EPA-600/1-76-031
September 1976
Environmental Health Effects Research Series
THE IN-V/VO METABOLISM OF
EP 600/1
76-031
iialtfc Iffesti
Agency
27711
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environ-
mental Protection Agency, have been grouped into five series. These five broad
categories were established to facilitate further development and application
of environmental technology. Elimination of traditional grouping was con-
sciously planned to foster technology transfer and a maximum interface in
related fields. The five series are
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4, Environmental Monitoring
5. Socioeconomic Environmental Studies
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS
RESEARCH series, "his series describes projects and studies relating to the
tolerances of man for unhealthful substances or conditions This work is gener-
ally assessed from a medical viewpoint, including physiological or psycho-
logical studies. In addition to toxicology and other medical specialities, study
areas include biomed/ca! instrumentation and health research techniques uti-
lizing animalsbut always with intended application to human health measures.
This document is available to the public through the' National Technical Informa-
tion Service, Springf-eld, Virginia 22161.
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EPA-600/1-76-031
September 1976
THE IN-VIVO METABOLISM OF PENTACHLOROANILINE
IN RHESUS MONKEYS
By
A. Philip Leber and R. I. Freudenthal
Battelle Columbus Laboratories
505 King Avenue
Columbus, Ohio 43201
Contract No. 68-02-1715
Project Officer
Dr. Ronald L. Baron
Environmental Toxicology Division
Health Effects Research Laboratory
Research Triangle Park, N.C. 27711
LTT5PARY
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
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DISCLAIMER
This ropo7l h.-.s: been reviewed by the Hoalc!i H^" feels Research
Lauor.'itoj y , '-.''. '".:;v; I'oiiinentai Piutecfion Agent} , ai.a pu,)roved fcr
publiC'iTiuu. Ap--' i1:-.' .;. :;r "or,")!', r^i :-J p "':.c!'.H-f .-.
const! I ite endorjenenl c-' : eco^jr-ond-it ion for use.
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk
of existing and new man-made environmental hazards is necessary for the
establishment of sound regulatory policy. These regulations serve to
enhance the quality of our environment in order to promote the public
health and welfare and the productive capacity of our Nation's population.
The Health Effects Research Laboratory, Research Triangle Park
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects. These
studies address problems in air pollution, non-ionizing radiation,
environmental carcinogenesis and the toxicology of pesticides as well as
other chemical pollutants. The Laboratory develops and revises air quality
criteria documents on pollutants for which national ambient air quality
standards exist or are proposed, provides the data for registration of new
pesticides or proposed suspension of those already in use, conducts research
on hazardous and toxic materials, and is preparing the health basis for
non-ionizing radiation standards. Direct support to the regulatory function
of the Agency is provided in the form of expert testimony and preparation of
affidavits as well as expert advice to the Administrator to assure the
adequacy of health care and surveillance of persons having suffered imminent
and substantial endangerment of their health.
Studies of the metabolic fate of toxic chemicals give the Agency further
insight into the significance of these agents in the environment. The metabolism
of toxicants generally results in formation of chemicals of unknown toxicological
properties. Chemical identification and toxicological evaluation of these
chemicals and their metabolites continues to be an integral part of the
environmental assessment necessary for continued safe use of chemicals.
John H. Knelson, M.D.
Director
Health Effects Research Laboratory
111
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INTRODUCTION*. .......................... ]
EXPERIMENTAL. ......................... 2
Materials 2
Methods. ......................... 2
RESULTS , . . . . ....,.., 4
Pharmacol; inet ic Profile, ................. 4
Metabo' is.m of PCA ^ ..-...,.,.,.. 4
Wate£-Sc3ublo Metabolites. .............. 6
Mutagenefils Assay. 6
DISCUSSION 7
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INTRODUCTION
Pentachloronitrobenzene (PCNB) was first registered for agricultural
use in 1955 and is manufactured under the trade name Terrachlor© by Olin
Corporation. The chemical is registered primarily for use as a soil fungi-
cide and as a seed treatment.
Up to 12 percent of the U. S. cotton acreage and 2 to 3 percent of
the peanut acreage is treated with PCNB. It is also used as a soil fungicide
for nursery plants and vegetables. Maximum tolerance limits on edible food
crops is 0.1 ppm, except for peanuts which has a tolerance limit of 1.0 ppm
(U. S. EPA, 1976).
PCNB is applied to many types of storage crops, vegetable and grain
seeds as a storage fungicide. No tolerance limits have been set since these
seeds are not to be used for feed.
PCNB has been shown to rapidly disappear from submerged soil follow-
ing its application. Ko and Farley (1969) demonstrated that the half-life for
PCNB is approximately 7 days, and during that period, a corresponding increase
in pentachloroaniline (PCA) occurs. This conversion is favored by anaerobic
conditions and is carried out by microorganisms in the soil. The same experi-
ments showed that PCA may be very persistent in soil since no decrease was
seen during a two-week period under soil conditions which rapidly lead to the
disappearance of PCNB.
Previous work which examined the metabolism of PCNB has been
reported. It was learned that PCA is a major metabolite of the pesticide in
rabbits (Betts. et al., 1955), cows (St. John, et al., 1965), phytopathogenic
fungi (Nakanishi and Oku, 1969), and plant seedlings, rats, and beagle dogs
(Kuchar, et al., 1969; Borzelleca, et al., 1971). Methylpentachlorophenyl
sulfide has also been shown to be a metabolite of PCNB in plants and animals
in several of these studies.
The purpose of this work was to examine the pharmacokinetic
properties of PCA in the rhesus monkey and to identify any major metabolites
which may be formed in vivo.
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California PIMIUC ca- Corp.: rat: i :- .. '-
Uiiidbeled peiiLach^or ;;i:,: Ixn^ (?CA) i,: . o""taLn'.:d ~r - ' ; lu C"; 't'.r--rl(M:. :U 1
solvents used foi crga ;ic extractions and thin-lay-. ,: : aroma to.^raphy were
spectral quality (Bur ; »_ck -Jackson; . J>CC cocktail (.'jneisham-Searle) was used
as P. medium for liqui:, pclni.illar.ion counting of samples.
Ad1, '-i iTifiie C--8 kg) rhesus monkeys vert ob; aineJ frotn
Imports Company. A:\iija IP were quarar-cined Ln-house fo<" at least 6 weeks prior
to use.
Methods
Five male rhesus monkeys w^ra us fid in thtj 3'rudy. The ariTnals were
fasted for 14 hours prior to oral do.-ivng with 100 nCl ^ ^P-PCA at naxirns]
specific activity, Eich a^Lna] iec«=-i.ved 17.3 ;j\g PC A .-.]uiv-.l-:it to frro'vi 2,7
ing/k^ Lo 2.9 mg/l'fe, Tlie c'nemicvl yj-.-, 3.'>->JnLstr"ed it- ''.O ml corn oil '.i?ing a
feeding, needle. A.::.iii''\lr-: ;-'e'i e vriair:;;a ' .led on vrg^e> ad ilbltor.. Acces tu
monkvy chow (Fucina) w-is resumed " hours follo-.ying PCA admi r,istraticn.
Blood samples, urine, and feces ware coJleci'ed at designated tines
following dosing. To determine total radioactivities , aqueous suspensions of
feces and blood saraples (0.2 ml) were added to 1 volume of 60 percent: per
chloric acid, followed by 2 volumes of 30 percent hydrogen peroxide, and
digested in sealed scintillation vials for 2 hours at 70 C. Counting cocktail
was added to these sample (urine directly) and the total radioactivity in
each biological sample was dc r.enn i rie:: by liquid scirt illation, counting. The
data, reported
~{ -<-<['. rv, qu--
Tr
i , \.erc-- d"-ri\-d \tc,u , ;-. r rpt
-------
The N-hydroxylamine of PGA was chemically synthesized by the method
of Berry, et al. (1969) according to the scheme in Figure 1. Hexachlorobenzene
(Brothers Chemical Co., Orange, New Jersey), 25 g (0.88 mole); cyclohexylamine
(freshly distilled, b.p. 132-134 C), 28.6 ml (24.8 g, 0.25 mole); and sulfolane
(tetrahydrothiophene-1, 1-dioxide), 175 ml, were placed in a 250-ml round-
bottomed flask equipped with a reflux condenser and heated to 145-150 C with
stirring for 14 hours. The solution was cooled and the precipitate collected
by suction filtration. The solid was dissolved in ice-cold sulfuric acid,
filtered to remove hexachlorobenzene, and poured onto ice. Pentachlorophenyl-
cyclohexylamine precipitated and was collected by filtration, air dried, and
recrystallized from ethanol to yield 10.9 g (36 percent). The m.p. (64-66 C,
lit. 70 C), and the IR spectrum confirmed the identity of this product.
N-pentachlorophenylcyclohexylamine, 5.0 g (14.4 mmole), 19 ml of
chloroform, 19 ml of formic acid (90 percent), and 4 ml of hydrogen peroxide
(30 Percent) were placed in a flask and stirred magnetically for 2 hours. The
precipitate which formed was filtered to give 255 mg (6.3 percent yield) of
product. The filtrate was let stand overnight and an additional 393 mg (9.7
percent) of precipitate formed and was collected. A 250-mg portion of the
crude product was recrystallized from 25 ml of acetone with only light heating
to yield 180 mg of pure N-hydroxypentachloroaniline, m.p. 174-176 C (lit.
161-163 C, impure). The structure of this product was confirmed by IR and mass
spectroscopy (Figures 2 and 3).
Three procedures which were initially tried proved to be unsuccessful
for the synthesis of N-hydroxypentachloroaniline. They induced attempts at
reduction of pentachloronitrobenzene with (a) zinc metal, (b) Raney nickel-
hydrogen, and (c) palladium on charcoal-hydrogen. Procedures (a) and (c)
resulted in partial reduction to PCA, while (b) resulted in no appreciable
reduction of the starting material.
Mass spectral data were obtained with either a Finnigan Model 1015
electron impact mass spectrometer or a Finnigan Model 3200 gas chromatograph
chemical ionization mass spectrometer (GC-CI-MS). A System Industries 250
data system controlled the mass spectrometer scan function and processed the
signal output data. A 1.83-m x 2-mm glass column packed with 3 percent OV-1
on 100/120 nesh Gas Chrom Q was used for the GC-CI-MS work. The injection
port temperature and the line between the GC and MS were kept at 200 C. The
flow rate of the carrier gas (methane) was set at 20 ml/min. The column temp-
erature was programmed from 100 to 280 C at 10 C/min.
The infrared data were obtained with a Digilab FTS-14 Infrared
Spectrometer. Fourier transform technique was used in generating the infrared
spectrum. The sample was examined as a film on KC1 plates.
PCA and its major metabolite were tested for mutagenic activity by
the Ames bacterial assay (McCann, et al., 1975). Rat liver microsomes were
used as a source of oxidative enzymes in the activating system.
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i i: &.-(.'* .:;i-ure -. , ""- data ,>! ic r> ; ..r,,'/.
l' « .Ltu r< <>],..'' T o ' "e t.ir ; r OLV'" rac;l:>--
act-j.'-n ty, v£. \ I 'i,-, fro;> '. aoir (Rh:'e-.. A a~id B) LC .'? r>our,s (V.l.esus C ^ri-i D) ..
The t.x.'re. r.;. ;. aa L»ac tivi' - tor each aniiiaJ ;- g'i\'(-n xn Tal it 1, The
larger portioT cf tro radioactivity was eKcrel.ed via tl-.e urine (33 to 67 per-
cent) while R i^s:-i~-L .;n-oint (6--13 peiT.ent) was excTei;<-_d in : he feces,
In an attempt ;:o explain the large variations see:i in the blood data
(Figure^4), several ptrtiuent data vjcre compiled in Table 2. The higher values
for the renal excretion of radioactivity in Monkeys A, Bs and E match the days
for which peak radioactivities were observed in the blood, as would be expected.
The data also s.iggest a more rapid intestinal removal of radioactivity in
these three animals which would also correlate with errlier peak blood levels
for these monkeys.
Metabolism of PGA
Organic extraction of radioactivity followed by TLC shows that only
unchanged -^C-FCA is excreted in the feces (Figure 5), as the radioactivity
cochromatographed with urlabeled PCA (Rf = 0.50).
TLC scans cf hc>>;,Ti:e extracts oi urine indicate z more complex pattern
of inet. abrlisir- . Fi^^ie t ccpjctc a. typical radiochroriatogrdin of these ox tracts .
Peaks having', Rf vjl'e^ '" ". , ;iC , 0,M6. 0 .SO, and 0,70 --ere- detected. I\
".e\ i-/:i L cxt r <. : . , _ --._( i-.i ~, > s set t ii;^ 1 ess t ',' ." 0.2 y r;r -en.;. .'< r ih:
chro;i:at..~rop , ' - .' : «... 't *-.<: :-.:- Rr -- )..'! :)nt r;i a-,; i t: y ; '-,-
"-f ) i; ;' ' e ;tL
. ! - ._lty r >
M
-------
believed to be a decomposition product characteristic of organic amines, and
further characterization was not pursued.
The substance isolated from the Peak 1 region was ultimately
determined to be the primary metabolite of PCA in rhesus monkeys. It was
found to be unstable as this region of the TLC plate rapidly became discolored
upon standing in the light. Subsequent TLC of this discolored material
resulted in the appearance of four peaks (Figure 9) whose Rf values correspond
to those seen in the original urine extract radiochromatogram (Figure 6).
Mass spectral analysis was performed on freshly prepared Peak 1
material. Initial analysis of the metabolite by electron impact and isobutane
chemical ionization mass spectrometry indicated the molecular weight of the
metabolite is 279. The mass spectra are shown in Figures 10 and 11. The
cluster of peaks around the molecular ion (Figure 10) and the protonated mole-
cular ion (Figure 11) region exhibit the same isotope ratio of pentachloroa-
niline in Figures 12 and 13, indicating the metabolite also has five chlorine
atom. The proton nuclear magnetic resonance spectrum of the metabolite did
not show any peaks in region confirming that none of the chlorine atoms had
been displaced by a hydrogen atom. The fragment ion at tn/e 262 (Figures 10
and 11) is what one would expect from a hydroxylated metabolite of PCA.
The molecular weight of 279 is odd in number indicating that it
contains an odd number of nitrogen atoms. It is also 16 units higher than
PCA implying that perhaps an oxygen atom is incorporated into the PCA molecule.
In the infrared spectrum, a sharp NH absorption band was observed at 3295 cm"-'-
and a broader NH or OH absorption band centered at 3205 cm . The identify of
the direct probe mass spectra of the Peak 1 metabolite (Figure 11) and
synthetic N-hydroxypentachloroaniline (Figure 3) confirms the structure of the
metabolite.
To further characterize the metabolite, trimethylsilylation was
performed with bis-trimethylsilyl-trifluoroacetamide. The derivative was
analyzed with GC-CI-MS. To enhance the intensity of the peaks at the mole-
cular ion region, ammonia was used as chemical ionization reagent gas. The
total ion current (TIC) trace is shown in Figure 14. The mass spectrum of the
major peak is shown in Figure 15. The hydroxyl group was silylated giving a
protonated molecular ion at m/e 353. This and the fragment ion at m/e 262
confirm that the metabolite has a hydroxyl group and it has a molecular weight
of 279. The mass spectrum of triraethylsilylated derivative of synthetic N-
hydroxypentachloroaniline is identical to that shown in Figure 16.
Attempts were made to analyze the unsilylated metabolite with GC-MS.
The GC trace is shown in Figure 17. Neither of the peaks corresponds to
N-hydrcxypentachloroaniline. The latter peak gives an identical spectrum to
that of PCA, and the earlier peak appears to be pentachloronitrosobenzene
(Figure 18). Hydroxylamines are known to undergo disproportionation to form
the nitroso and primary amine compounds. This would explain the appearance of
PCA and nitrosopentachlorobenzene following exposure of N-hydroxypentachloro-
aniline to the elevated temperatures of the GC system.
-------
actlvatia?, SVI'L^.US de. 1vf-:d from rat /Livers. No increase in rei'ertants was
seen in tne presence if 100 ug of either chemical (,'i^.bie ixi , Both :he raicro-
somal activati.ng system and the bacteria were shown to be active through the
use of positive chemical controls.
-------
DISCUSSION
14
Blood levels of radioactivity following C-PCA administration to
monkeys indicate wide variation between animals. These data would suggest
differences between rates of absorption of PCA from the GI tract. All monkeys
were fasted for 14 hours prior to treatment which should eliminate food matter
as a complicating factor. The use of corn oil as a vehicle for chemical
administration to animals has not, to our knowledge, led to irregularities in
chemical absorption in the GI tract. However, since the low urinary levels of
C on Day 1 for Rhesus C and D correlate with low blood levels of radio-
activity on that same day, it is apparent that the chemical was not readily
absorbed in these two monkeys during the first day. Also, their delayed fecal
excretion suggest a decreased GI motility which may play a role in the
diminished early absorption of PCA.
TLC scans suggest that only PCA is excreted in the feces. TLC of
urinary extracts indicates the presence of four radioactive compounds.
Figure 21 is a scheme which summarizes the metabolic information collected in
this study with PCA. PCA is metabolized oxidatively to the N-hydroxylamine,
as confirmed by mass spectroscopy and chemical synthesis of this compound.
Both PCA and N-hydroxypentachloroaniline are conjugated and fora water-soluble
metabolites which can be deconjugated by aryl sulfatase-glucuronidase.
Formation of nitrosopentachlorobenzene apparently results from a
spontaneous disproportionation of N-hydroxypentachloroaniline in the urinary
medium prior to extraction procedures. Fresh samples of urine had less of the
nitroso compound present upon TLC than did older samples. GC of purified
N-hydroxypentachloroaniline demonstrated the formation of the nitroso compound
following its exposure to elevated temperatures, and TLC indicates the
decomposition of N-hydroxypentachloroaniline to nitrosopentachlorobenzene,
as well as to PCA. Both PCA and N-hydroxypentachloroaniline partially decom-
posed to a brown substance, the structure of which was not pursued.
Although the mutagenesis assays in two bacterial systems indicate
that neither PCA or N-hydroxypentachloroaniline is mutagenic, this assay system
uses rat liver microsomal enzymes as an activation system. Since the
metabolism of PCA in the rat has not been determined, the use of the standard
assay activation system leaves unresolved the mutagenic potential of PCA and
N-hydroxypentachloroaniline in primates.
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3.3
tt 1
*)
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TABLE 2. RADIOACTIVITY EXCRETION RATIOS FOLLOWING
14C-PCA ADMINISTRATION TO RHESUS MONKEYS,
Rhesus
Day of
Peak Blood
Radioactivity
Ratio Urinary
Radioactivity,
Day l;Day 2
Ratio Fecal
Radioactivity,
Days l-3:Davs 4-5
A
B
C
D
E
1
1
2
2
1
1.24
2.54
0.15
0.19
4.69
2.1
14.2
1.1
0.6
5.6
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Caetiii cal
PCA
K-OH PCA
Controls
No chemicals
Mutagens, 20 pg
*; : -.ti. 'i Strain
TA-1538
TA-98
TA-1538
TA-98
TA-1583
TA-98
TA-1538
TA-98
hever: <.i
Amcunc ,;
?C 50
23 11,5
37 35,5
13,5 14 o 5
42,5 34
+AS
13
29
2NF*-2 -AS
28L6
2'V36
: o ic a. i (is /]''! -,-} le
Chc:,i I-?;"! Vg_
100 50-AS~^
17.5 8
47,5 44
19 . 5 10
41.5 41
-AS
200
45
2AA^3'+A
2469
3794
-------
Cl
Cl
Sulfolane
Cl
Heat
(145-150 )
Cl
NHOH
FIGURE 1. OXIDATIVE SYNTHESIS OF N-HYDROXYLPENTACHLOROANILINE
11
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Conjugates
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Rhesus
A Rhesus
Rhesus
Cl
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Cl
N-OH PCA (Peak 1)
Nonenzymatic
decomposition
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Cl
Cl
Nitrosopentachloro-
benzene (Peak 4)
PCA (Peak 3)
FIGURE 21. METABOLIC SCHEME FOR PCA IN RHESUS MONKEYS
31
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BIBLIOGRAPHY
Berry, D. J., Collins, I., Roberts, S. M., Suschitsky, H., and
Wakefield, B. J., Polyaromatic Compounds. Part V. Preparation
and Oxidation of Pentachlorophenyl-substituted Tertiary Amines and
Reactions of N-Butyl-lithium and other Nucleophiles with Various
Pentachlorophenyl Derivatives, J. Chem. Soc. (C) 1285-1294 (1969).
Betts, J. J., James, S. P., and Thorpe, W. V. , The Metabolism of
Pentachloronitrobenzene and 2, 3, 4, 6-tetrachloronitrobenzene and the
Formation of Mercapturic Acids in the Rabbit, Biochem. J,. , 61:
611-617 (1955).
Borzelleca, J. F., Larson, P. S., Crawford, E. M., Henniger, G. R. , Jr.,
Kuchar, E. J. and Klein, H., Toxicologica] and Metabolic Studies on
Pentachloronitrobenzene Toxicol, Appl. Pharmacol., 18: 522-534 (1971).
Kuchar, E. J., Geentiy, F. 0., Griffith, W. P., and Thomas, R. J. ,
Analytical Studies of Metabolism of Terrachlor in Beagle Dogs, Rats,
and Plants, J. Agr. Food Chem., 17: 1237-1240 (1969).
McCann, J., Spingam, N. E., Kobori, J. , and Ames, B. N. , Detection of
Carcinogens as Mutaj>ens: Bacterial Tester Strains with R Factor Plasmids,
Proc. Nat. Acad. Sci., 72.: 979-983 (1975),,
Nakanishi, T. and Oku, H., Mechanism of Selective Toxicity of Fungicides:
Metabolism of Pentachloronitrobenzene by Phytopathogenic Fungi, Ann.
Phytopath. Soc. Japan, 35.: 339-346 (1969).
St. John, L. E., Jr., Ammering, J. W., Wagner, D. G. , Warner, R. G. ,
and Lisk, D. J., Fate of 2, 4-dinitro-2-isobutylphenol, 2-chloro-4-6-
bis-(ethylamino)-S-trazine, and pentachloronitrobenzene in the dairy
cow, J. Dairy Sci., 48_: 502-503 (1965).
U. S. EPA, Report on the Initial Scientific Review of PCNB, Office of
Pesticide Programs, Washington, D.C., April, 1976.
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\
TECHNICAL REPORT DATA
PlLasc read Instruction!, on the reverse before completing)
RF-'ORT NO
LP-\-600/l-76-031
\ ~< ; LE AND SUBTITLE
THE IN-VIVO METABOLISM OF PENTACHLOROANILINE IN
RHESUS MONKEYS
3 RECIPIENT'S ACCESS! Of* NO.
5. REPORT DATE
September 1976
6. PERFORMING ORGANIZATION CODE
7 AUTHOR(S)
A. Philip Leber and R. I. Freudenthal
8. PERFORMING ORGANIZATION REPORT NO.
9 PERFORMING ORGANIZATION NAME AND ADDRESS
Battelle
Columbus Laboratories
505 King Ave.
Columbus, OH 43201
10. PROGRAM ELEMENT NO.
1EA615
11. CONTRACT/GRANT NO.
68-02-1715
12 SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratories
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
13. TYPE OF REPORT AND PERIOD COVERED
Interim
14. SPONSORING AGENCY CODE
EPA-ORD
15. SUPPLEMENTARY NOTES
IS ABSTRACT
The metabolism of pentachloroaniline was determined in the rhesus monkey.
14c-pentachloroaniline was orally administered to five rhesus monkeys. Blood,
urine and feces were collected at designated times following dosing. The radio-
active material in the biological samples was extracted and then separated by
chromatographic procedures. The chemical structure of the major metabolite was
characterized by mass spectrometry and nuclear magnetic resonance spectrometry,
uring a chemically synthesized reference standard.
Radioactivity levels in the blood samples indicate large variation between
individual animals with respect to rate of absorption and time of peak plasma
radioactivity. Urinary excretion accounts for 33 to 67 percent of the administered
dose while from 6 to 15 percent is excreted in the feces.
The major metabolite of pentachloroaniline, N-hydroxypentachloroaniline, is
excreted in the urine. Only unchanged pentachloroaniline is found the feces. A
small amount of nitrosopentachlorobenzene, found in the urine samples, results from
the spontaneous disproportionate of the N-hydroxy metabolite.
Both pentachloroani1ine and the N-hydroxy metabolite were tested for mutageni
activity using the two Salmonella tester strains, TA-1358 and TA-98 along with an
activating system. Neither pentachloroaniline nor the N-hydroxy metabolite is
niutagenic in the Ames assay system.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
Metabolism
In vivo analysis
laboratory animals
monkeys ,
b.IDENTIFIERS/OPEN ENDED TERMS C. COS AT I F leld/Group
pentachloroaniline
06, T, P
= IBUT1ON STATEMENT
RELEASE TO PUBLIC
J19 SECURITY CLASS (Thi; Report/ 21 NO OF PAGES
j UNCLASSIFIED I 36
120 SECURITY CLASS (Thi\ pa^c; |22 PRICE
i UNCLASSIFIED
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