec)
5.15 x 10"11
1.20 x 10"10
2.02 x 10"10
1.64 x 10"10
Indirect (OH )
Photodegradation tm (hr)
2.5 (e)
1.1 (e)
0.6 (e)
0.8 (e)
Stability in Water
(Hydrolysis) (t1/2)
0.003 (e)
Not applicable
Not applicable
Not applicable
5

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Table 1. Summary of Physical-Chemical Properties and Environmental Fate Data
Endpoints
N-Ethvlanilinc
N-Ethvl-//i-toluidine
N,N-Dimethyl-/;-
N,N-Diethylaniline



toluidine


(103-69-5)
(102-27-2)
(99-97-8)
(91-66-7)
Fugacity (Level III Model)




Air (%)
0.88
0.176
0.156
0.2
Water (%)
42.2
32.5
26.8
22.3
Soil (%)
56.8
67
72.7
76.8
Sediment (%)
0.149
0.305
0.33
0.718
Biodegradation


No Data

at 28 days (%)
0 (m)
0 (m)
0 (RA)
0 (m)

Not readily
Not readily
Not readily
Not readily

biodegradable
biodegradable
biodegradable
biodegradable
(m) = measured data (i.e., derived from experiment); (e) = estimated data (i.e., derived from modeling);
2. Environmental Effects - Aquatic Toxicity
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 2. The table also indicates
where data for tested category members are read-across (RA) to untested members of the category.
Acute Toxicity to Fish
N-Ethyl-m-toluidine (CAS No. 102-27-2)
Fathead minnows (P. promelas) were exposed to N-cthvl-wMoluidinc (measured concentrations not stated) under
flow-through conditions for 96 hours.
96-h LC50 = 49.5 mg/L
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
In two separate studies, fathead minnow (P. promelas, 20/concentration) were exposed to N,N-dimethyl-/?-toluidine
at measured concentrations of 11.1-71.3 mg/L under flow-through conditions for 96 hours. Behavior and toxicity
were observed at 4, 24, 48, 72 and 96 hours. Signs of toxicity included loss of schooling behavior, hypoactivity,
under-reactivity to external stimuli and increased respiration. No loss of equilibrium was observed prior to death.
96-h LCS0 = 41.5 - 52 mg/L
N,N-Diethylaniline (CAS No. 91-66-7)
(1)	Fathead minnows (Pimephales promelas, 10/concentration) were exposed to N,N-diethylaniline at measured
concentrations of 6.5, 13.1, 20.6, 27.9 and 33.9 mg/L under flow-through conditions for 96 hours. Behavior and
toxicity were observed at 4, 24, 48, 72 and 96 hours.
96-h LC50 = 16.4 mg/L
(2)	Rainbow trout (Oncorhynchus mykiss) were exposed to nominal concentrations (not provided) of N,N-
diethylaniline under static conditions for 96 hours.
96-h LC50 = 38.5 mg/L
Acute Toxicity to Aquatic Invertebrates
N-Ethylaniline (CAS No. 103-69-5)
Daphnia magna were exposed to N-ethylaniline (nominal concentrations not stated) for 48 hours.
48-h ECS0 = 18 mg/L
6

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N,N-Diethylaniline (CAS No. 91-66-7)
D. magna were exposed to N,N-diethylaniline (measured concentrations not stated) under static conditions for 48
hours.
48-h ECS0 = 1.3 mg/L
Toxicity to Aquatic Plants
N-Ethylaniline (CAS No. 103-69-5)
Green algae (S. subspicatus) were exposed to N-ethylaniline at nominal concentrations (not stated) for 96 hours.
96-h ECS0 = 98 mg/L
N,N-Diethylaniline (CAS No. 91-66-7)
Green algae (Scenedesmus subspicatus) were exposed to N,N-diethylaniline at nominal concentrations (not stated)
for 72 hours.
72-h ECS0 = 5.6 mg/L
o-Toluidine (CAS No. 636-21-5; supporting chemical)
Green algae (
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3. Human Health Effects
A summary of health effects data submitted for SIDS endpoints is provided in Table 3. The table also indicates
where data for tested category members are read-across (RA) to untested members of the category.
Acute Oral Toxicity
N-Ethylaniline (CAS No. 103-69-5)
(1)	Sprague-Dawley rats (5/sex/dose) were administered single doses of undiluted N-ethylaniline via gavage at 275,
307, 342, 381 and 425 mg/kg-bw. Pale skin was noted at the two lower doses. Ataxia, pale skin and mortality were
observed at 307 and 381 mg/kg-bw. Ataxia and mortality were observed at 425 mg/kg-bw. At necropsy, dark
pigmented lungs were observed.
LDS0 = 362.7 mg/kg-bw
(2)	Sprague-Dawley rats (5/sex/dose) were administered N-ethylaniline in corn oil (dose levels not stated) via
gavage. No clinical observations were noted.
LDS0 = 478 mg/kg-bw
N-Ethyl-m-toluidine (CAS No. 102-27-2)
(1)	Wistar rats (5/sex/dose) were administered N-cthvl-wMoluidinc via gavage at doses of 0.5, 0.6, 0.7, 0.8, 1.0 and
1.2 mL/kg (~ 500, 600, 700, 800, 1000 and 1200 mg/kg-bw, respectively) and observed for 14 days. At doses >
600 mg/kg-bw, all rats displayed slight symptoms of intoxication from 15 minutes post-application until death. The
clinical symptoms observed were cyanosis and generally poor condition. Females also lost weight. Mortality was
3/10, 7/10, 7/10, 9/10 and 10/10 in 600, 700, 800, 1000 and 1200 mg/kg-bw, respectively, and occurred within 4
days post-treatment.
LDS0 = 650 mg/kg-bw
(2)	Sprague-Dawley rats (5/sex/dose) were administered N-cthvl-wMoluidinc in corn oil via gavage at doses of 100,
500, 750 and 1000 mg/kg-bw. Clinical observations were not reported.
LDS0 = 787 mg/kg-bw
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
Sprague-Dawley rats (10/sex/dose) were administered N,N-dimethyl-/?-toluidine via gavage at unspecified doses.
LDS0 = 1650 mg/kg-bw
N,N-Diethylaniline (CAS No. 91-66-7)
Wistar rats (10 males/dose) were administered N,N-diethylaniline via gavage at doses of 0.1, 0.5, 0.6, 0.7 and 0.8
mL/kg (~ 100, 500, 600, 700 and 800 mg/kg-bw, respectively) and observed for 14 days. There were no mortalities
at 100 mg/kg-bw, one at 500 mg/kg-bw, two at 600 mg/kg-bw and six at 700 mg/kg-bw; all animals died at 800
mg/kg-bw. Clinical observations included cyanosis, palmospasms, imbalance, increased diuresis and generally
impaired condition.
LDS0 = 606 mg/kg-bw
Acute Dermal Toxicity
N-Ethylaniline (CAS No. 103-69-5)
(1)	New Zealand White rabbits (5/sex/dose) were exposed to undiluted N-ethylaniline via the dermal route. No
clinical observations were reported.
LDS0 > 2000 mg/kg-bw
(2)	Rats (6/sex/dose) were exposed to undiluted N-ethylaniline via the dermal route at 1200, 1483, 1833, 2265 and
2800 mg/kg-bw. Clinical observations included black urine, loss of appetite, decreased activity and death.
LDS0 =1347 - 1915 mg/kg-bw
8

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N-Ethyl-m-toluidine (CAS No. 102-27-2)
New Zealand White rabbits (5/sex/dose) were exposed to N-cthvl-wMoluidinc via the dermal route at 2000 mg/kg-
bw/day. No clinical observations were reported.
LDS0 > 2000 mg/kg-bw
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
New Zealand White rabbits (10/sex/dose) were exposed to N,N-dimethyl-/?-toluidine via the dermal route at 2000
mg/kg-bw/day. No clinical observations were reported.
LDS0 > 2000 mg/kg-bw
N,N-Diethylaniline (CAS No. 91-66-7)
(1)	Rats were exposed to N,N-diethylaniline via the dermal route at 5000 mg/kg-bw/day. No signs of intoxication or
irritation were observed.
LDS0 > 5000 mg/kg-bw
(2)	Rabbits (4/dose) were exposed to N,N-diethylaniline via the dermal route at 468 and 935 mg/kg-bw. No
mortalities occurred at 468 mg/kg-bw and all animals died at 935 mg/kg-bw.
LDS0 = 468 - 935 mg/kg-bw
Acute Inhalation Toxicity
N-Ethylaniline (CAS No. 103-69-5)
Rats (5/sex/dose) were exposed to N-ethylaniline via inhalation at chamber concentrations of 0.01, 0.026, 0.3, 1.13,
1.38, 1.42 and 1.48 mg/L for a single 4-hour period. The clinical observations included body weight loss, nasal
discharge, decreased activity and respiratory difficulty subsequent to exposure. Necropsy did not reveal any
exposure-related effects.
LCS0 = 1.13 - 1.48 mg/L
N-Ethyl-m-toluidine (CAS No. 102-27-2)
Rats (strain and number not stated) were exposed to N-ethyl-m-toluidine via inhalation for 4 hours. The clinical
observations included labored breathing, decreased muscle tone, cyanosis and the loss of reflexes.
LCS0 = 2.4 mg/L
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
Sprague-Dawley rats (number not stated) were exposed to N, N-dimethyl-p-toluidine via inhalation for 4 hours. The
concentrations tested and clinical observations were not reported.
LCS0 = 1.4 mg/L
N,N-Diethylaniline (CAS No. 91-66-7)
Rats (number not stated) were exposed to N,N-diethylaniline via inhalation at measured concentrations
(concentrations not stated) for 4 hours. The clinical observations included ataxia, tremors in animals exposed to
concentrations^ 1.97 mg/L.
LCS0 = 1.92 mg/L
Repeated-Dose Toxicity
N-Ethyl-m-toluidine (CAS No. 102-27-2)
Sprague-Dawley rats (male and female) were exposed to N-cthvl-wMoluidinc via inhalation at 5.6, 32.8 or 67.6 ppm
(-0.03, 0.18, 0.37 mg/L, respectively), 6 hours/day, 5 days/week for 14 days. There were no deaths or changes in
body weight, food consumption, clinical observations or clinical chemistry at any exposure. However,
methemoglobinemia was increased at all concentrations in both sexes. Enlarged spleens, increased red blood cells
in the spleen, bone marrow and liver and other hematological changes were consistent with the induction of
hemolytic anemia at concentrations > 5.6 ppm (0.03 mg/L). Kidney effects were considered secondary to hemolytic
anemia. The lowest dose was designated the NOAEL because the increase in methemoglobin was not accompanied
by adverse histopathology or clinical signs.
LOAEL = 0.18 mg/L (based on hematological changes consistent with hemolytic anemia)
NOAEL = 0.03 mg/L
9

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Aniline (CAS No. 62-53-3, supporting chemical)
Male rats were exposed to aniline via inhalation at 10, 30 or 90 ppm (0.038, 0.114 or 0.34 mg/L, respectively) daily
(3, 6 or 12 hours/day), 5 days/week for 2 weeks and observed for 14 days post-treatment. At concentrations at and
above 30 ppm (0.114 mg/L), splenic congestion, hemolysis, increased mean corpuscular volume (MCV) and mean
corpuscular hemoglobin (MCH) and changes in methemoglobin levels were observed. After 14 days, the
methemoglobin values returned to normal levels.
LOAEL = 0.114 mg/L (based on hematological effects and changes in splenic congestion)
NOAEL = 0.038 mg/L
m-Toluidine (CAS No. 108-44-1, supporting chemical)
In a combined repeated-dose/reproductive/developmental toxicity screening test, Crj:CD (SD) rats were
administered w/-toluidinc via gavage at 30, 100 and 300 mg/kg-bw/day. The critical effect at 100 and 300 mg/kg-
bw/day was hemolytic anemia with decreased erythrocyte counts and hemoglobin concentration. Other effects
observed were renal tubular epithelium lesions accompanied by pigmentation in the kidneys. At the lowest dose,
marginal pigment deposits and extramedullary hematopoiesis in spleen were observed.
LOAEL = 30 mg/kg-bw/day (based on pigmentation and hematopoiesis in spleen)
NOAEL = Not established
N,N-Diethylaniline (CAS No. 91-66-7)
Wistar rats (male and female) were administered N,N-diethylaniline via gavage at 10, 50 or 250 mg/kg-bw/day, 7
days/week for 28 days. There were no deaths or changes in growth or food and water consumption. At all doses the
following hematological changes were observed: decreased red cell counts, decreased hemoglobin concentrations,
decreased packed cell volume (PCV) in both sexes and increased mean corpuscular volume (MCV) and mean
corpuscular hemoglobin (MCH)in the females. In addition, increased absolute and relative weights and black
pigmentation of the spleen were observed. Changes in spleen histology revealed hemosiderosis, extramedullary
hematopoiesis and splenic hyperemia. In the liver, hemosiderosis of the Kupffer cells was observed. At 50 mg/kg-
bw/day, an increased frequency of respiratory sounds was seen in the males. At 50 and 250 mg/kg-bw/day, other
observations were hyperbilirubinemia, polychromasia, swollen spleens and an increase in the extramedullary
hematopoiesis of the liver. At 250 mg/kg-bw/day, there were decreased potassium levels and histopathological
findings in the kidneys of both sexes, increased frequency of respiratory sounds and salivation and black
pigmentation in the kidneys of females, and increased albumin levels in males.
LOAEL = 10 mg/kg-bw/day (based on hematological changes and histopathological changes in the spleen and
liver)
NOAEL = Not established
Reproductive Toxicity
Aniline (CAS No. 62-53-3, supporting chemical)
(1)	In a chronic toxicity study, Fischer 344 rats (50/sex/dose) were administered aniline hydrochloride in the diet at
7, 22 and 72 mg/kg-bw/day for 104 weeks. At 26 weeks (10/sex/dose), 52 weeks (10/sex/dose) and 78 weeks
(20/sex/dose), animals were sacrificed and necropsied. The remaining animals were sacrificed at the termination of
the study at 104 weeks. No treatment-related effects (changes in testes weight and histopathology) were observed
for the male reproductive system when compared to control animals. In the females, absolute and relative weights
of the ovaries were slightly higher in the treated animals at 26, 52 and 78 weeks. For the females sacrificed at 104
weeks, the relative ovary weights at the high dose were significantly (p-value not stated) lower than the controls. In
females sacrificed at 78 weeks, there was an increased incidence of uterine endometrial polyps. The study authors
state that this finding is common in this strain of rat and because there was no dose-response, considered the finding
incidental.
(2)	In a National Toxicology Program chronic toxicity/carcinogenicity study, Fischer 344 rats (50/sex/dose) were
administered aniline hydrochloride in the diet at 0.3 and 0.6% (-174.4 and 350.5 mg/kg-bw/day, respectively) for
103 weeks. Histopathological examination of the male reproductive organs indicated that no treatment-related
effects were observed. In female rats, after 103 weeks, increased incidences of uterine endometrial polyps were
observed when compared to control groups. These polyps are considered a common finding in this strain of rat. No
other treatment-related effects were observed, [http://ntp-apps.niehs.nih.gov/ntp_tox/]
10

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(3) In a National Toxicology Program carcinogenicity study, B6C3F1 mice (50/dose) were administered aniline
hydrochloride at 0.6 and 1.2% (~ 737 and 1510 mg/kg-bw/day, respectively) for 103 weeks. Histopathological
examination of the male and female reproductive organs indicated that no treatment-related effects were observed at
the highest dose tested, [http://ntp-apps.niehs.nih.gov/ntp_tox/]
m-Toluidine (CAS No. 108-44-1, supporting chemical)
In the combined repeated-dose/reproductive/developmental toxicity screening study with Cij:CD (SD) rats described
previously, the critical toxic effect observed was hemolytic anemia. The observed effects on reproduction were
implantation losses at 100 and 300 mg/kg-bw/day.
LOAEL (systemic toxicity) = 30 mg/kg-bw/day (based on pigmentation and hematopoiesis in spleen)
NOAEL (systemic toxicity) = Not established
LOAEL (reproductive toxicity) = 100 mg/kg-bw/day (based on implantation losses)
NOAEL (reproductive toxicity) = 30 mg/kg-bw/day
Developmental Toxicity
Aniline (CAS No. 62-53-3, supporting chemical)
Pregnant female F344 rats were administered aniline via gavage at 10, 30 or 100 mg/kg-bw/day during days 7-20
of gestation. In dams, there was a dose-dependent increase in relative spleen weights at doses > 10 mg/kg-bw/day
with a large increase in methemoglobin and hematopoietic activity at 100 mg/kg-bw/day. There was an increased
relative liver weight and hematopoietic activity in the fetuses at 100 mg/kg-bw/day.
LOAEL (maternal toxicity) = 10 mg/kg-bw/day (based on changes in relative spleen weights)
NOAEL (maternal toxicity) = Not established
LOAEL (developmental toxicity) = 100 mg/kg-bw/day (based on hematopoietic activity and increased relative
liver weight)
NOAEL (developmental toxicity) = 30 mg/kg-bw/day
m-Toluidine (CAS No. 108-44-1, supporting chemical)
In the combined repeated-dose/reproductive/developmental toxicity study with Crj:CD (SD) rats described
previously, the critical toxic effect observed was hemolytic anemia. For developmental toxicity, pup mortality was
observed at all concentrations and was attributed to the lack of nursing activity. Two of ten females at 100 mg/kg-
bw/day and all females at 300 mg/kg-bw/day showed total implantation losses in utero. At 30 and 100 mg/kg-
bw/day, all surviving offspring developed normally during the 4-day lactation observation period.
LOAEL (maternal toxicity) = 30 mg/kg-bw/day (based on changes in spleen)
NOAEL (maternal toxicity) = Not established
LOAEL (developmental toxicity) = 300 mg/kg-bw/day (based on pup mortality)
NOAEL (developmental toxicity) = 100 mg/kg-bw/day
N,N-Diethylaniline (CAS No. 91-66-7)
Pregnant female Sprague-Dawley rats (24 or 29/dose) were administered N,N-diethylaniline via gavage at 50, 250 or
500 mg/kg-bw/day during days 6 - 15 of gestation. At all doses, the mean food consumption was lower than the
controls and there was excessive salivation. No adverse treatment-related effects were evident from the uterine
implantation data or the evaluation of recovered fetuses (external, visceral and skeletal malformations). At 50 and
250 mg/kg-bw/day, no maternal mortality or changes in mean fetal weight or fetal sex distribution were observed.
At 250 and 500 mg/kg-bw/day, maternal effects included excessive lacrimation and staining of the fur in the ano-
genital area. At 500 mg/kg-bw/day, two females died and three females were found in a moribund position and
killed. The mean fetal weight was statistically (p value not stated) lower than the control and there was an increase
in the incidence of fetuses with unossified sternebral elements; suggestive of delayed ossification.
LOAEL (maternal toxicity) = 500 mg/kg-bw/day (based on mortality)
LOAEL (developmental toxicity) = 500 mg/kg-bw/day (based on decreased fetal weights and unossified
sternebral elements)
NOAEL (maternal/developmental toxicity) = 250 mg/kg-bw/day
11

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Genetic Toxicity - Gene Mutation
In vitro
N-Ethylaniline (CAS No. 103-69-5)
in a bacterial reverse mutation assay, Salmonella typhimurium strains TA97, TA98, TA100 and TA1535 were
exposed to N-ethylaniline up to 1666 |.ig/platc with and without metabolic activation. The use and performance of
controls was not reported.
N-Ethylaniline was not mutagenic in this assay.
N-Ethyl-m-toluidine (CAS No. 102-27-2)
(1)	S. typhimurium strains TA97, TA98, TA100 and TA1535 were exposed to N-cthvl-wMoluidinc up to 5000
|j.g/platc with and without metabolic activation. Without metabolic activation, cytotoxicity was observed at 2500
|j.g/platc (3330 |-ig/platc in TA100). Otherwise, no mutagenic activity was observed without metabolic activation.
With metabolic activation, cytotoxicity was observed at 5000 |.ig/platc (3330 |.ig/platc in TA100). N-Ethyl-/;/-
toluidine was considered positive when tested with metabolic activation.
N-Ethyl-i-toluidine was not mutagenic without metabolic activation, but was mutagenic with metabolic
activation in this assay.
(2)	S. typhimurium strains TA97, TA98, TA100 and TA1535 were exposed to N-cthvl-wMoluidinc up to 200
|j.g/platc with and without metabolic activation. Information on controls was not provided.
N-Ethyl-i-toluidine was mutagenic in this assay.
(3)	Escherichia coli strain WP2uvrA was exposed to N-cthvl-wMoluidinc up to 5000 |.ig/platc with and without
metabolic activation. Cytotoxicity was observed at 5000 |ag/plate.
N-Ethyl-i-toluidine was not mutagenic in this assay.
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
S. typhimurium strains (not stated) were exposed to N,N-dimethyl-/?-toluidine up to 5000 |.ig/platc with and without
metabolic activation. Without metabolic activation, cytotoxicity was observed at 1000 |ag/plate. In a similar assay
using concentrations up to 100 |.ig/platc. the cytotoxic concentration was 100 |.ig/platc. It is not clear if positive
controls were used.
N,N-Dimcthyl-/>-toluidinc was not mutagenic in these assays.
N,N-Diethylaniline (CAS No. 91-66-7)
In several Ames, assays S. typhimurium strains were exposed to N,N-diethylaniline up to 5000 |.ig/platc with and
without metabolic activation. No mutagenic activity was observed.
N,N-Diethylaniline was not mutagenic in these assays.
Genetic Toxicity - Chromosomal Aberrations
In vitro
Aniline (CAS No. 62-53-3, supporting chemical)
In several cytogenetic assays, aniline was tested in Chinese hamster lung fibroblast, ovary and v79 cells at
concentrations up to 5000 ng/mL with and without metabolic activation.
Aniline induced chromosomal aberrations in these assays.
m-Toluidine (CAS No. 108-44-1, supporting chemical)
Cultured Chinese hamster lung (CHL/IU) cells were exposed to w/-toluidinc up to 1.1 mg/mL with and without
metabolic activation. The positive controls gave expected responses. Structural chromosomal aberrations were not
induced up to the highest concentrations tested. Polyploidy was significantly increased (p < 0.05), but remained
within historical controls and was not considered positive.
i-Toluidine did not induce chromosomal aberrations in this assay.
12

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p-Toluidine (CAS No. 106-49-0, supporting chemical)
In two in vitro chromosomal aberration studies, cultured Chinese hamster lung cells were exposed to /Moluidinc up
to 1000 iig/mL with and without metabolic activation. The positive controls gave expected responses. The
cytotoxic concentration in the presence of metabolic activation was 25 |ig/mL. The induction of chromosomal
aberrations was only observed in the presence of metabolic activation at concentrations > 12.5 |ig/mL. No
chromosomal aberrations were observed in the absence of metabolic activation.
/7-Toluidine induced chromosomal aberrations in these assays.
N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
In a cytogenetic assay, Chinese Hamster V79 cells were exposed to N,N-dimethyl-p-toluidine up to 1.2mM without
metabolic activation. Cytotoxicity was observed at 1.2 mM, where > 10% survival was estimated by colony
formation. It is not clear if positive controls were used.
N,N-Dimcthyl-/>-toluidine induced chromosomal aberrations in this assay.
In vivo
Aniline (CAS No. 62-53-3, supporting chemical)
In several cytogenetic assays with mice (oral and intraperitoneal administration) and rats (gavage) tested up to 1000
mg/kg, aniline tested positive.
Aniline induced chromosomal aberrations in these assays.
p-Toluidine (CAS No. 106-49-0, supporting chemical)
In an in vivo mouse micronucleus test, CD-I male and female mice were administered 43.75, 87.50 and 175.0
mg/kg-bw/day /Holuidinc via the intraperitoneal route of exposure. Signs (not stated) of clinical toxicity and
mortality were observed. No cytotoxicity was seen. One hundred immature erythrocytes were scored per animal
instead of 2000.
/7-Toluidine did not induce chromosomal aberrations in this assay.
N,N-Diethylaniline (CAS No. 91-66-7)
In an in vivo micronucleus assay, Bor:NMRI mice were administered N,N-diethylaniline via intraperitoneal injection
at 600 mg/kg-bw. There was an altered ratio between polychromatic and normochromatic erythrocytes. No
increase in micronuclei was observed.
N,N-Diethylaniline did not induce micronuclei in this assay.
Genetic Toxicity - Other
In vitro
N,N-Diethylaniline (CAS No. 91-66-7)
In an unscheduled DNA synthesis assay in vitro, primary cultured rat hepatocytes were exposed to N,N-
diethylaniline at 0.15 - 150 |ag/mL. No unscheduled DNA synthesis was observed in this assay.
N,N-Diethylaniline did not induce unscheduled DNA synthesis in this assay.
In vivo
Aniline (CAS No. 62-53-3, supporting chemical)
Wistar-derived rats were administered 75, 150 and 200 mg/kg-bw aniline via the intraperitoneal route of exposure
over 5 days. The positive control gave an appropriate response. No evidence of a dominant lethal effect was
observed.
Aniline did not induce dominant lethal effects in this assay.
p-Toluidine (CAS No. 106-49-0, supporting chemical)
In an in vivo alkaline elution assay, male Swiss CD-I mice were administered /Holuidinc via a single intraperitoneal
injection of 35 mg/kg-bw. Solvent was used as the negative control. Single strand breaks were observed in the
DNA of liver and kidney nuclei. p-Toluidine was considered positive for this assay.
/7-Toluidine did not induce chromosomal effects in this assay.
13

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N,N-Dimethyl-p-toluidine (CAS No. 99-97-8)
In two in vivo alkaline elution assays, Balb/c mice were administered N,N-dimethyl-/?-toluidine via intraperitoneal
injection at up to 1080 mg/kg-bw for up to 24 hours. DNA fragmentation increased in liver cells to about 2.4 times
the control at the highest dose only and suggested that N,N-dimethyl-/?-toluidine was weakly positive in this assay.
Similar results were obtained when N,N-dimethyl-/?-toluidine was tested in Sprague-Dawley rats.
N,N-Dimethyl-p-toluidine induced chromosomal effects in these assay.
Additional Information
Eye Irritation
N-Ethyl-m-toluidine (CAS No. 102-27-2)
New Zealand White rabbits (6 females) eyes were exposed to 0.1 mL of undiluted N-cthvl-wMoluidinc without
rinsing. The animals were scored at 24 hours and all signs of irritation had cleared by 72 hours. N-cthvl-w/-
toluidine was not considered irritating to the eye under these conditions.
N-Ethyl-i-toluidine was not irritating to rabbit eyes in this assay.
N,N-Diethylaniline (CAS No. 91-66-7)
N,N-diethylaniline was not irritating to the eyes when tested on rabbits. (No additional information is provided.)
N,N-Diethylaniline was not irritating to rabbit eyes in this assay.
Skin Irritation
N-Ethyl-m-toluidine (CAS No. 102-27-2)
New Zealand White rabbits (3/sex) were exposed to undiluted N-ethyl-p-toluidine for 4 hours under an occlusive
dressing. All animals were scored after unwrapping and at day 7. N-Ethyl-wMoluidinc was slightly irritating to the
skin under these conditions.
N-Ethyl-m-toluidine was slightly irritating to rabbit skin in this assay.
N,N-Diethylaniline (CAS No. 91-66-7)
N,N-Diethylaniline was slightly irritating to the skin when tested on rabbits. (No additional information is
provided.)
N,N-Diethylaniline was slightly irritating to rabbit skin.
Skin Sensitization
N-Ethyl-m-toluidine (CAS No. 102-27-2)
An undiluted sample of 0.3 mL N-cthvl-wMoluidinc in acetone was tested in rabbits (10/sex) via dermal application.
The rabbits were challenged with a 50% solution of N-cthvl-wMoluidinc. Irritation was observed in some control
animals at 24 hours. The irritation had resolved by 48 hours. The response of the challenged animals was
comparable to the controls. N-Ethvl-wMoluidinc was not considered a sensitizer under these conditions.
N-Ethyl-m-toluidine was not a skin sensitizer in rabbit in this study
N,N-Diethylaniline (CAS No. 91-66-7)
A 10% solution of N,N-diethylaniline was tested in guinea pigs via dermal application. The dermal challenge
exposure using 1 or 2% solutions of N,N-diethylaniline did not elicit a response. N,N-Diethylaniline was not
considered a skin sensitizer under these conditions.
N,N-Diethylaniline was not a skin sensitizer in guinea pig in this study.
Carcinogenicity
Carcinogenicity bioassays conducted by the National Toxicology Program for supporting chemicals aniline, N,N-
Dimethylaniline, and o-toluidine) provide insights regarding the potential carcinogenicity of the monocyclic
aromatic amines category members.
14

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Aniline Hydrochloride (CAS No. 142-04-1, supporting chemical)
In a National Toxicology Program carcinogenicity bioassay, groups of 50 male and female Fischer 344 rats and
B6C3Fi mice were fed high and low dietary concentrations of aniline hydrochloride of 0.6 and 0.3 percent for rats
and 1.2 and 0.6 percent for mice. After a 103-week period of compound administration, observation of the rats and
mice continued for up to an additional 5 weeks. In male rats the incidences of several types of tumors were
associated with administration of the compound. In mice of both sexes no tumors occurred in statistically
significant increased incidences among dosed groups when compared to controls. [http://ntp-
apps.niehs.nih.gov/ntp_tox/]
Under the conditions of this bioassay, dietary administration of aniline hydrochloride was carcinogenic to
male and female Fischer 344 rats, inducing hemangiosarcomas and a combination of fibrosarcomas and
sarcomas NOS of the spleen and a combination of fibrosarcomas and sarcomas NOS of multiple body organs.
There was no evidence of compound-induced carcinogenicity in B6C3Fi mice of either sex.
N,N-Dimethylaniline (CAS No. 121-69-7; supporting chemical)
In a National Toxicology Program carcinogenicity bioassay, groups of 50 male and female Fischer 344 rats and
B6C3Fi mice were administered N,N-dimethylaniline in corn oil by gavage at 0, 3, or 30 mg/kg for rats and 0, 15, or
30 mg/kg for mice, 5 days per week for 103 weeks. Under the conditions of these 2-year gavage studies, there was
some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased
incidences of sarcomas or osteosarcomas (combined) of the spleen. There was no evidence of carcinogenic activity
of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 years. There was
no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3Fi mice given 15 or 30 mg/kg body
weight by gavage for 2 years. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for
female B6C3Fi mice, as indicated by an increased incidence of squamous cell papillomas of the forestomach. Both
rats and mice could have tolerated doses higher than those used in these studies. [http://ntp-
apps.niehs.nih.gov/ntp_tox/]
Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of N,N-
dimethylaniline for male F344/N rats, there was no evidence of carcinogenic activity of N,N-dimethylaniline
for female F344/N rats, there was no evidence of carcinogenic activity of N,N-dimethylaniline for male
B6C3Fi mice and there was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female
B6C3Fi mice.
o-Toluidine (CAS No. 636-21-5)
In a National Toxicology Program carcinogenicity bioassay, groups of 50 male and female F344 rats and B6C3Fi
mice were administered o-toluidine hydrochloride at one of several doses, either 3000 or 6000 ppm for rats and
either 1000 or 3000 ppm for the mice, for 101 to 104 weeks. In rats, the administration of the test chemical induced
several types of sarcomas of the spleen and other organs in both males and females, mesotheliomas of the abdominal
cavity or scrotum in males, and transitional-cell carcinomas of the urinary bladder in females. Administration of the
o-toluidine hydrochloride also resulted in increased incidences of fibromas of the subcutaneous tissue in the males
and fibroadenomas or adenomas of the mammary gland in females. In mice, hemangiosarcomas were induced at
various sites in males, and hepatocellular carcinomas or adenomas were induced in females. [http://ntp-
apps.niehs.nih.gov/ntp_tox/]
Under the conditions of this bioassay, o-toluidine hydrochloride was carcinogenic in both male and female
F344 rats and B6C3Fi mice, producing a significant increased incidence of one or more types of neoplasms.
Conclusion: Acute oral and dermal toxicity of category members is low and acute inhalation toxicity of category
members is high. The category members are slightly irritating to the skin and eyes of rabbits; but are not sensitizing.
Repeated oral exposure to N,N-diethyl aniline resulted in decreased red cell counts and hemoglobin concentrations
and histopathological changes in the liver and spleen (changes in relative and absolute weights, hemosiderosis and
hematopoiesis). Repeated inhalation exposure to N-cthvl-wMoluidinc resulted in methemoglobinemia in rats at all
exposure concentrations. Enlarged spleens, increased production of red cells in the spleen, bone marrow and other
hematological changes were seen that were consistent with the induction of hemolytic anemia. Repeated oral
inhalation studies with the supporting chemicals, w/-toluidinc and aniline, respectively, corroborated these findings.
Rats and mice with the chronically exposed to the supporting chemical, aniline, had decreased ovary weights. In a
combined repeated-dose/reproductive/developmental toxicity screening test with the supporting chemical,
15

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w/-toluidinc. effects on reproduction were implantation losses. Effects observed in developmental toxicity studies in
rats exposed to N,N-diethylaniline and the supporting chemicals, aniline and w/-toluidinc. include decreased fetal
weights, hematopoietic activity, increased liver weights and pup mortality. The category members, N-ethylaniline,
N,N-diethylaniline and N,N-dimethyl-/>-toluidine, were not mutagenic in vitro; N-cthvl-wMoluidinc induced gene
mutations in the presence of metabolic activation. Based on data from the supporting chemicals, N-Ethyl-w/-
toluidine is not expected to induce chromosomal aberrations and other category members have potential to induce
chromosomal aberrations with or without metabolic activation. In NTP chronic toxicity/carcinogenicity studies in
F-344 rats and B6C3F1 mice with the supporting chemicals aniline, N,N-dimethylaniline and o-toluidine positive
evidence for carcinogenicity was seen (see study summaries for details [http://ntp-apps.niehs.nih.gov/ntp_tox/].
16

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Table 3. Summary of Human Health Data
Endpoints
Aniline
(supporting
chemical)
62-53-3
/fi-Toluidinc
(supporting
chemical)
108-44-1
/;-Toluidine
(supporting
chemical)
106-49-0
N-Ethvlaniline
103-69-5
N-Ethvl-///-
toluidine
102-27-2
N,N-
Dimcthylanilinc
(supporting
chemical)
121-69-7
N,N-Dimcthyl-/>-
toluidine
99-97-8
N,N-Diethyl
aniline
(91-66-7)
Acute Oral Toxicity
LDS0 (mg/kg-bw)
	* *
	* *
	* *
363 - 478
650 - 787
	* *
1650
606
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
	* *
	* *
	* *
1347- 1915 (rat)
> 2000 (rabbit)
>2000
	* *
>2000
> 5000 (rat)
468 - 935
(rabbit)
Acute Inhalation Toxicity
LC50 (mg/L/6h/day)
	* *
	* *
	* *
1.13-1.48
2.4
	* *
1.4
1.92
Repeated-Dose Toxicity
Oral
NOAEL/LOAEL
(mg/kg-bw/day)
	* *
NOAEL = Not
established
LOAEL = 30
	* *
No Data
NOAEL = Not
established
LOAEL = 10
(RA)
No Data
NOAEL = Not
established
LOAEL = 10
(RA)
NOAEL = Not
established
LOAEL = 31
No Data
NOAEL = Not
established
LOAEL = 10
(RA)
NOAEL = Not
established
LOAEL = 10
Repeated-Dose Toxicity
Inhalation
NOAEL/LOAEL
(mg/L/day)
NOAEL = 0.04
LOAEL = 0.11
	* *
	* *
No Data
NOAEL = 0.04
LOAEL = 0.11
(RA)
NOAEL = 0.03
LOAEL = 0.18
	* *
No Data
NOAEL = 0.03
LOAEL = 0.18
No Data
NOAEL = 0.03
LOAEL = 0.18
Reproductive Toxicity
NOAEL/LOAEL
(mg/kg-bw/day)
(26 week)
NOAEL = 72
NOAEL = 30
LOAEL =100
	* *
No Data
NOAEL = 30
LOAEL = 100
(RA)
No Data
NOAEL = 30
LOAEL = 100
(RA)
	* *
No Data
NOAEL = 30
LOAEL = 100
(RA)
No Data
NOAEL = 30
LOAEL = 100
(RA)
Developmental Toxicity
NOAEL/LOAEL
(mg/kg-bw/day)
Maternal Toxicity
NOAEL = NE
LOAEL = 10
NOAEL = NE
LOAEL = 30
	* *
No Data
NOAEL = NE
LOAEL = 10
No Data
NOAEL = NE
LOAEL = 30
	* *
No Data
NOAEL = 250
LOAEL = 500
NOAEL = 250
LOAEL = 500
Developmental Toxicity
NOAEL = 30
LOAEL = 100
NOAEL =100
LOAEL = 300

NOAEL = 30
LOAEL = 100
(RA)
NOAEL = 100
LOAEL = 300
(RA)

NOAEL = 250
LOAEL = 500
(RA)
NOAEL = 250
LOAEL = 500
17

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Table 3. Summary of Human Health Data
Endpoints
Aniline
(supporting
chemical)
62-53-3
/fi-Toluidinc
(supporting
chemical)
108-44-1
/;-Toluidine
(supporting
chemical)
1 (16-49-0
N-Ethvlaniline
103-69-5
N-Ethvl-/H-
toluidinc
102-27-2
N,N-
Dimcthvlanilinc
(supporting
chemical)
121-69-7
N,N-Dimethyl-/;-
toluidine
99-97-8
N,N-Diethvl
aniline
(91-66-7)
Genetic Toxicity -
Gene Mutation
In vitro
	* *
	* *
	* *
Negative
Positive
	* *
Negative
Negative
Genetic Toxicity -
Chromosomal
Aberrations In vitro
Positive
Negative
Positive
No Data
Positive
(RA)
No Data
Negative
(RA)
	* *
No Data
Positive
(RA)
No Data
Positive
(RA)
Genetic Toxicity -
Chromosomal
Aberrations In vivo
Positive
	* *
Negative
No Data
Positive
(RA)
No Data
Positive
(RA)
	* *
No Data
Positive
(RA)
Negative
Genetic Toxicity - Other








Unscheduled DNA
synthesis (in vitro)
Alkaline elution assay (in
vivo)
Dominant lethal assay (in
vivo)
	
	
Negative
	**
	**
	**
	
Positive
	
	*
	*
	*
	*
	*
	*
	**
	**
	**
	*
Weak positive
	*
Negative
	*
	*
Additional Information
Skin Irritation
Eye Irritation
Skin Sensitization
Carcinogenicity
	
	
	
Positive evidence
	**
	**
	**
	
	
	
Positive evidence
	*
	*
	*
Slightly
irritating
Not irritating
Negative
	**
	**
	**
Positive evidence
	*
	*
	*
Slightly
irritating
Not irritating
Negative
Measured data in bold; (RA) = Read-Across;  indicates endpoint not addressed for this chemical; * indicates endpoint not necessary for non-SIDS endpoint; ** indicates
endpoint not necessary for supporting chemical
18

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4. Hazard Characterization
The log Kow values of the monocyclic aromatic amines category members indicate that their potential to
bioaccumulate is low. The monocyclic aromatic amines category members are not readily biodegradable, indicating
that they have the potential to persist in the environment.
The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants for the monocyclic
aromatic amines category members indicates that the acute hazard to fish is low, to aquatic invertebrates is low (N-
ethylaniline) to moderate (N,N-diethylaniline) and hazard to aquatic plants is low (N-ethylaniline) to moderate
(N,N-diethylaniline).
Acute oral and dermal toxicity of category members is low and acute inhalation toxicity of category members is
high. The category members are slightly irritating to the skin and eyes of rabbits; but are not sensitizing. Repeated
oral exposure to N,N-diethyl aniline resulted in decreased red cell counts and hemoglobin concentrations and
histopathological changes in the liver and spleen (changes in relative and absolute weights, hemosiderosis and
hematopoiesis). Repeated inhalation exposure to N-cthvl-wMoluidinc resulted in methemoglobinemia in rats at all
exposure concentrations. Enlarged spleens, increased production of red cells in the spleen, bone marrow and other
hematological changes were seen that were consistent with the induction of hemolytic anemia. Repeated oral
inhalation studies with the supporting chemicals, w/-toluidinc and aniline, respectively, corroborated these findings.
Rats and mice with the chronically exposed to the supporting chemical, aniline, had decreased ovary weights. In a
combined repeated-dose/reproductive/developmental toxicity screening test with the supporting chemical,
w/-toluidinc. effects on reproduction were implantation losses. Effects observed in developmental toxicity studies in
rats exposed to N,N-diethylaniline and the supporting chemicals, aniline and w/-toluidinc. include decreased fetal
weights, hematopoietic activity, increased liver weights and pup mortality. The category members, N-ethylaniline,
N,N-diethylaniline and N,N-dimethyl-/>-toluidine, were not mutagenic in vitro; N-cthvl-wMoluidinc induced gene
mutations in the presence of metabolic activation. Based on data from the supporting chemicals, N-Ethyl-w/-
toluidine is not expected to induce chromosomal aberrations and other category members have potential to induce
chromosomal aberrations with or without metabolic activation. In NTP chronic toxicity/carcinogenicity studies in
F-344 rats and B6C3F1 mice with the supporting chemicals aniline, N,N-dimethylaniline and o-toluidine positive
evidence for carcinogenicity was seen (see study summaries for details [http://ntp-apps.niehs.nih.gov/ntp_tox/].
The potential health hazard of the monocyclic aromatic amines category is moderate via the oral exposure route and
high via the inhalation exposure route based on repeated-dose and developmental toxicity. Related chemicals
supporting the category members show evidence of carcinogenicity.
5. Data Gaps
No data gaps have been identified under the HPV Challenge Program.
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Appendix
Monocyclic Aromatic Amines Category
CAS No.
Chemical Name
Structure
Sponsored Chemicals
103-69-5
N-Ethylaniline
^ X.J
102-27-2
N-Ethyl-wMoluidinc
K * CH,
99-97-8
N.N-Dimcthvl-/Moluidinc

91-66-7
N,N-Diethylaniline

Supporting Chemicals
62-53-3
Aniline

121-69-7
N,N-Dimethylaniline

636-25-1
o-Toluidine
CH3
108-44-1
/w-Toluidine
d		
106-49-0
p-Toluidinc

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Chemical Name
CAS Number
R1
R2
R3
R4
N,N-Diethyl aniline
91-66-7
C2H5
c2h5
H
H
N,N-Dimethyl-p-toluidine
99-97-8
CO
X.
0
ch3
CHs
H
N-Ethyl m-toluidine
102-27 2
C2H5
H
H
gh3
N-Ethyl aniline
103-89-5
C2H5
H
H

Chemical Name
CAS Number
R1
R2
R3
R4
R5
o-Toimdine
95-53-4
H
H
H
H
ch3
p-Toluidine | 106-49-0
H
H
0
1
jinO
H
H
m-Toluidine | 108-44-1
H
H
H
CH3 i H
Aniline I 62-53-3
H
H
H
H i H
N,N-Dimethyl aniline] 121-69-7
ch3
ch3
H
H
H
21

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