-------
DISCLAIMER
This report Is 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
-------
-------
EXECUTIVE SUMMARY
Caprolactam 1s a white hygroscopic, crystalline solid at room tempera-
ture and has a unique odor (Fischer and Crescent1n1, 1982). It Is soluble
In many common organic solvents Including petroleum distillates, methanol,
ethanol and ether and 1s very soluble In water (Fischer and Crescentlnl,
1982; Hawley, 1981; Wlndholz, 1983). Current domestic manufacturers are
Allied Corp. 1n Hopewell, VA, BASF 1n Freeport, TX, and N1pro, Inc., 1n
Augusta, GA (CMR, 1986). During 1985, 189.5 million pounds of caprolactam
was produced In the United States (USITC, 1986). The most recent Import
data available Indicate that 18.973 million pounds was Imported Into the
United States through, principal U.S. customs districts during 1983 (USITC,
1984). Allied uses phenol and BASF and N1pro use cyclohexane as feedstock
1n the manufacture of caprolactam (CMR, 1986). The use pattern for capro-
lactam 1s as follows (CMR. 1986): Nylon 6 fibers Including monofllaments,
87%; Nylon 6 resins and film. 10%; exports, 3%.
If released to air, this compound 1s expected to exist almost entirely
1n the vapor phase (E1senre1ch et al., 1981). The half-life for caprolactam
vapor reacting with photochemically generated hydroxyl radicals was
estimated to be 3.5 days (U.S. EPA, 1987a). Small amounts of the compound
may be removed by wet deposition. Reaction with ozone and removal by dry
deposition are not expected to be significant fate processes. If released
to water, aerobic blodegradatlon and chemical degradation are expected to be
significant removal mechanisms (t-i/o of <1<5 weeks) (Fortman and
Rosenberg, 1984). B1oaccumulat1on In aquatic organisms and adsorption to
suspended solids and sediments should not be significant. If released to
1v
-------
soil, caprolactam may undergo significant blodegradatlon. Based on Us
estimated low K value, residual caprolactam In soil may leach Into
groundwater.
Caprolactam may be released to the environment 1n the effluent from
production and use facilities and 1n leachates from waste disposal sites
(Abrams et al., 1975). This compound was detected In drinking water 1n the
United States and 1n Germany (Kopfler et al., 1977; Shackelford and Keith,
1976; Kool et al., 1982), surface waters downstream from a tire fire runoff
zone 1n Virginia (Peterson et al., 1986), the final effluent from a dye
manufacturing plant In Massachusetts (Games and H1tes, 1977) and the
effluent water from landfill sites 1n Delaware (Shackelford and Keith, 1976).
Little Information was available concerning toxlclty of caprolactam to
aquatic organisms. The two available studies (Loewengart, 1984; Stuplna and
Blleka, 1973) Indicated that caprolactam was relatively nontoxlc to aquatic
b-lota.
Pharmacoklnetlc studies of caprolactam Indicate that the compound Is
nearly completely and rapidly absorbed from the gastrointestinal tract and
distributed throughout the body with peak concentrations In most tissues
except the kidney and bladder, similar to blood levels (Unger et al., 1981;
Maddell et al., 1984). No tissue appears to have a tendency to retain
caprolactam. A whole-body autoradlography study using pregnant mice
Indicated that caprolactam distributes to, but does not concentrate 1n fetal
tissues (Waddell et al., 1984).
Little 1s known about the metabolism of caprolactam. Goldblatt et al.
(1954) found an Increase In urinary ami no adds In rats Injected Intraperl-
toneally with caprolactam, so It Is likely that the compound Is hydrolyzed
to c-am1nocapro1c acid. Because an Increase In urinary ami no adds was
-------
not observed 1n rabbits, Goldblatt et al. (1954) suggested that rabbits
metabolize caprolactam more completely than rats. Unger et al. (1981) found
two unidentified metabolites and unmetabollzed caprolactam 1n the urine of
male F344 rats orally dosed with the compound. Caprolactam and Us metabo-
lites were excreted predominantly In the urine and expired air of rats
(Goldblatt et al., 1954; linger et al., 1981). Mice excrete caprolactam or
Us metabolites (or both) through the kidneys and through the liver (Waddell
et al., 1984).
No subchronlc Inhalation studies of caprolactam toxlclty were available.
In an occupational study, no effects on general health were observed In
workers exposed to 0.2-12.3 ppm (0.9-56.9 mg/m3) caprolactam vapor for up
to 18 years (Ferguson and Wheeler, 1973). Irritation, however, was reported
at >7 ppm (32 mg/m3). Occupational exposure to caprolactam dust at >6
mg/m3 was associated with respiratory and dermal Irritation (Kelman, 1986).
An early subchronlc study of caprolactam found that water Intake and
body weight was depressed 1n rats that were given drinking water containing
caprolactam at 0.75 g/100 ml (Goldblatt et al., 1954). No other param-
eters were examined.
Three studies completed In the Netherlands, summarized by Gross (1984),
found hyaline droplet degeneration 1n the epithelium of the proximal
convoluted tubules of kidneys In rats exposed to caprolactam In the diet at
>0.05% for up to 90 days. Hale rats were more sensitive than female rats.
Other effects observed at 1% of diet Included body weight depression and
Increased liver and kidney weights. Powers et al. (1984) found reversible
renal effects 1n stressed rats fed low (0.01-0.5X) levels of caprolactam In
the diet for 90 days. In unstressed rats, elevated BUN and hyaline droplet
degeneration 1n the kidney occurred at 0.5% but not at 0.1% of the diet.
vl
-------
The only effects noted In the 13-week NTP (1982) study were weight gain
and food Intake depression 1n F344 rats fed caprolactam at levels >2500 ppm,
and weight gain depression In mice fed caprolactam at levels >5000 ppm.
In a 90-day study (Burdock et a!., 1984)* female beagle dogs fed capro-
lactam 1n the diet at 1% showed an Insignificant decrease 1n body weight.
No effects were noted at dietary levels <0.5X.
In the NTP (1982) study, weight gain and food consumption were depressed
In F344 rats fed at 3750 and 7500 ppm for 103 weeks. Caprolactam In the
diet at 7500 and 15,000 ppm reduced body weight gain In B6C3F1 mice but had
no effect on food Intake. No other effects were noted.
Acute exposures of humans to caprolactam vapor at 100 ppm (463 mg/m3)
resulted In severe nose, throat and eye discomfort (Ferguson and Wheeler,
1973). At 7 ppm (32 mg/m3) no distress was noted. Tuma et al. (1981)
reported a case of dermatitis, fever and grand mal seizures In a man occupa-
tlonally exposed to caprolactam for 3 days.
Guinea pigs exposed to caprolactam dust at 118-261 mg/m3, 7 hours/day
for 7 days coughed occasionally (Goldblatt et al., 1954).
The only significant effect noted In rats fed caprolactam In the diet at
levels >5000 ppm were pale mottled kidneys In all groups of male rats (NTP,
1982). No effects were observed In mice at dietary levels of 5000-30,000 ppm.
Acute toxic signs observed 1n rats Injected 1ntraper1tonea11y with
caprolactam Include cries, tremors, apprehension, depression of temperature,
chromodacryorrhea (500-600 mg/kg), convulsions and death (900 mg/kg)
(Goldblatt et al., 1954). Oral LD5Q values 1n rats vary from 1.15 g/kg
(Bormann and Loeser, 1959) to "2.5 g/kg (Friedman and Salerno. 1980).
The NTP (1982) oral cardnogenldty study of caprolactam did not result
1n Increased tumor Incidences 1n either rats or mice. The carclnogenlclty
of caprolactam has not been studied by any other route of exposure.
-------
Negative results were found 1n mutation assays 1n S. typh1mur1um. 1n
mltotlc gene conversion, chromosome aneuploldy, mltotlc segregation and
mitochondria! mutation 1n yeast, 1n assays for DNA single-strand breaks,
sister chromatld exchange and metabolic cooperation In mammalian cells and
cell transformation assays 1n C3H10T1/2, Balb/c 3T3, Fischer rat embryo and
CHO cells. Positive results were found 1n assays for nuclear mutation 1n
yeast, somatic recombination and mutation In J). melanoqaster. chromosomal
aberrations 1n human lymphocytes and Chinese hamster lung cells, and cell
transformations 1n Syrian hamster embryo cells.
Khadzhleva (1969a) reported a concentration-related decrease 1n the
percent of pregnant rats, the average number of young/litter and the average
fetal weight of fetuses from pregnant rats exposed to caprolactam vapor at
139.2 and 473.4 mg/m3 for various segments of the gestation period.
In teratogenlclty studies by Gad et al. (1984), rats treated by gavage
with caprolactam at 0, 100, 500 or 1000 mg/kg/day on gestation days 6-12
experienced a significant Increase In fetal resorptlons In the high-dose
groups. In rabbits treated by gavage at 150 mg/kg/day on gestation days
6-28, maternal body weights were decreased and fetal weights were signifi-
cantly reduced. No effects were noted at 50 mg/kg/day.
Gross (1984) summarized Russian studies (Hartynova, 1972; Khadzhleva,
1969b, 1972; Pestrl, 1970; Nadezhdlna and Talaklna, 1971; Hartynova et al.,
1972) and found an excess of dysmenorrhea, menorrhagla, ollgomenorrhea and
obstetrical complications In women occupatlonally exposed to caprolactam at
levels ranging from 1-400 mg/m3. Reproductive effects reported In Russian
studies where rats were exposed to caprolactam vapor at 425-525 or 120-150
mg/m3 Include a shortening of the rutting phase and a lengthening of the
resting phase with an Increase In the number of corpora lutea (Khadzhleva,
1969b, 1972).
V111
-------
Results of a 3-generatlon study (Serota et al., 1984) showed lower body
weights 1n the offspring of F344 rats fed caprolactam at 5000 and 10,000
ppm. An Increase In the severity of spontaneous nephropathy was observed In
parental rats at 10,000 ppm. No other hlstopathologlcal effects were noted.
Caprolactam was assigned the EPA Class E, evidence of noncardnogenlclty
to humans based on a negative NTP (1982) bloassay using rats and mice. Lack
of pertinent data precludes recommendation of an RfD for Inhalation exposure
to caprolactam. An RfD for subchronlc oral exposure of 0.5 mg/kg/day (35
mg/day) was based on a NOAEL for kidney effects In rats (Powers et al.,
1984), and further supported by a NOAEL of 50 mg/kg/day for fetotoxldty
without maternal effects 1n another study (Gad et al., 1984). An RfD of 0.5
mg/kg/day (35 mg/day) for chronic oral exposure was based on a NOAEL for
reduced body weight of offspring 1n rat pups 1n a dietary 3-generat1on-
reproductlon study (Serota et al., 1984). An RQ of 1000 was based on
reduced rate of body weight gain In rats 1n a 13-week subchronlc dietary
experiment.
1x
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TABLE OF CONTENTS
Page
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 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Reaction with Hydroxyl Radicals . . 5
2.1.2. Reaction with Ozone 5
2.1.3. Physical Removal Processes. 5
2.2. WATER 5
2.2.1. Chemical Degradation 5
2.2.2. Mlcroblal Degradation ..... 6
2.2.3. Bloconcentratlon . . . . 1
2.2.4. Adsorption 7
2.3. SOIL 7
2.3.1. Chemical Degradation -. . 7
2.3.2. B1odegradat1on 7
2.3.3. Adsorption 7
2.4. SUMMARY 8
3. EXPOSURE 9
3.1. WATER 9
3.2. SUMMARY 9
4. AQUATIC TOXICITY 10
4.1. ACUTE TOXICITY 10
4.2. CHRONIC EFFECTS 10
4.3. PLANT EFFECTS 10
4.4. SUMMARY 10
5. PHARMACOKINETCS 11
5.1. ABSORPTION 11
5.2. DISTRIBUTION 11
5.3. METABOLISM 13
5.4. EXCRETION 14
5.5. SUMMARY 15
-------
TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 17
6.1. SYSTEMIC TOXICITY 17
6.1.1. Inhalation Exposures 17
6.1.2. Oral Exposures 18
6.1.3. Other Relevant Information 23
6.2. CARCINOGENICITY 25
6.2.1. Inhalation 25
6.2.2. Oral 25
6.2.3. Other Relevant Information 27
6.3. MUTAGENICITY 27
6.4. TERATOGENICITY 30
6.5. OTHER REPRODUCTIVE EFFECTS 32
6.6. SUMMARY 34
7. EXISTING GUIDELINES AND STANDARDS ; 38
7.1. HUMAN 38
7.2. AQUATIC 38
8. RISK ASSESSMENT 39
8.1. CARCINOGENICITY 39
8.1.1. Inhalation. ... 39
8.1.2. Oral 39
8.1.3. Other Routes 39
8.1.4. Weight of Evidence 39
8.1.5. Quantitative Risk Estimates 39
8.2. SYSTEMIC TOXICITY 39
8.2.1. Inhalation Exposure 39
8.2.2. Oral Exposure 41
9. REPORTABLE QUANTITIES 46
9.1. BASED ON SYSTEMIC TOXICITY 46
9.2. BASED ON CARCINOGENICITY 50
10. REFERENCES 51
APPENDIX A: LITERATURE SEARCHED 62
APPENDIX B: SUMMARY TABLE FOR CAPROLACTAM 65
x1
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LIST OF TABLES
No. Title Page
1-1 Current Domestic Manufacturers of Caprolactam 3
6-1 Acute and LQ$Q Values for Caprolactam 26
6-2 Mutagenldty Testing of Caprolactam 28
9-1 Oral Tox1c1ty Summary for Caprolactam 47
9-2 Oral Composite Scores for Caprolactam 48
9-3 Caprolactam: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 49
-------
LIST OF ABBRIVIATIONS
ALP Alkaline phosphatase
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CNS Central nervous system
COD . Chemical oxygen demand
CS Composite score
DMA DeoxyMbonuclelc acid
GABA Y-am1nobutyr1c acid
GFR Glomerular filtration rate
HPLC High performance liquid chromatography
K Soil sorptlon coefficient
K Octanol/water partition coefficient
ow r
LOH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
MAC Maximum acceptable concentration
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RQ Reportable quantity
RV. Dose-rating value
RV Effect-rating value
RfD Reference dose
SHE Syrian hamster embryo
STEL Short-term-effect level
TAT Tyroslne amlnotransferase
TLV Threshold-limit value
TPO Tryptophan oxygenase
TWA Time-weighted average
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Caprolactam Is also known as e-caprolactam, hexahydro-2H-azep1-2~one
and 2-oxohexamethylene1m1ne (Wlndholz, 1983). The structure, molecular
weight* empirical formula and CAS Registry number are as follows:
Molecular weight: 113.16
Empirical formula: C,H,,ON
o 11
CAS Registry number: 105-60-2
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Caprolactam Is a white, hygroscopic, crystalline solid at room tempera-
ture and has a unique odor (Fischer and Crescent1n1, 1982). It Is a cyclic
amide and undergoes reactions typical of this class of compounds such as
hydrolysis, N-a1ky1at1on, 0-alkylatlon, nltrosatlon and halogenatlon
(Fischer and Crescent1n1, 1982). Caprolactam Is soluble 1n many common
organic solvents Including petroleum distillates, methanol, ethanol and
ethyl ether (Fischer and Crescent1n1, 1982; Hawley, 1981; Wlndholz, 1983).
Selected physical properties are given below.
Melting point, °C:
Boiling point, °C:
Vapor pressure (25°C):
Hater solubility (25°C):
Log Kou:
69.3
266.9
1.9xlO"3 mm Hg
5.25x1O6 mg/l
-0.19
Fischer and Crescentlnl, 1982
Fischer and Crescentlnl, 1982
Jones, 1960
Fischer and Crescentlnl, 1982
Hansch and Leo, 1981
0065d
-1-
01/20/88
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Density (77°C): 1.02 g/cm3 R1dd1ck et al., 1986
Refractive Index, njj1: 1.4935 Fischer and Crescentlnl, 1982
Flashpoint (°C): 125 (closed cup) Rlddlck et al.. 1986
Water odor threshold
(60°C): 59.7 ppm Llllard and Powers, 1975
1.3. PRODUCTION DATA
Current domestic manufacturers of caprolactam are listed 1n Table 1-1.
During 1985, 1089.5 million pounds of caprolactam was produced 1n the United
States (USITC. 1986). The most recent Import data available Indicate that
18.973 million pounds was Imported Into the United States through the prin-
cipal U.S. customs districts during 1983 (USITC, 1984). Allied Corp. uses
phenol, and BASF and Nlpro use cyclohexane as feedstock In the manufacture
of caprolactam (CHR, 1986). Cyclohexanone, obtained either by catalytic
hydrogenatlon of phenol or by oxidation of cyclohexane, Is reacted with
hydroxylamlne to form cyclohexanone oxlme. Cyclohexanone oxlme In the
*
presence of oleum can then be converted to caprolactam by Beckmann re-
arrangement (Fischer and Crescentlnl, 1982).
1.4. USE DATA
The use pattern for caprolactam 1s as follows (CHR, 1986): Nylon 6
fibers Including monofllaments, 87%; Nylon 6 resins and film, 10%; exports,
3%. Small amounts of caprolactam (<1X) are used 1n special coatings, brush
bristles and textile stlffeners and as a reactive additive for floor
polishes (IARC, 1979a). Allied Corp. uses Us entire output of caprolactam
captWely 1n the production of fibers and plastics. BASF uses the bulk of
Us output captlvely for fiber production and sells both monomer and polymer
products. Nlpro uses Us entire output of caprolactam to supply the
merchant market (Fischer and Crescentlnl, 1982; CMR, 1986).
0065d -2- 01/20/88
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TABLE 1-1
Current Domestic Manufacturers of Caprolactam3
Company
Allied Corp.
BASF
N1pro, Inc.
Location
Hopewell, VA
Freeport, TX
Augusta, GA
Annual Capacity
(millions of pounds)
560b
350
180C
aSource: CMR, 1986
^Allied 1s planning an Incremental expansion of plant capacity to 600
million pounds by 1988.
cN1pro has 180 million pounds of Idled capacity at this plant.
0065d -3- 06/16/87
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1.5. SUMMARY
Caprolactam 1s a white hygroscopic, crystalline solid at room tempera-
ture and has a unique odor (Fischer and Crescent1n1, 1982). It 1s soluble
1n many common organic solvents Including petroleum distillates, methanol,
ethanol and ether and Is very soluble In water (Fischer and Crescentlnl,
1982; Hawley, 1981; Wlndholz, 1983). Current domestic manufacturers are
Allied Corp. In Hopewell, VA, BASF In Freeport, TX, and Nlpro, Inc., 1n
Augusta, GA (CMR, 1986). During 1985, 189.5 million pounds of caprolactam
was produced 1n the United States (USITC, 1986). The most recent Import
data available Indicate that 18.973 million pounds was Imported Into the
United States through principal U.S. customs districts during 1983 (USITC,
1984). Allied uses phenol and BASF and Nlpro use cyclohexane as feedstock
In the manufacture of caprolactam (CHR, 1986). The use pattern for capro-
lactam 1s as follows (CHR, 1986): Nylon 6 fibers Including monofllaments,
87%; Nylon 6 resins and film, 10%; exports, 3%.
0065d -4- 01/20/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data pertaining to the environmental fate and transport of
caprolactam could not be located In the available literature as cited 1n
Appendix A. Information concerning the fate and transport of this compound
was derived from physical property data or molecular structure.
2.1. AIR
Based on a vapor pressure of 1.9xlO~a mm Hg at 25°C (Jones, 1960}
caprolactam 1s expected to exist almost entirely 1n the vapor phase In the
atmosphere (Elsenrelch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. The estimated half-life for
caprolactam vapor reacting with photochemlcally generated hydroxyl radicals
1n the atmosphere 1s 3.5 days using an ambient hydroxyl radical concentra-
tion of 8.0x10" molecules/cm3 and an estimated reaction rate constant of
2.89x10'" cmVmolecule-sec at 25°C (U.S. EPA, 1987a).
2.1.2. Reaction with Ozone. Caprolactam 1s not susceptible to oxidation
by ozone In the atmosphere (U.S. EPA, 1987a).
2.1.3. Physical Removal Processes. Because of the relatively high water
solubility of caprolactam (see Section 1.2.), significant amounts of this
compound may be removed from the atmosphere by wet deposition. It appears
that removal by dry deposition would not be significant since this compound
1s expected to exist almost entirely 1n the vapor phase 1n the atmosphere.
2.2. WATER
2.2.1. Chemical Degradation. Degradation of 50 ppm caprolactam 1n
sterilized natural water samples at 20°C was >355i In lake water and 50% In
0065d -5- 01/20/88
-------
stream water over a 3-week period, which Indicates that chemical degradation
of caprolactam may be a significant removal mechanism (Fortman and
Rosenberg, 1984). Amides may be susceptible to chemical hydrolysis under
environmental conditions (Lyman et al., 1982).
2.2.2. M1crob1al Degradation. Degradation of caprolactam In natural
water samples was markedly higher 1n unsterlUzed samples than In sterilized
water samples, which suggests that blodegradatlon Is an Important mechanism
for the removal of caprolactam from natural waters (Fortman and Rosenberg,
1984). Degradation of 50 ppm caprolactam In unsteMUzed lake and stream
water samples at 20°C was 75-100% after 3 weeks (!,.„ <1.5 weeks),
compared with >35 and 50% degradation In sterilized lake and stream water
samples, respectively (Fortman and Rosenberg, 1984). 14COp evolution
from unsterlUzed lake and stream waters containing 40.4 ppm 14C-capro-
lactam was <5% after 3 weeks, which suggests that primary degradation of the
compound to an Intermediate product Is more easily mediated by microorgan-
isms than mineralization (Fortman and Rosenberg, 1984). Provided suitable
acclimation can be achieved, caprolactam can be degraded by conventional
biological sewage treatment (Thorn and Agg, 1975). Results of blodegradatlon
screening studies Indicate that caprolactam 1s degraded rapidly by accli-
mated activated sludge (Zahn and Wellens, 1980; Zahn and Huber, 1975; Pagga
and Guenthner, 1982; PUter, 1976). For example, caprolactam at an Initial
concentration equivalent to 200 mg/l COD underwent 94.3% COD removal when
Incubated with adapted activated sludge 1n the dark at 20°C for 20 days
(PUter, 1976). A wide variety of microorganisms are known to degrade
caprolactam Including Achromobacter. Arthrobacter, Asperglllus. Bacillus.
0065d -6- 01/20/88
-------
CorynebacteMum and Pseudomonas (Shama and Wase, 1981). A proposed mecha-
nism for the metabolism of caprolactam 1s shown below (Shama and Wase, 1981).
a-tttoglutiHc g1ut*»1c «cid
•eld .
CHO COO
I I
(CH,), (CHj).
- "I *'* ">«^ ^S- 'j ?'< 'l t '4
Uctwm COON ftninoeaproic «cid COOH idipic COOt-
trtnttnintsc Mtii*ldt»ydt
dtnydro?tn«tc
t-c«prolict«- c-Mrinoc*proi: idipic idipic
add MBitlMhydt tcid
2.2.3. B1oconcentrat1on. A BCF of <1 was estimated by using a measured
log KQw of -0.19 (Hansch and Leo, 1985) and the linear . regression
equation, log BCF = 0.76 log KQW - 0.23 (Lyman et al., 1982). This BCF
value suggests that bloaccumulatlon of caprolactam In aquatic organisms
would not be significant.
2.2.4. Adsorption. Considering the relatively high water solubility of
caprolactam [5.25x106 mg/l (Jones, I960)] and Its estimated KQC value
of 0.8 (Section 2.3.3.), physical adsorption to suspended solids and
sediments 1s not expected to be significant.
2.3. SOIL
2.3.1. Chemical Degradation. Amides may be susceptible to chemical
hydrolysis under environmental conditions (Lyman et al., 1982); however,
lack of quantitative kinetic data precludes determination of the signifi-
cance of this reaction.
2.3.2. Blodegradatlon. Although no quantitative kinetic data on the
blodegradatlon of caprolactam 1n natural soil are available, based on Us
blodegradatlon 1n aquatic media (see Section 2.2.2.), blodegradatlon 1s
expected to be a significant loss process In soil as well.
2.3.3. Adsorption. The K for caprolactam was estimated to be 0.8 by
using a log K of -0.19 (Hansch and Leo, 1985) and the linear regression
0065d -7- 01/20/88
-------
equation, log KQC = 0.544 log K - 0.006 (Lyman et al., 1982). Based
on this KQC value, caprolactam 1s expected to be highly mobile 1n soil
(Swann et al., 1983).
2.4. SUMMARY
If released to air, this compound Is expected to exist almost entirely
1n the vapor phase (E1senre1ch et al., 1981). The half-life for caprolactam
vapor reacting with photochemically generated hydroxyl radicals was
estimated to be 3.5 days (U.S. EPA, 1987a). Small amounts of the compound
may be removed by wet deposition. Reaction with ozone and removal by dry
deposition are not expected to be significant fate processes. If released
to water, aerobic blodegradatlon and chemical degradation are expected to be
significant removal mechanisms (t-i/o Qf <1<^ weeks) (Fortman and
Rosenberg, 1984). Bloaccumulatlon 1n aquatic organisms and adsorption to
suspended sol Ids and sediments should not be significant. If released to
soil, caprolactam may undergo significant blodegradatlon. Based on Us
•
estimated low K value, residual caprolactam In soil may leach Into
groundwater.
0065d -8- 06/16/87
-------
3. EXPOSURE
Pertinent data regarding human exposure to caprolactam by Inhalation,
1ngest1on of contaminated food or dermal contact could not be located 1n the
available literature as dted In Appendix A. This compound may be released
to the environment 1n the effluent from production and use facilities and In
leachate from waste disposal sites (Abrams et a!., 1975).
3.1. WATER
Caprolactam was qualitatively Identified In drinking water In the United
States (Kopfler et a!., 1977; Shackelford and Keith, 1976) and In Germany
(Kool et al., 1982). The U.S. EPA STORET Data Base reports 110 occurrences
of caprolactam 1n whole water samples (U.S. EPA, 1987b). The minimum,
maximum and mean concentrations detected were 500.0, 1000.0 and 513.6
vg/l, respectively. This compound was detected 1n surface waters down-
stream from a tire fire runoff zone In Winchester, VA (Peterson et al.,
1986). Caprolactam was detected at a concentration of 36-150 yg/J. 1n
the final effluent of a dye manufacturing plant In Massachusetts during July
1976 (Games and Hltes, 1977). It was also detected In effluent water from
landfill sites In Delaware (Shackelford and Keith, 1976).
3.2. SUMMARY
Caprolactam may be released to the environment In the effluent from
production and use facilities and 1n leachates from waste disposal sites
(Abrams et al., 1975). This compound was detected 1n drinking water In the
United States and In Germany (Kopfler et al., 1977; Shackelford and Keith,
1976; Kool et al., 1982), surface waters downstream from a tire fire runoff
zone 1n Virginia (Peterson et al., 1986), the final effluent from a dye
manufacturing plant 1n Massachusetts (Games and Hltes, 1977) and the
effluent water from landfill sites In Delaware (Shackelford and Keith, 1976).
0065d -9- 01/20/88
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Pertinent data regarding acute toxlclty of caprolactam to aquatic
organisms could not be located 1n the available literature as cited In
Appendix A. The only Information available was a statement by Loewengart
(1984) that caprolactam had a "low toxic potential" 1n bluegllls, Lepomls
macrochlrus. fathead minnows, Plmephales promelas. channel catfish,
Ictalurus punctatus and Daphnla magna.
4.2. CHRONIC EFFECTS
Pertinent data regarding chronic toxlclty of caprolactam to aquatic
organisms could not be located 1n the available literature as dted 1n
Appendix A.
4.3. PLANT EFFECTS
Stuplna and Blleka (1973) reported that growth of the algae Anklstro-
desmus braunll. Chlorella pyrenoldosa and Scenedesmus quadrlcauda was
Inhibited by caprolactam concentrations of 8-10 g/i. At lower concentra-
tions, caprolactam apparently was a nitrogen source for these algae, causing
Increased total nitrogen content and protein content at a concentration of 3
g/l. Loewengart (1984) reported that caprolactam had a "low toxic poten-
tial" In duckweed and algae.
4.4. SUMMARY
Little Information was available concerning toxlclty of caprolactam to
aquatic organisms. The two available studies (Loewengart, 1984; Stuplna and
Bllenka, 1973) Indicated that caprolactam was relatively nontoxlc to aquatic
biota.
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5. PHARMACOKINETICS
5.1. ABSORPTION
Caprolactam Is absorbed readily from the gastrointestinal tract of rats.
In the first 24 hours after dosing, male F344 rats that were Intubated with
[carbonyl-14C]-caprolactam at 0.18 mg/kg excreted ~77.6, 3.5 and 1.5X of
the dose of radioactivity 1n the urine, feces and expired air, respectively
(Unger et al., 1981). Excretion 1n the urine and expired air was the most
rapid during the first 6 hours after treatment, after which the rate of
excretion was reduced markedly.
Unger et al. (1981) sacrificed rats treated as described above to deter-
mine tissue levels of radioactivity at 0.5, 1, 2, 3, 4, 6, 15 and 24 hours
after treatment (Section 5.2.). They determined a half-life of 1.87 hours
for radioactivity 1n the stomach and Us contents. The short half-life 1n
the stomach coupled with the observation that the concentration of radio-
activity 1n the small Intestine and Us contents did not exceed the concen-
tration In blood by >35-40X 1n the first 15 hours after treatment suggested
to the Investigators that passive absorption occurred rapidly directly from
the stomach. A whole-body autoradlography study 1n mice (Waddell et al.,
1984) also Indicated that [carbonyl-14C]-caprolactam 1s absorbed rapidly
from the gastrointestinal tract, particularly from the stomach. No quanti-
tative absorption data were provided.
5.2. DISTRIBUTION
In a low-dose study of the disposition of caprolactam, a group of 40
male F344 rats were orally dosed with [14C]-caprolactam at 0.18 mg/kg
(Unger et al., 1981). Five rats were sacrificed 0.5, 1, 2, 3, 4, 6, 15 and
24 hours after dosing and tissue radioactivity was determined. Radioactiv-
ity levels In most tissues were similar to those found 1n blood, In which a
0065d -11- 01/20/88
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maximum (128 ng equivalents caprolactam/g tissue) was reached at 1 hour
after dosing. The exceptions were the stomach, kidneys and bladder In which
concentrations were higher than those found 1n the blood, and adipose
tissue, In which concentrations were lower than those found In the blood.
In a high-dose experiment (Unger et al., 1981), five rats were given
oral doses of 1.5 g/kg [14C]-capro1actam and were sacrificed 6 hours
later; six rats were pretreated with unlabeled caprolactam at 1.5 g/kg/day
for 7 days before a 1.5 g/kg dose of labeled compound. Results of this
experiment agreed with those of the low-dose study; most tissue concentra-
tions were similar to blood values In rats receiving one or eight doses of
1.5 g/kg. An exception was the stomach, where 42.3% of the high dose and
6.2% of the low dose remained In the stomach 6 hours after dosing, which
suggested that passive absorption from the stomach was saturated at the
higher dose. Pretreatment with caprolactam had little effect on distribu-
tion of radioactivity.
Using whole-body autoradlography, Waddell et al. (1984) examined the
distribution of [carbony1-14C]-capro1actam 1n male mice and pregnant and
nonpregnant female mice. One nonpregnant female and five pregnant (gesta-
tion day 14.5) Swiss Webster mice were dosed by gavage with [14C]-capro-
lactam at 6.5-6.7 mg/kg. Two male mice were Injected Intravenously with
labeled compound at 6.4-6.9 mg/kg. Pregnant mice were frozen and prepared
for autoradlography 20 minutes, 1. 3, 9 or 24 hours after dosing, while the
nonpregnant female mouse was frozen 3 hours after dosing and the male mice
were frozen 20 minutes or 9 hours after dosing.
During the first hour after dosing, radioactivity Increased 1n the
fetuses and brain of the dams, but only the kidney and nasal epithelium
showed affinity to the radioactivity. After 1 hour, the bile ducts In the
0065d -12- 01/20/88
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liver were heavily labeled, which Indicated hepatic excretion. At 3 and 9
hours, evidence of renal excretion and hepatic excretion Into the Intestines
was observed. No evidence of enterohepatlc circulation was noted. Levels
of radioactivity In most tissues of the dam were decreasing, although higher
levels were observed 1n the brain, nasal epithelium, optic lens, bone, Inner
ear and Harderlan gland. Radioactivity levels were higher 1n the fetuses
but decreased over time. At 24 hours, small residues of radioactivity were
present In the umbilical cord, amnlon and yolk sac, and 1n the optic lens,
Harderlan gland and liver of the dam. Results 1n the nonpregnant mouse were
similar. In the male mice. Intravenous administration resulted In a more
rapid equilibrium 1n tissue levels of radioactivity.
5.3. METABOLISM
Goldblatt et al. (1984). administered 1ntraper1toneal doses of 12.3-17.3
mg caprolactam nitrogen (-99-140 mg caprolactam) to rabbits and determined
the cumulative percentages of the doses excreted In the urine as unmetabo-
11 zed compound and as an Increase over background urinary concentrations of
ami no add. Considerable variation was observed In the excretion by rats,
with urinary recovery of unmetabollzed compound accounting for 10-65% of the
administered dose. Increased ami no acid excretion over background levels
ranged from undetectable to 60.2% of the dose. The excess ami no acid excre-
tion was assumed to be c-amino caprolc add. Increased urinary excretion
of ami no add was not observed 1n caprolactam-treated rabbits. Unmetabo-
llzed compound 1n the urine accounted for <14% of the administered dose.
The Investigators concluded that rabbits metabolize caprolactam more
completely than rats.
Six hours after a 0.18 mg/kg oral dose of [14C]-caprolactam, 78.1,
16.9 and 3.9% of the radioactivity 1n the urine of male F344 rats was
0065d -13- 01/20/88
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Identified by HPLC as metabolite I, metabolite II and the parent compound,
respectively (Unger et al., 1981). Metabolite I and II were not further
Identified. In contrast, 6 hours after a 1.5 g/kg dose 25.1, 14.1 and 55.2%
of the urinary radioactivity was 1n the form of metabolite I, II and the
parent compound, which suggested that the metabolic pathway for formation of
the major metabolite (metabolite I) had become saturated at the higher dose.
5.4. EXCRETION
Goldblatt et al. (1954) examined the urinary excretion of caprolactam
and ami no add N 1n albino rats and rabbits following 1ntraper1toneal doses
of caprolactam. The authors found that rats excreted 10-65% of a 99-140 mg
caprolactam dose In the urine as unchanged compound, generally over a 2- to
5-day period. Comparison of ami no acid N levels with control values In
urine Indicated that Injections of caprolactam resulted In the excretion of
excess ami no adds 1n some rats but not In others. The amount of capro-
lactam excreted In the urine, presumably as e-am1nocapro1c add, was
estimated to range from an Insignificant amount to as much as 60.2% of the
dose. Together, unmetabollzed compound and excess ami no add accounted for
a total of -32-103% of the administered dose over a 2- to 5-day period.
Three rabbits Injected with caprolactam at 400 mg/kg excreted 8.7, 22.3 and
10.1% of the dose 1n the urine and feces as the parent compound. No addi-
tional ami no add N over background concentrations was detected 1n the urine.
The Importance of renal excretion 1s Indicated by higher levels of
radioactivity In the kidneys and bladder than 1n other tissues of male F344
rats following oral dosing with [14C]-caprolactam (Unger et al., 1981).
Twenty-four hours after male rats were orally dosed with 0.18 mg/kg
[14C]-caprolactam, 77.6, 3.5 and 1.5% of the radioactivity had been elimi-
nated In the urine, feces and expired air, respectively. In male rats given
0065d -14- 01/20/88
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a 1.5 g/kg dose, 13.8% of the radioactivity was eliminated 1n the urine 6
hours after dosing, compared with 38.6% eliminated 6 hours after a 0.18
mg/kg dose. Differences between the two dose groups 1n the excretion of
radioactivity In the feces were not observed. In rats pretreated with 1.5
g/kg caprolactam for 7 days, 0.25% of the administered radioactivity was
excreted 1n the expired air compared with 0.05% excreted 1n rats receiving
one dose at 1.5 g/kg.
Autoradlography of mice killed at several time points up to 24 hours
after oral or Intravenous administration of [carbonyl-14C]-capro!actam
Indicated that excretion of radioactivity occurred efficiently through the
kidney or the liver (Waddell et al., 1984). Enterohepatlc reclrculatlon was
not observed.
5.5. SUMMARY
Pharmacoklnetlc studies of caprolactam Indicate that the compound 1s
rapidly and almost completely absorbed .from the gastrointestinal tract and
distributed throughout the body with peak concentrations In most tissues,
except the kidney and bladder, similar to blood levels (Unger et al., 1981;
Waddell et al., 1984). No tissue appears to have a tendency to retain
caprolactam. A whole-body autoradlography study using pregnant mice Indi-
cated that caprolactam, distributes to, but does not concentrate In fetal
tissues (Waddell et al., 1984).
Little 1s known about the metabolism of caprolactam. Goldblatt et al.
(1954) found an Increase In urinary ami no adds In rats Injected 1ntraper1-
toneally with caprolactam so It 1s likely that the compound 1s hydrolyzed to
c-am1nocapro1c add. Because an Increase 1n urinary ami no adds was not
observed In rabbits, Goldblatt et al. (1954) suggested that rabbits metabo-
lize caprolactam more completely than rats. Unger et al. (1981) found two
0065d -15- 01/20/88
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unidentified metabolites and unmetabollzed caprolactam In the urine of male
F344 rats orally dosed with the compound. Caprolactam and Its metabolites
were excreted predominantly In the urine and expired air of rats (Goldblatt
et al., 1954; Unger et al., 1981). Mice excrete caprolactam and Us metabo-
lites through the kidneys and through the liver (Haddell et al., 1984).
0065d -16- 01/20/88
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6. EFFECTS
6.1. SYSTEHIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC ~ Pertinent data regarding the toxlclty of
caprolactam following subchronlc Inhalation exposure could not be located In
the available literature as cited In Appendix A.
6.1.1.2. CHRONIC — Ferguson and Wheeler (1973) found no differences
In the general health of an unspecified number of workers occupatlonally
exposed to caprolactam vapor over an 18-year period compared with unexposed
workers. Concentrations 1n the factories were measured at 0.2-12.3 ppm
(0.9-56.9 mg/m3). Generally, Irritation was not reported at <7 ppm
(32 mg/m3).
In an examination of eight caprolactam-exposed workers, Kelman (1986)
found no consistent abnormalities In blood counts, urinary B.-mlcroglobu-
I1n levels, or In liver and lung function tests. A few workers reported
eye, nose or throat Irritation, and all but one experienced peeling of the
hands and sometimes the feet. The Individuals examined had worked at the
factory between 9 months and 13 years (mean 4.8 years). Caprolactam dust
levels, measured with a static sampler, were found to range from 22-168
mg/m3. Dust levels of 6-131 mg/m3 were found with personal samplers.
Gross (1984) summarized a number of Russian studies of caprolactam
exposed workers (Martynova, 1972; Bashurov, 1964; Spath, 1967; Antonova,
1968; PestM, 1970; Petrov, 1975). Exposure levels varied from below the
MAC of 10 mg/m3 to peak levels as high as 400 mg/m3. Exposures to other
compounds Including dlnyl (a mixture of dlphenyl and dlphenyl oxide), cyclo-
hexane, cyclohexanol, cylcohexanone, benzene, acetone and trlchloroethylene
were commonly reported. High noise levels, temperatures and humidity were
0065d -17- 01/20/88
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also reported 1n some factories. Effects noted Included neurological
effects (neurosis, neurasthenia, autonomlc vascular dystonla, polyneurltls
and polyradlculltls), gynecological effects (Section 6.5.). gastrointestinal
effects (nausea, heartburn, ulcers and chronic gastritis), cardiovascular
effects (sinus bradycardla, hypotension and palpitation) and dermatologlcal
and 1mmunolog1cal changes.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — In an early subchronlc study (Goldblatt et
al., 1954), a group of six rats was provided with caprolactam 1n drinking
water at 0.75 g/100 ml for 70 days. A second group of six rats served as
controls. Fluid Intake, measured throughout the study, was found to be
lower 1n treated rats. Initial average body weight of both groups of rats
was 124 g. By 70 days, the treated rats weighed less than controls.
Following the treatment period, all rats were not treated for 20 days. At
the end of the recovery period, weights of treated rats Increased to near
the control level, Indicating to the Investigators that the weight differ-
ence observed at the end of the exposure period was a result of decreased
water Intake In the caprolactam-treated rats and was completely reversible.
This Is supported by an additional phase of the study 1n which the original
control rats were treated for 29 days, while the first treatment group was
left untreated. Body weights at the end of this period were lower In the
treated rats compared with the untreated rats. No other parameters were
examined In this study.
Wljnands and Feron (1969) fed an unspecified number of male and female
CIVO Wlstar rats caprolactam 1n their diets for 28 days at 0.2-5.0%
(170-3800 mg/kg/day). Body weights of rats fed >1% were depressed; the
depression was greater In males than females. Liver weights were Increased
0065d -18- 01/20/88
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1n males at >1% and 1n females at 5%. Kidney weights were Increased 1n both
sexes at 1%t and hyaline droplet degeneration 1n the epithelium of the
proximal convoluted tubules occurred at >1% 1n both sexes.
In other studies, male and female CIVO Ulstar rats were fed diets
containing caprolactam at 0.1-2.0% (110-1700 mg/kg/day; 1% = 980 mg/kg/day)
(De Knecht-van Eekelen and van der Meulen, 1970) and male and female
Sprague-Dawley rats were fed diets containing caprolactam at 0.05-1.0%
(50-710 mg/kg/day; 1% = 700 mg/kg/day) (De Knecht-van Eekelen et al., 1971).
Both strains of rats showed weight depression at 1%. CIVO male rats had
Increased liver weight at 0.3%, while female CIVO rats and both sexes of
Sprague-Dawley rats had Increased liver weight at 1%. In CIVO males, kidney
weights were Increased at >1%, and hyaline droplet degeneration 1n the
epithelium of the proximal convoluted tubules was observed at >0.3%. In
Sprague-Dawley male rats, kidney weights were Increased at 1%, and hyaline
droplet degeneration 1n the epithelium of proximal convoluted tubules
occurred at >0.05%. Kidney effects were not noted 1n females of either
strain of rats. The significance of the kidney effects 1s not clear because
Increases In urinary proteins were not observed.
To further explore the effects of caprolactam on renal function. Powers
et al. (1984) conducted a subchronlc study 1n F344, Sprague-Dawley and
Ulstar rats. In this three phase study, male and female rats of all three
strains were fed caprolactam In the diet at 0, 0.01, 0.05, 0.1 or 0.5% for
90 days. Phase I of the study consisted of resting renal function tests,
extracellular volume expansion tests, urine concentrating ability tests and
limited pathologic examination; all tests were conducted Immediately after
the 90-day treatment period. In the resting renal function tests, urine
samples collected for 24 hours were analyzed for volume, sodium, potassium.
0065d -19- 01/20/88
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chloride, protein and glucose concentration, ALP and LDH activities,
osmolalHy, pH, creatlnlne concentration and microscopic sediment content.
Blood samples were analyzed for BUN, protein, creatlnlne, sodium, potassium
and chloride concentration, hematocrH and osmolalHy. At this time,
extracellular volume expansion studies were also conducted. Rats were given
1ntraper1toneal Injections of Isotonlc saline at 2.5% of body weight and
urine was collected every 3 hours for 9 hours and analyzed for urine volume,
sodium, potassium, chloride, osmolalHy and creatlnlne. In a measurement of
urine concentrating ability, other rats were placed 1n metabolism cages and
deprived of drinking water. Urine from the first 6 hours was discarded and
the two consecutive 24-hour samples were analyzed for the parameters
examined above. In the limited pathologic examination of the phase I study,
six rats/straln/sex/group were sacrificed, kidney-to-body weight ratios were
determined and the kidneys were examined by light microscopy. In phase I of
the study, 180 rats were used. In phase II of the study, renal parameters
• , .
of caprolactam treated rats were studied using Invasive techniques. The
parameters examined Included urine flow rate, fractional reabsorptlon of
water, Ion excretion rates and GFR. In phase II of the study 240 rats were
used. In phase III, phase I procedures were repeated In rats that were fed
caprolactam for 90 days, followed by a 90-day recovery period. The number
of rats used 1n phase III was not stated.
The results of the phase I 24-hour urlnalysls showed no effect on renal
function In any of the three strains of rats tested. A dose-related
Increase In BUN was noted In male F344 and Sprague-Dawley rats at 0.1 and
0.5%. This Increase was significant (p<0.05) only 1n Sprague-Dawley males
at 0.5%. Results of the extracellular volume study showed an abnormal
response 1n males of all strains and In Vllstar females. A dose-related
0065d -20- 06/16/87
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decrease 1n urine sodium was observed 1n F344 males at all dose levels
(0.01, 0.05 and 0.1% p<0.05; 0.5% p<0.01). Sprague-Dawley and Wlstar males
showed a dose-related decrease 1n urine volume at 3 hours after the saline
Injection. In Wlstar males and females, the urine volume was significantly
Increased by 9 hours postlnjectlon. In the urine concentrating ability
test, F344 rats were the only strain that exhibited effects. A dose-related
Increase 1n urine volume was observed 1n F344 males (p<0.05) and urine
osmolallty was decreased at >0.05%. A similar response was observed In F344
females with the effect beginning at the 0.1% dose level. Kidney-to-body
weight ratios were Increased In Sprague-Dawley males at 0.1 and 0.5%
(p<0.05) and In Wlstar males at 0.5% (p<0.05). Changes 1n kidney-to-body
weight ratios were not observed 1n other groups. Results of microscopic
examination of the kidneys revealed an Increased frequency of eoslnophlUc
hyaline droplets In the renal tubules of male rats of all three strains at
0.5%. According to the authors, the degree of susceptibility appeared to be
Sprague Dawley > F344 > Wlstar. The kidneys of female rats were not
affected.
The only change observed In the phase II Invasive studies was lower
fractional reabsorptlon of water when expressed as a kidney weight ratio In
male F344 and Sprague-Dawley rats at 0.5%. This effect corresponds with the
altered urine concentrating response observed 1n phase I.
After a 90-day recovery period, phase III studies revealed no effects on
urine concentrating ability. Elevated kidney weight was observed In male
Wlstar rats but this effect was less than that observed In phase I. Micro-
scopic examination of kidneys of phase III rats showed recovery; the kidneys
appeared almost normal In all groups.
0065d -21- 01/20/88
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Powers et al. (1984) stated that "dietary caprolactam Is capable of
altering renal function at low doses, but only In the stressed animal. This
appears to be more of a physiological than a lexicological effect 1n that It
Is morphologically and functionally reversible and does not compromise the
health of the animal."
In a 13-week study by the NTP (1982), groups of 12 F344 rats/sex were
fed diets containing caprolactam at 0, 625, 1250, 2500, 5000 or 7500 ppm,
and groups of 10 B6C3F1 mice/sex were fed diets containing 0, 5000, 10,000,
15,000, 20,000 or 30,000 ppm. Clinical observations were made twice dally
and animals were weighed weekly. Weight gain depression (<12% for males and
<14% for females) was not dose related. Food consumption by rats fed 7500
ppm as compared with controls was decreased 23 and 19% for males and
females, respectively. No compound-related hlstopathologlc effects were
observed (NTP. 1982).
In the same study (NTP, 1982), three female mice died at doses >20,000
ppm. A depression In mean body weight gain was observed In all dosed mice,
but mean body weight gain was no different for male mice fed 30,000 ppm
(36%) than for those fed 5000 ppm. However, weight gain depression for
females was dose related (NTP, 1982).
In a 90-day study (Burdock et al., 1984), groups of four male and four
female beagle dogs were fed caprolactam In the diet at 0, 0.1, 0.5 or 1.0%
(0, 32, 160 or 292 mg/kg/day 1n males and 0, 33, 158 or 390 mg/kg/day In
females). During the study, the dogs were observed for signs of toxic
effects, and body weights and food consumption were recorded weekly. At
weeks 0, 5, 8 and 13, blood (hematocrH, hemoglobin, platelet counts,
differential leukocyte counts, total protein, albumin, ALP, total bHlrubln,
BUN, calcium, fasting glucose, aspartate amlnotransferase, alanlne amlno-
transferase, sodium and potassium) and urine (pH, glucose, ketones, total
0065d -22- 01/20/88
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protein and blUrubln) analyses were completed. Preliminary ophthalmologlc
examinations were conducted. At the end of the study, ophthalmologlc
examinations and complete necropsies were performed on all dogs. The only
possible treatment-related effect noted In this study was a decrease In body
weight 1n females fed caprolactam at IX. This effect was not statistically
significant and was not observed 1n males. The other parameters, examined.
Including food Intake, were not affected by caprolactam treatment.
6.1.2.2. CHRONIC — In the NTP (1982) chronic study, groups of 50
male and 50 female F344 rats were fed diets containing caprolactam at 0,
3750 or 7500 ppm for 103 weeks. Groups of 50 B6C3F1 mice/sex were fed diets
containing caprolactam at 0, 7500 or 15,000 ppm for 103 weeks. After 105
weeks, both rats and mice were sacrificed and comprehensive hlstopatho-
loglcal examinations were completed.
The results of the study showed weight gain depression In both sexes of
rats and mice 1n both dose groups. The weight gain depression was dose-
related In rats. Male and female rats also showed a dose-related decrease
In food consumption that was 70-80% of control levels In the high-dose
groups. Survival of all groups of rats and mice was comparable with
controls. H1stolog1c examination of tissues did not reveal any compound-
related toxic lesions 1n either rats or mice.
6.1.3. Other Relevant Information. In a study by Ferguson and Wheeler
(1973), human responses to caprolactam at vapor concentrations of 10-100 ppm
(46-463 mg/m3) were examined. Subjects were exposed In monomer or polymer
plants for periods of 30 minutes. Concentrations of 100 ppm resulted 1n
severe discomfort consisting of burning nose and throat and eye Irritation.
No eye Irritation was noted at <25 ppm (116 mg/m3), although transient
nose and throat Irritation occurred In some Individuals at levels >10 ppm
(46 mg/m3). At ~7 ppm (32 mg/m3), no distress was observed.
0065d -23- 01/20/88
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Tuma et al. (1981) reported a case of dermatitis, fever and grand mal
seizures In a 22-year-old man occupatlonally exposed to caprolactam for 3
days (concentration not reported). A comprehensive neurological Investiga-
tion revealed no CNS abnormalities. Because convulsive disorders have been
observed In laboratory animals, and because the sunburned-Uke appearance of
the skin was similar to reports of caprolactam Induced dermatitis, the
authors concluded that the seizures were likely a result of caprolactam
exposure.
Goldblatt et al. (1954) exposed three guinea pigs to caprolactam dust at
118-261 mg/m3, 7 hours/day for 7 days. The guinea pigs coughed occasion-
ally, but no other adverse effects were noted.
In a 14-day study (NTP, 1982), groups of five F344 rats/sex and five
B6C3F1 mice/sex were fed caprolactam In the diet at 0, 5000, 10,000, 15,000,
20,000 or 30,000 ppm. No deaths occurred 1n either species. Pale mottled
kidneys were observed at Incidences of 60-100% In all groups of dosed male
rats. No compound-related effects were noted 1n mice.
Goldblatt et al. (1954) Injected rats Intraperltoneally with caprolactam
at 500-600 mg/kg; toxic signs observed Included cries, tremors, apprehen-
sion, depression of temperature and chromodacryorrhea. Deaths, preceded by
convulsions, occurred at 900 mg/kg. In rabbits, apprehension, salivation,
accelerated respiration, cries, muscular tremors, convulsions, oplsthotonos
and mydrlasls were observed at single 1ntraper1tonea1 doses of 100-300
mg/kg. No deaths occurred.
Goldblatt et al. (1954) found that rats Injected Intraperltoneally with
veronal (sodium salt of 5,5-d1ethyl barbituric add) at 36 mg/kg followed by
a lethal Injection of caprolactam (1 g/kg) did not die or develop the signs
of acute caprolactam toxldty. This protective effect was observed up to 2
hours after the rats were Injected with veronal. Only 1/6 rats died that
0065d -24- 01/20/88
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were Injected with caprolactam at 0.8 g/kg followed by an Injection of 36
rag/kg veronal, compared with 4/6 receiving just 0.8 g/kg caprolactam.
Severe signs of toxlclty were observed 1n both groups. Veronal and other
barbiturates have clinical use In the prevention of convulsions.
Kerr et al. (1976), using urethane anaesthetized rabbits, found that
caprolactam 1s a GABA antagonist; positive field potentials evoked In the
substantla nlgra by stMopalUdal stimulation were blocked following
Intravenous admlnstratlon of caprolactam. The dose required to produce this
response was not stated.
Friedman and Salerno (1980) found that the enzymes TAT and TPO were
Induced 1n rats given a single dose of caprolactam 1n food or water at 1.5
g/kg. The maximum enzyme levels were observed 6 hours postdoslng. No
change 1n the activity of fructose-l,6-d1phosphatase was observed. Rats
given eight dally Intraperltoneal Injections of caprolactam showed an
Increase 1n TAT and TPO activities after the first Injection, but by the
eighth Injection, enzyme activities were comparable with controls.
Acute and LD5Q values for caprolactam are shown In Table 6-1. As
Indicated 1n the table, the oral toxlclty of caprolactam 1s relatively low.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenldty of
caprolactam following Inhalation exposure could not be located 1n the
available literature data as cited 1n Appendix A.
6.2.2. Oral. In an NTP (1982) carclnogenlclty study, groups of 50 F344
rats/sex and 50 B6C3F1 mice/sex were fed caprolactam 1n their diets for 2
years. The rats ate diets containing caprolactam at 0, 3750 or 7500 ppm,
while the mice were fed at 0, 7500 or 15,000 ppm. This dosing regimen did
not result In significantly Increased tumor Incidences 1n either rats or
0065d -25- 01/20/88
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TABLE 6-1
Acute and 1059 Values for Caprolactam
Species/Strain/Sex
Mouse/NR/NR
Mouse/NR/NR
Mouse/NR/NR
Mouse/NR/NR
Mouse/NR/NR
Mouse/B6C3Fl/male
Mouse/B6C3Fl/female
Rat/F344/male
Rat/F344/female
Rat/F344/NR
Rat/NR/NR
Route of
Administration
Inhalation
Intraperltoneal
Intravenous
subcutanous
oral
oral
oral
oral
oral
oral
oral
1050 Value
0.45 mg/l
(450 mg/m3)*
0.58 g/kg
0.48 g/kg
0.75 g/kg
1.2 g/kg
(LD100)
2.07 g/kg
2.49 g/kg
1.65 g/kg
1.21 g/kg
-2.5 g/kg
1.15 g/kg
Reference
Lomonova, 1966
Hohensee, 1951
Hohensee, 1951
Hohensee, 1951
Hohensee, 1951
NTP, 1982
NTP, 1982
NTP, 1982
NTP, 1982
Friedman and
Salerno, 1980
Bormann and
Loeser, 1959
*Durat1on of exposure not reported
0065d
-26-
01/20/88
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mice, and according to NTP, 1t 1s highly likely that the animals were
receiving the maximum tolerated dose.
6.2.3. Other Relevant Information. Additional data concerning the card-
nogenldty of caprolactam could not be located 1n the available literature
as cited 1n Appendix A.
6.3. MUTAGENICITY
Hutagenldty data for caprolactam are summarized 1n Table 6-2. Capro-
lactam was one of several chemicals tested In a large number of mutation
assays 1n an International collaborative program sponsored by the Inter-
national Programme for Chemical Safety (IPCS). All of these studies are
found In Progress 1n Mutation Research, as cited 1n the reference section.
Negative results were found In all mutation assays 1n Salmonella typhl-
imirlum (Venltt et al., 1985), and In mltotlc gene conversion, chromosome
aneuploldy, mltotlc segregation and mitochondria! mutation studies In yeast
(Parry et al., 1985). Positive results 1n assays'for nuclear mutation were
observed 1n one strain of yeast. Caprolactam tested positive In three
studies of somatic recombination and mutation 1n Drosophlla melanoqaster
(Vogel et al., 1985).
In studies using mammalian cells, negative results were reported In
assays for DNA single-strand breaks, unscheduled DNA synthesis (Williams et
al., 1985), sister chromatld exchange (Dean et al., 1985), gene mutation
(Garner et al., 1985) and metabolic cooperation (Elmore and Nelmes, 1985).
An Increased number of chromosomal aberrations were noted In human lympho-
cytes and Chinese hamster lung cells, but not In other cell types tested
(Dean et al., 1985). Cell transformation assays 1n Syrian hamster embryo
cells were also positive (McGregor et al., 1985), although negative or
equivocal results were found 1n C3H10T1/2, Balb/c 3T3, Fischer rat embryo
and CHO cells.
0065d -27- 01/20/88
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TABLE 6-2
Nutagentclty Testing of Caprolactara (>99X pure)
Assay
Reverse and
forward
mutation
Nilotic gene
conversion
Chromosome
aneuploldy
Hltotlc
segregation
Nuclear
nutation
Mitochondria!
mutation
Somatic
recombination
and mutation
DMA single-
strand breaks
Unscheduled
ONA synthesis
Indicator /Organism
Salmonella typhl-
myrlum strains
TA97. 98. 100.
102. 1535. 35.
37. 38. TN677
Saccharorevces
cerevlslae strains
JD-1. 0-7
S. cerevlslae
strains 061 -N. D-6
S. cerevlslae
strains 061 -H. 0-6
S. cerevlslae
strains 06. 061 -N.
XV185-14C. PN52.
07; Saccharomyces
pombe strain PI;
Asperglllus
nldulans strain 35
S. cerevlslae
Ttraln 05
Drosophlla
roelanogaster
rat hepatocytes.
CHO
Hela cells, male
rat hepatocytes
Application
plate Incorpora-
tion, pretncuba-
tlon. treat and
plate
treat and plate
treat and plate
treat and plate
treat and plate
Asperglllus
treatment on
solid medium
treat and plate
acute feeding of
larvae or con-
tinuous feeding
of larvae
cultures exposed
1-3 hours
cultures exposed
2.5-18 hours
Concentration/ Activating
Dose System
30-10.000 n9/ »S-9
plate
maximum *S-9
2000 pg/mt
maximum +S-9
5000 vg/nt
maximum »S-9
15.000 vg/l
maximum tested . .+S-9
In negative
studies 2000
vg/mt. lowest
effective con-
centration In
positive studies
100 ug/ml
max none
5000 ug/t
1-200 mg/l NA
max »S-9
11,300 pg/ot
max ±S-9
10,000 vg/on
Response Comment
« Negative results were
found In five studies
conducted at five
different laboratories
• Negative results from
two laboratories
• Negative results from
two laboratories
• Negative results from
two laboratories
t XVI 85-1 4C reverse Results from six
mutation producing laboratories
arglnlne* prototrophs
» XVI 85-1 4C forward
mutations; equivocal
or negative results In
remaining strains
Results from one
laboratory
«• 1n all three tests Results from three
laboratories; endpolnts
studied: wlng-mosalclsm,
whlte-zeste eye mosaic -
Ism and white/white-
coral eye mosaic Ism
Negative results from
three laboratories
Negative results from
five laboratories
Reference
Venltt
et al..
Parry
et al..
Parry
et al..
Parry
et al..
Parry
et al..
\
Parry
et al..
Vogel
et al..
U1 11 lams
et al..
Williams
et al..
1985
1985
1985
1985
1985
1985
1985
1985
1985
(Holtzman. F344)
-------
TABLE
(cont.)
en
0.
Assay
Chromosomal
aberrations
Indicator/Organism Application
human lymphocytes. cultures exposed
CHO. CH lung flbro- 3-48 hours
blasts CH liver
flbroblasts. rat
liver -epithelial
like (RL4)
Concentration/ Activating
Dose System
max 16.980 pg/l »S-9
LPC 270 pg/l
human lymphocytes
LPC 12.000 pg/m
CH lung
Response
i In human lymphocytes
I In CH lung flbroblasts
= In other cell types
Comment Reference
Results from eight Dean et al..
laboratories; the 1985
results In CH lung
flbroblasts should be
Interpreted with
caution — S-9 LPC
concentration was
cytotoxlc
I
IN;
Sister
chromatld
exchange
Mammalian
cell gene
mutation
Metabolic
cooperation
Cell trans-
formation
CHO. V79 (lung).
RL4
mouse L5178Y TK*'-;
human TK6. AHH-1;
hamster V79. CHO
CH V79 lung cells
SHE.
C3H10T1/2 cells.
Balb/c 3T3 cells.
Fischer rat embryo
CHO cell cultures
cultures exposed
1-32 hours
cultures exposed
3-28 hours
compound added
to culture 3
days -continuous
added to
cultures
max »S-9
16.980 pg/mt
max »S-9
11.320 pg/mft
max none
>2 mg/mt
max frS-9
1000 pg/mt
lowest positive
response 10 mg/mt
Results from six
laboratories
Results from 12
laboratories
Results from three
laboratories
t In SHE cells Results from eight
colony morphology laboratories; endpolnts
= or equivocal In other examined: colony morph-
assays ology, viral dependence
and altered growth In agar
Dean et .al..
1985
Garner
et al.. 1985
Elmore and
Nelmes. 1985
McGregor
et al.. 1985
max ° Maximum negative concentration tested; LPC • lowest concentration Inducing structural aberration
oo
-J
-------
6.4. TERATOGENICITY
Khadzhleva (1969a) examined the reproductive parameters of albino rats
exposed to caprolactam by Inhalation. The study was completed using 107
female and 12 male rats. Groups of 46 and 40 pregnant rats were exposed to
caprolactam at 473.4 and 139.2 mg/m3, respectively, while a group of 21
pregnant rats served as controls. The rats were exposed 4 hours/day for
various exposure regimens. An unspecified number of rats were exposed
beginning on gestation days 1-5, while others were exposed beginning on
gestation days 6-12 or gestation day 13. Exposures generally continued to
gestation day 24 or until parturition. One dam, exposed at 473.4 mg/m3
died on gestation day 21, the 17th day of caprolactam exposure. Fetuses
from this dam had unspecified abnormalities. After delivery, the remaining
rats were sacrificed and the number of corpora lutea, Implantation sites,
live and dead young and fetal weights were determined. The results of the
study showed a dose-related decrease 1n the percent of pregnant rats, the
average number of young/Utter and the average fetal weight. The average
duration of pregnancy was longer than controls 1n the high-dose group (27.8
vs. 23.2 days) but shorter (22.6 days) In the low-dose group. The report
does not Indicate whether the fetuses were examined for teratogenlc effects.
In a teratology study, groups of 20 mated F344 rats were dosed by gavage
with caprolactam In distilled water at 0. 100, 500 or 1000 mg/kg/day on
gestation days 6-15 (Gad et al., 1984). Body weights and food consumption
were measured on gestation days 6, 11, 15 and 20. The dams were sacrificed
on gestation day 20 and the number of corpora lutea, Implants, resorptlons
and live and dead fetuses were determined. Fetal weights, crown-rump length
and sex were recorded. The fetuses were examined for gross anomalies, with
one-third examined for visceral anomalies and two-thirds examined for skel-
etal anomalies. Survival of dams at 100 and 500 mg/kg/day was not affected.
0065d -30- 01/20/88
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At 1000 mg/kg/day, nine dams died, resulting In a survival rate signifi-
cantly (p<0.05) lower than controls. Clinical signs noted In treated groups
at a slightly higher Incidence than 1n controls Included urine stains, rough
hair coat, red discharge from the vagina, bloody crust around the eye(s),
mouth and nose, hunched and thin appearance, and depression. A dose-related
decrease In mean body weight was observed throughout the study. Mean body
weights of the 500 and 1000 mg/kg/day groups were significantly (p<0.05)
lower than controls at various times during the experiment. Food consump-
tion In the low-dose group was similar to controls; while food consumption
In the middle- and high-dose groups was lower than controls. No treatment-
related effects were noted 1n pregnancy rate, the number of corpora lutea,
the mean number of Implantations per group or 1n the Incidence of fetal
death. The Incidence of resorptlons In the high-dose group was signifi-
cantly (p<0.05) higher than the control value. A slight but nonsignificant
decrease In mean fetal body weights was observed 1n all treated groups
except low-dose females. Crown-rump measurements were slightly but not
significantly decreased 1n high-dose fetuses, but were similar to controls
In other dose groups. Results of gross, visceral and skeletal examinations
did not reveal a teratogenlc effect.
In another study (Gad et a "I., 1984), groups of 25 Inseminated New
Zealand White rabbits were dosed by gavage with caprolactam at 0, 50, 150 or
250 mg/kg/day on gestation days 6-28. A group of 18 rabbits dosed with
6-am1non1cot1nam1de at 3 mg/kg/day on gestation day 9 served as positive
controls. The does were sacrificed on gestation day 29, and examinations
similar to those described for the rat study were completed. Four rabbits
treated at 250 mg/kg/day died. Survival 1n other groups was not affected.
0065d -31- 01/20/88
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High- and mid-dose rabbits had significant (p<0.05) losses of weight between
gestation days 6 and 9. Through the rest of the study, body weights of
these two groups continued to be lower than controls. Body weights of
rabbits treated at 50 mg/kg/day were not affected. No effects on the number
of live fetuses, resorptlons or postlmplantatlon losses were noted. Fetal
weights from the 150 and 250 mg/kg/day rabbits were decreased significantly
(p<0.05 and p<0.01, respectively), and the Incidence of thirteenth ribs was
significantly (p<0.05) Increased at 250 mg/kg/day. Caprolactam treatment
did not affect the Incidence of major malformations.
6.5. OTHER REPRODUCTIVE EFFECTS
Gross (1984) summarized Russian studies (Hartynova, 1972; Khadzhleva,
1969b; Pestrl, 1970; Nadezhdlna and Talaklna, 1971; Khadzhleva, 1972;
Hartynova et al., 1972) that found gynecological effects In women occupa-
tlonally exposed to caprolactam and other compounds (see Section 6.1.1.2.}.
Exposure concentrations fluctuated and were reported to be as high as
100-400 mg/m3 during some processes and low as 1-10 mg/m3 at other
times. Adverse effects observed 1n excess In exposed women as compared with
controls were dysmenorrhea, menorrhagla, ollgomenorrhea and obstetrical
complications Including postpartum hemorrhage, toxemia of pregnancy,
premature birth and Inadequate uterine contractions during labor.
Rats exposed to caprolactam at 425-525 or 120-150 mg/m3 developed a
shortening of the rutting phase and a lengthening of the resting phase
(Khadzhleva, 1969a; Martynova et al.. 1972). The number of follicles 1n
these rats were reduced, and the number of corpora lutea were Increased.
Serota et al. (1984) conducted a 3-generat1on study of caprolactam In
which groups of 10 male and 20 female F344 rats were fed caprolactam In the
diet at 0, 1000, 5000 or 10,000 ppm for 10 weeks before mating. The first
0065d -32- 01/20/88
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Utter (F-ja) was sacrificed and gross necropsies were conducted on about
one-third of the pups. The parental generation was mated a second time 7-13
days after the first Utter was sacrificed. Ten male and 20 female rats,
selected from the second Utter (F,. ) served as the P- generation, while
the remaining pups were sacrificed. At weaning of the F,. pups, the P,
rats were sacrificed and complete necropsies were performed. The P? rats
were fed caprolactam at the same level as their parents. After 10 weeks of
treatment, the P~ rats were mated twice as described for the P,
generation, except that the P2 rats were not necropsled. The P. rats,
selected from the F2b generation, were treated for 10 weeks and mated
twice. Gross necropsies Including kidney weights were completed on about
half of the F,.. pups. The remaining pups and the P« rats were discarded
without necropsy. All Utters were observed and the number of live and dead
pups, body weights and evidence of abnormality were recorded on days 1, 7
and 21 of lactation.
Lower mean body weights and food consumption of both sexes were observed
1n the Pp and P~ generations treated at 5000 and 10,000 ppm. Body
weights were significantly lower (p<0.05) 1n most offspring of the high-dose
group and In some offspring of the middle-dose group at various times. Body
weight and food consumption were not affected In rats treated at 1000 ppm.
Gross examinations of all three generations of parental rats revealed no
abnormalities. Microscopic examination of kidneys of P, males treated at
10,000 ppm showed a slight Increase In the severity of spontaneous nephro-
pathy, which was accompanied by granular casts In three rats that were
examined. No other hlstopathologlcal effects were noted.
No effects on pregnancy and fertility Indices (live birth, neonatal and
weaning survival, percentage of male offpsrlng) were noted. Hale and female
pup body weights were consistently lower at the two highest dose levels 1n
0065d -33- 01/20/88
-------
all generations. This response was dose-related and significant (p<0.05) at
10,000 ppm. Analysis of kidney-to-body weight ratios In the F«. pups
revealed no significant differences.
6.6. SUMMARY
No subchronlc Inhalation studies of caprolactam toxlclty were available.
In an occupational study, no effects on general health were observed In
workers exposed to 0.2-12.3 ppm (0.9-56.9 mg/m3) caprolactam vapor for up
to 18 years (Ferguson and Wheeler, 1973). Irritation, however, was reported
at >7 ppm (32 mg/m3). Occupational exposure to caprolactam dust at >6
mg/m3 was associated with respiratory and dermal Irritation (Kelman, 1986).
An early subchronlc oral study of caprolactam found that water Intake
and body weight was depressed 1n rats provided with drinking water contain-
ing caprolactam at 0.75 g/100 ml (Goldblatt et al., 1954). No other
parameters were examined.
Wljnands and Feron (1969), De Knecht-van Eekelen and van der Meulen
(1970) and De Knecht-van Eekelen et al. (1971) all found hyaline droplet
degeneration 1n the epithelium of the proximal convoluted tubules of kidneys
In rats exposed to caprolactam 1n the diet at >0.05X for up to 90 days.
Male rats were more sensitive than female rats. Other effects observed at
IX of diet Included body weight depression and Increased liver and kidney
weights. Powers et al. (1984) found reversible renal effects 1n stressed
rats fed low (0.01-0.5X) levels of caprolactam 1n the diet for 90 days. In
unstressed rats, elevated BUN and hyaline droplet degeneration In the kidney
occurred at 0.5X but not at 0.1% of the diet.
The only effects noted In the 13-week NTP (1982) study were weight gain
and food Intake depression In F344 rats fed caprolactam at levels >2500 ppm,
and weight gain depression 1n mice fed caprolactam at levels >5000 ppm.
0065d -34- 01/20/88
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In a 90-day study (Burdock et a!., 1984), female beagle dogs fed capro-
lactam In the diet at 154 showed an Insignificant decrease In body weight.
No effects were noted at dietary levels <0.5X.
In the NTP (1982) study, weight gain and food consumption were depressed
1n F344 rats fed at 3750 and 7500 for 103 weeks. Caprolactam 1n the diet at
7500 and 15,000 ppm reduced body weight gain 1n B6C3F1 mice but had no
effect on food Intake. No other effects were noted.
Acute exposures of humans to caprolactam vapor at 100 ppm (463 mg/m3)
resulted In severe nose, throat and eye discomfort (Ferguson and Wheeler,
1973). At 7 ppm (32 mg/m3), no distress was noted. Tuma et al. (1981)
reported a case of dermatitis, fever and grand mal seizures In a man occupa-
tlonally exposed to caprolactam for 3 days.
Guinea pigs exposed to caprolactam dust at 118-261 mg/m3, 7 hours/day
for 7 days coughed occasionally (Goldblatt et al., 1954).
The only significant effect noted In rats fed caprolactam 1n the diet at
levels >5000 ppm were pale mottled kidneys In all groups of male rats (NTP,
1982). No effects were observed 1n mice at dietary levels of 5000-30,000
ppm.
Acute toxic signs observed In rats Injected 1ntraper1tonea11y with
caprolactam Include cries, tremors, apprehension, depression of temperature,
chromodacryorrhea (500-600 mg/kg), convulsions and death (900 mg/kg)
(Goldblatt et al., 1954). Oral LD5Q values In rats vary from 1.15 g/kg
(Bormann and Loeser, 1959) to -2.5 g/kg (Friedman and Salerno, 1980).
The NTP (1982) oral cardnogenldty study of caprolactam did not result
In Increased tumor Incidences In either rats or mice. The cardnogenldty
of caprolactam has not been studied by any other route of exposure.
0065d -35- 01/20/88
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Negative results were found 1n mutation assays In S. typhlmuMum (Venltt
et al., 1985), In mltotlc gene conversion, chromosome aneuploldy, mltotlc
segregation and mitochondria! mutation In yeast (Parry et al., 1985), In
assays for DNA single-strand breaks and unscheduled DNA synthesis (Williams
et al., 1985), sister chromatld exchange, gene mutation (Dean et al., 1985;
Garner et al., 1985) and metabolic cooperation (Elmore and Nelmes, 1985) In
mammalian cells and cell transformation assays 1n C3HTOT1/2, Balb/c 3T3,
Fischer rat embryo and CHO cells (McGregor et al., 1985). Positive results
were found 1n assays for nuclear mutation 1n yeast (Parry et al., 1985),
somatic recombination and mutation In D_. melanogaster (Vogel et al., 1985),
chromosomal aberrations In human lymphocytes and Chinese hamster lung cells
(Dean et al., 1985), and cell transformations In Syrian hamster embryo cells
(McGregor et al., 1985).
Khadzhleva (1969a) reported a concentration-related decrease In the
percent of pregnant rats, the average number of young/Utter and the average
fetal weight of fetuses from pregnant rats exposed to caprolactam vapor at
139.2 and 473.4 mg/m3 for various segments of the gestation period.
Gad et al. (1984) completed teratogenlclty studies 1n rats and rabbits.
In rats treated by gavage with caprolactam at 0, 100, 500 or 1000 mg/kg/day
on gestation days 6-12 a significant Increase was observed In fetal resorp-
tlons In the high-dose groups. In rabbits treated by gavage at 150 mg/kg/
day on gestation days 6-28, maternal body weights were decreased and fetal
weights were significantly reduced. No effects were noted at 50 mg/kg/day.
Gross (1984) summarized Russian studies that found an excess of
dysmenorrhea, menorrhagla, ollgomenorrhea and obstetrical complications 1n
women occupatlonally exposed to caprolactam at levels ranging from 1-400
mg/m3. Reproductive effects reported 1n Russian studies In rats exposed
0065d -36- 01/20/88
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to caprolactam vapor at 425-525 or 120-150 mg/m3 Include a shortening of
the rutting phase and a lengthening of the resting phase with an Increase In
the number of corpora lutea (Khadzhleva, 1969b, 1972).
Results of a 3-generat1on study (Serota et al., 1984) showed lower body
weights 1n the offspring of F344 rats fed caprolactam at 5000 and 10,000
ppm. An Increase In the severity of spontaneous nephropathy was observed 1n
parental rats at 10,000 ppm. No other hlstopathologlcal effects were noted.
0065d -37- 01/20/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The ACGIH (1986a,b) Is currently 1n the process of changing the TLV-TWA
for caprolactam. The old TLV-TWA guideline 1s 5 ppm (20 mg/m3) for capro-
lactam vapor and 1 mg/m3 for dust, with TLV-STELs of 10 ppm (40 mg/m3)
for vapor and 3 mg/m3 for caprolactam dust. The proposed TWA for capro-
lactam vapor and aerosol Is 1 mg/m3 or 0.22 ppm when present as a vapor.
No STEL value Is recommended. The TLV Is designed to prevent skin Irri-
tation.
Other guidelines or standards for caprolactam could not be located In
the available literature as cited 1n Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of caprolactam could not be located 1n the available literature
as cited 1n Appendix A.
0065d -38- 01/20/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of
caprolactam following Inhalation exposure could not be located 1n the avail-
able literature as cited In Appendix A.
8.1.2. Oral. In the NIP (1982) carclnogenlclty study, no Increased tumor
Incidences were found In male and female rats fed caprolactam at 0, 3750 or
7500 ppm and male and female mice fed at 0, 7500 or 15,000 ppm.
8.1.3. Other Routes. Pertinent data regarding the cardnogenldty of
caprolactam following other routes of exposure could not be located 1n the
available literature as cited In Appendix A.
8.1.4. Weight of Evidence. Caprolactam was negative 1n carclnogenlclty
studies using rats and mice (NTP, 1982). The epidemlologic data base Is
Inadequate to demonstrate or refute carcinogenic potential. The negative
results 1n two species receiving the maximum tolerated dose In the presence
of Inadequate data for cardnogenesls among exposed humans permits the
we1ght-of-ev1dence classification of Group E for caprolactam (U.S. EPA,
1986b), evidence of noncarclnogenldty for humans.
8.1.5. Quantitative Risk Estimates. Caprolactam was negative 1n a
cardnogenldty study using rats and mice (NTP, 1982), and 1t 1s not
possible to derive risk assessment values based on carclnogenlclty.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Because of the
lack of data concerning the toxldty of caprolactam following subchronlc
Inhalation exposure, the chronic Inhalation RfD of 0.01 mg/kg/day or 0.7
mg/day for a 70 kg human based on the ACGIH (1986a) proposed TLV of 1
mg/m3 1s adopted as the subchronlc Inhalation RfD (Section 8.2.1.2.).
0065d -39- 01/20/88
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8.2.1.2. CHRONIC EXPOSURES — No effects on general health were noted
In workers exposed to caprolactam at 0.2-12.3 ppm over an 18-year period
(Ferguson and Wheeler, 1973). Kelman (1986) found no consistent abnormali-
ties 1n blood counts, urinary B2-m1croglobul1n levels, or In liver and
lung function tests 1n eight caprolactam-exposed workers. Several workers
complained of eye, nose or throat Irritation and all but one experienced
peeling of the hands and feet.
In contrast to the above studies, Gross (1984) summarized a number of
Russian studies (Martynova, 1972; Bashurov, 1964; Spath, 1967; Antonova,
1968; PestM, 1970; Petrov, 1975) 1n which effects were reported In workers
exposed to caprolactam as well as to other compounds and high noise levels,
temperatures and humidity. The effects observed Included neurological
effects, gynecological effects, gastrointestinal effects, cardiovascular
effects and dermatologlcal and 1mmuno1og1cal changes.
Given the lack of appropriate experimental data, the proposed TLV of 1
mg/m3 for vapors and dust (ACGIH, 1986a) may be considered a basis for an
RfD for chronic Inhalation exposure to caprolactam. The proposed TLV of 1
mg/m3 Is a weak basis for an RfD because 1t 1s designed primarily to
prevent early signs of Irritation and dermal effects 1n exposed workers.
The limited occupational data available, however, suggest that adverse
health effects do not occur In workers exposed to vapors at 0.2-12.3 ppm
(0.9-56.9 mg/m3) (Ferguson and Wheeler, 1973) or to dust at 6-131 mg/m3
(Kelman, 1986). Generally, 7 ppm (32 mg/m3) appears to be the threshold
for Irritation associated with exposure to the vapor (Ferguson and Wheeler,
1973). Since the TLV for vapors and dust of 1 mg/m3 appears to be the
lowest NOAEL for Irritation and health effects associated with exposure to
caprolactam, 1t 1s selected as the basis of an RfD for chronic Inhalation
0065d -40- 01/20/88
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exposure. The concentration of 1 mg/m3 1s multiplied by 10 m3, the
reference human Inhalation volume for a workday, and 5 days/7 days to expand
from occupational to continuous exposure to derive an equivalent dosage of
7.14 mg/day. An uncertainty factor of 10 to protect unusually sensitive
humans 1s applied to the equivalent dosage of 7.14 mg/day to derive an RfD
for chronic Inhalation exposure of 0.01 mg/kg/day or 0.7 mg/day for a 70 kg
human. However, because the TLV without adequate supporting studies Is an
Inappropriate basis for the derivation of an RfD, this value cannot be
endorsed for use at this time.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — An early
subchronlc study of caprolactam found that water Intake and body weight were
depressed 1n rats provided with drinking water containing caprolactam at
0.75 g/100 ml (Goldblatt et al., 1954). No other parameters were examined
In this study, which 1s Inadequate for use In risk assessment.
Wljnands and Feron (1969) observed body weight depression 1n CIVO Mlstar
rats fed caprolactam at >1X for 28 days. Other effects observed at dietary
levels of 1 and 5X Included Increased liver and kidney weights and hyaline
droplet degeneration 1n the epithelium of the proximal convoluted tubules.
Males were more sensitive to all effects noted.
Changes 1n body weight, liver and kidney weights, and hyaline droplet
degeneration were also found In 90-day studies using CIVO Wlstar (De Knecht-
van Eekelen and van der Meulen, 1970) and Sprague-Dawley rats (De Knecht-van
Eekelen et al., 1971). The most sensitive effect, hyaline droplet forma-
tion, was observed at >0.1X In CIVO Wlstar rats and at >0.05% 1n Sprague-
Dawley rats, with males of both strains more sensitive than females.
0065d -41- 01/22/88
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In an examination of renal function In caprolactam-fed male rats of
three strains, Powers et al. (1984) found elevated BUN 1n rats treated at
>0.5X for 90 days. Microscopic examination of kidneys revealed Increased
frequencies of hyaline droplets 1n renal tubules of male rats of all three
strains at 0.5%. The degree of susceptibility appeared to be Sprague-Dawley
> F344 > Wlstar. All kidney effects were found to be reversible 1n rats
treated with caprolactam In the diet for 90 days followed by a 90-day
recovery period.
The only effects noted In the 13-week NTP (1982) study were weight gain
and food Intake depression In F344 rats fed caprolactam at levels >2500 ppm
and weight gain depression 1n mice fed caprolactam at levels >5000 ppm.
In a 90-day study (Burdock et al., 1984), female beagle dogs fed capro-
lactam 1n the diet at 1% showed an Insignificant decrease In body weight.
No effects were noted at dietary levels <0.5X. The parameters examined
Included food consumption, blood and urine analyses, ophthalmologlc examina-
tions and complete necropsies.
Gad et al. (1984) completed teratogenlclty studies 1n which rats were
gavaged with caprolactam at 0, 100, 500 or 1000 mg/kg/day on gestation days
6-20, and a dose-related decrease 1n maternal body weights was observed. A
slightly Increased Incidence of fetal resorptlons was observed at 1000
mg/kg/day (p<0.05). In rabbits gavaged with 150 mg/kg/day on gestation days
6-28, maternal body weights were decreased and fetal weights were signifi-
cantly (p<0.05) reduced. No effects were noted at 50 mg/kg/day.
The subchronlc rat studies summarized by Gross (1984) 1n which kidney
effects were observed In male rats (Wljnands and Feron, 1969; De Knecht-van
Eekelen and van der Heulen, 1970; De Knecht-van Eekelen et al., 1971) are
not appropriate for risk assessment because Insufficient details of these
0065d -42- 01/20/88
-------
studies were available and because the toxlcologlcal significance of hyaline
droplet formation 1n the kidney of male rats 1s not clear. [Hale rats are
predisposed to the "formation of hyaline droplets, which 1s believed to be
associated with the relatively large amount of protein that Is excreted by
the male kidney" (Calabrese, 1985).]
Th'e 90-day dog study (Burdock et al., 1984) 1s not appropriate for the
derivation of a subchronlc RfD. The NOAEL In this study was the 0.5%
dietary level which according to the authors provided a dally dose of -160
mg/kg. This dose level 1s above the LOAEL for fetotoxldty 1n rabbits (150
mg/kg/day) observed 1n the developmental toxldty study (Gad et al., 1984).
The most appropriate basis for an RfD for subchronlc oral exposure 1s
the kidney function study by Powers et al. (1984) 1n which groups of three
strains of rats were fed diets containing 0, 0.01, 0.05, 0.1 or 0.554 capro-
1actam for 90 days. The only adverse effect noted was a slightly elevated
BUN, which was statistically significant only In Sprague-Dawley male rats at
0.5%. The 0.1% dietary level, equivalent to 50 mg/kg/day assuming a food
factor for rats of 0.05, 1s a NOAEL. Since the NOAEL of 50 mg/kg/day Is
below the level associated with Increased fetal resorptlon In rats (1000
mg/kg/day) and below the level associated with fetotoxldty In rabbits (150
mg/kg/day) (Gad et al., 1984), 1t can serve as the basis for the RfD. This
NOAEL of 50 mg/kg/day Is further supported by the NOAEL of the fetotoxldty
study by Gad et al. (1984), but the Powers et al. (1984) study design and
critical effects are more useful for subchronlc RfD calculation. Applica-
tion of an uncertainty factor of 100, 10 to extrapolate from rats to humans
and 10 to protect unusually sensitive humans, results In an RfD for sub-
chronic oral exposure to caprolactam of 0.5 mg/kg/day, or 35 mg/day for a 70
kg human.
0065d -43- 01/20/88
-------
8.2.2.2. CHRONIC EXPOSURES — In the NTP (1982) cancer study, weight
gain depression was observed 1n F344 rats fed at 3750 and 7500 ppm for 103
weeks. Caprolactam in the diet at 7500 and 15,000 ppm reduced body weight
gain In B6C3F1 mice but had no effect on food Intake. Hlstopathologlc
effects were not observed In either rats or mice.
Results of a 3-generat1on study (Serota et a!., 1984) showed lower body
weights 1n the offspring of both sexes of F344 rats fed caprolactam at 5000
and 10,000 ppm. Parental body weight and food consumption were also reduced
at >5000 ppm. Body weight and food consumption were not affected at 1000
ppm. An Increase In the severity of spontaneous nephropathy was observed 1n
P, rats at 10,000 ppm. No other hlstopathologlcal effects were noted.
The lowest chronic LOAEL Is the decrease In pup and parental body
weights observed 1n the 3-generat1on study {Serota et al., 1984) In rats fed
caprolactam at 5000 ppm. This effect was not observed at the 1000 ppm
level. Multiplying the 1000 ppm level by a 0.05 rat food factor (U.S. EPA,
1985) results 1n a NOAEL of 50 mg/kg/day. This NOAEL Is Identical to the
subchronlc oral NOAELs Identified 1n a 90-day dietary rat study (Powers et
al., 1984) In which elevated BUN was observed 1n males at 250 mg/kg/day
(0.5% of diet), and the NOAEL of 50 mg/kg/day for rabbits 1n the Gad et al.
(1984) study. The Serota et al. (1984) study was selected for the chronic
RfD because these effects were seen 1n other studies and this was a
3-generat1on study. Dividing the rat NOAEL of 50 mg/kg/day by an uncer-
tainty factor of 100 (10 for Interspecles extrapolation and 10 to protect
sensitive Individuals) results In a human chronic RfD of 0.5 mg/kg/day or 35
mg/day for a 70 kg human.
0065d -44- 01/20/88
-------
Confidence In this RfD 1s high. The 3-generat1on study (Serota et al.,
1984) was adequate. The effect of concern was decreased body weight 1n both
pups and parental rats. This study Is supported by the NTP (1982) study 1n
which the only effect noted was decreased body weight and food consumption
1n rats and decreased body weights 1n mice fed caprolactam In the diet at
much higher levels. The study Is further supported by the NOAELs of the
subchronlc studies (Powers et al., 1984; Gad et al., 1984).
0065d -45- 01/20/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of caprolactam 1s discussed 1n Chapter 6. Data from
studies sufficient In length and adequately reported for derivation of CSs
are summarized 1n Table 9-1. The major effects attributed to chronic
exposure to caprolactam are weight gain depression In rats and mice (NTP,
1982), reduced body weights of fetuses of rabbits (Gad et al., 1984) or
offspring of rats (Serota et al., 1984), Increased fetal resorptlon In rats
(Gad et al., 1984) and compromised renal function Indicated by elevated BUN
1n male rats (Powers et al., 1984). Although chronic data regarding the
effect on body weight gain In rats and mice are available from the cancer
bloassay, data from the subchronlc (90-day) studies are Included In Table
9-1 because the effect occurred at lower levels 1n both species In the
subchronlc studies. An uncertainty factor of 10 was applied 1n estimating
the equivalent human dose to expand to chronic exposure 1n the subchronlc
studies of NTP (1982) and Powers et al. (1984). CSs based on these effects
are presented In Table 9-2.
CSs for the toxldty of caprolactam were similar, ranging from 5.4 for
elevated BUN In rats (Powers et al., 1984) to 8.8 for decreased body weight
gain 1n rats (NTP, 1982). All CSs corresponded to an RQ of 1000, with the
exception of the Powers et al. (1984) study which was a borderline CS value
between 5 and 6. The CS of 8.8 associated with reduced body weight gain In
rats 1s chosen to represent the chronic toxldty of caprolactam. This CS Is
presented In Table 9-3.
0065d -46- 01/20/88
-------
Oral Toxlclty Summary for Caprolactam
Species/
Strain
Rat/F344
Mouse/
B6C3F1
Rat/
Sprague-
Oawley
Rat/F344
Rabbit/
NZU
Rat/F344
No. at
Sex Start
M.F 12/sex
H.F 10/sex
H 6
F 20
F 25
M.F 10 M
20 F
Average
Weight
(kg)
0.35b
0.03b
0.35b
0.18f
3.9*
0.35°
Vehicle/
Physical
State
diet
diet
diet
distilled
water
distilled
water
diet
Purity Exposure
pure >2500 ppa In the
diet for 13 weeks
pure >SOOO ppm In the
diet for 13 weeks
NR 0.5X of diet for
90 days
NR 1000 ng/kg/day by
gavage on gesta-
tion days 6-15
NR 150 ng/kg/day by
gavage on gesta-
tion days 6-28
NR 5000 ppn In the
diet for three
generations
Transformed
Animal Dose
(mg/fcg/day)
125C
650e
250C
1000
150
250e
Equivalent
Human Dosea
(mg/kg/day)
2.14<1
4.90d
4.27d
137.0
57.3
42.7
Response
Height gain depression
Uelght gain depression
Elevated BUN
Increased fetal resorptlon
Maternal and fetal body
weights decreased
Lower mean body weights
of offspring
Reference
NTP. 1982
NTP. 1982
Powers
et al.. 1984
Gad et al..
1984
Gad et al..
1984
Serota
et al.. 1984
Calculated by multiplying the animal transformed dose by the cube root of the ratio of the animal body weight to the human body weight (70 kg).
bReference body weight (U.S. EPA. 1985)
^Calculated using 0.05 rat food factor (U.S. EPA. 1985)
dAn uncertainty factor was applied to expand from subchronlc to chronic exposure.
Calculated using 0.13 mouse food factor (U.S. EPA. 1985)
^Estimated from Investigators' data
NR = Not reported
-------
in
Q.
TABLE 9-2
Oral Composite Scores for Caprolactam
I\J
o
*v
CD
CD
Species
Rat
House
Rat
Rat
Rabbit
Rat
Transformed
Animal Dose
(mg/kg/day)
125
650
250
1000
150
250
Chronic
Human MED*
(mg/day)
150
343
299
9590
4011
2989
RVd
2.2
1.7
1.8
1
1
1
Effect
Weight gain depression.
decrease In food con-
sumption
Weight gain depression
Elevated BUN
Increased fetal resorp-
tlon
Decreased maternal and
fetal body weights
Lower mean body weights
of offspring
RVe
4
4
3
8
8
8
CS
9
7
5
8
8
8
RQ
1000
1000
1000
1000
1000
1000
Reference
NTP. 1982
NTP. 1982
Powers
et al.. 1984
Gad et al..
1984
Gad et al..
1984
Serota
et al.. 1984
*Est1mated by multiplying the equivalent human dose In Table 9-1 expressed In mg/kg/day by 70 kg to express
the HED In mg/day for a 70 kg human.
-------
TABLE 9-3
Caprolactam
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 150 mg/day
Effect: decrease In body weight gain
Reference: . NTP. 1982
RVd: 2.2
RVe: 4
Composite Score: 9
RQ: 1000
*Equ1valent human dose
0065d -49- 01/20/88
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9.2. BASED ON CARCINOGENICITY
Caprolactam was negative 1n carclnogenlcUy studies 1n rats and mice
(NTP, 1982), and no human carclnogenlcUy data are available. The compound
1s assigned an EPA classification of E ~ evidence of noncardnogenldty In
humans, so that the derivation of an RQ based on carclnogenlcUy Is not
applicable.
0065d -50- 01/20/88
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10. REFERENCES
Abrams, E.F., C.V. Derklcs, O.K. Fong, et al. 1975. Identification of
organic compounds 1n effluents from Industrial sources. Versar Inc.,
Springfield, VA. EPA 560/3-75-002.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986a.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
p. 95-96; 95(86): 96.2(86).
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Threshold Limit Values and Biological Exposure Indices for 1986-1987.
Cincinnati, OH.
Antonova, A.N. 1968; Hygienic evaluation of the educational Industrial
system of students 1n a professional-technical school specializing 1n the
twisting of acetate and capron fibers. Hater.-Nauch.-Prakt. Konf. Molodykh.
G1g. Sanlt. Vrachel. 11: 279. (CA 72:35487c)
Bashurov, A.A. 1964. Functional condition of the parenchymatous organs of
workers In the kapron Industry. (Translation) Gig. Sanlt. 29: 42. (Cited
1n Gross, 1984)
Bormann, G. and A. Loeser. 1959. Monomer-polymer studies with e-capro-
lactam and b1s-phenol A. Arznelmlhel-Forsh. 9: 9-13. (CA 53:111662f)
0065d -51- 01/20/88
-------
Burdock, G.A., B.A. Kulwlch, R.D. Alsaker and P.M. Marshall. 1984. Ninety-
day toxlclty study In dogs with caprolactam. In.: Proc. Symp. 2nd Approach
Chem. Risk Assess.: Caprolactam and Related Compounds as a Case Study.
p. 97-113.
Calabrese, E.J. 1985. Toxic Susceptibility. Male and Female Differences.
John Wiley and Sons Inc., New York. 336 p.
CMR (Chemical Marketing Reporter). 1986. Chemical Profile: Caprolactam.
October 18, 1986.
Dean, B.J., N. Danford, G. Douglas, et al. 1985. Summary report on the
performance of cytogenetlc assays In cultured mammalian cells. Prog. Mutat.
Res. 5: 69-83.
De Knecht-van Eekelen, A. and H.C. van der Meulen. 1970. Sub-chronic
(90-day) toxldty study with caprolactam 1n albino rats. Central Institute
for Nutrition and Food Research, Netherlands. (Cited 1n Gross, 1984)
De Knecht-van Eekelen, A., H.C. van der Meulen and H.P. T11. 1971. Sub-
chronic (90-day) toxldty study with caprolactam In Sprague-Dawley albino
rats. Central Institute for Nutrition and Food Research, Netherlands.
(Cited 1n Gross. 1984)
Elsenrelch, S.J., B.B. Looney and D.J. Thornton. 1981. Airborne organic
contaminants of the Great Lakes ecosystem. Environ. Sc1. Technol. 15(1):
30-38.
0065d -52- 01/20/88
-------
Elmore, E. and A.J. Nelmes. 1985. Summary report on the performance of the
Inhibition of metabolic cooperation assay. Prog. Mutat. Res. 5: 95-102.
Ferguson, W.S. and O.D. Wheeler. 1973. Caprolactam vapor exposures. Am.
Ind. Hyg. Assoc. J. 34: 384-389.
Fischer, W.B. and L. Crescentlnl. 1982. Caprolactam. In: K1rk-0thmer
Encyclopedia of Chemical Technology, Vol. 18, 3rd ed., H. Grayson and D.
Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 425-436.
Fortman, L. and A. Rosenberg. 1984. Fate of e-caprolactam In the aquatic
environment. Chemosphere. 13(1): 53-65.
Friedman, M.A. and A.J. Salerno. 1980. Influence of caprolactam on
rat-liver tyroslne amlnotransferase and tryptophan oxygenase. Food Cosmet.
Toxlcol. 18(1): 39-45.
Gad, S.C., W.J. Powers, K. Robinson, D.G. Serota and B.R. Colpean. 1984.
Rat and rabbit teratology studies of caprolactam. in: Proc. Symp. Ind.
Approach Chem. Risk Assess. Caprolactam Relat. Compd Case Study, p. 164-189.
Games, L.H. and R.A. HHes. 1977. Composition, treatment efficiency and
environmental significance of dye manufacturing plant effluents. Anal.
Chem. 49(9): 1433-1440.
Garner. R.C., D. Amacher, W. Caspary, et al. 1985. Summary report on the
performance of gene mutation assays 1n mammalian cells In culture. Prog.
Mutat. Res. 5: 85-94.
0065d -53- 01/20/88
-------
Goldblatt, M.W., H.E. Farquharson, G. Bennett and B.M. Askew. 1954.
e-Caprolactam. Br. 0. Ind. Med. 11: 1-10.
Gross, P. 1984. Biologic activity of e-caprolactam. CrH. Rev. Toxlcol.
13(3): 205-216.
Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 19. Pomona
College, Claremont CA.
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 191.
IARC (International Agency for Research On Cancer). 1979a. Monographs on
the Evaluation of Carcinogenic Risk of Chemicals to Humans. Caprolactam and
Nylon 6. IARC, WHO, Lyons, France. Vol. 19, p. 115-118.
IARC (International Agency for Research on Cancer). 1979b. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans - Some
Monomers, Plastics and Synthetic Elastomers and Acroleln. IARC, WHO, Lyons,
France. Vol. 19, p. 119-130.
Jones, A.H. 1960. Sublimation-pressure data for organic compounds. J.
Chem. Eng. Data. 5: 196-200.
Kelman, G.R. 1986. Effects of human exposure to atmospheric e-capro-
lactam. Hum. Toxlcol. 5(1): 57-59.
0065d -54- 01/20/88
-------
Kerr, D.I.B., B.J. Dennis, E.L.H. Breaker, et al. 1976. Antagonism of GABA
mediated Inhibition 1n the CNS by caprolactam derivatives. Brain Res. 110:
413-416.
Khadzhleva, E.D. 1969a. Effect of caprolactam on the reproductive func-
tions of albino rats. Hyg. SanH. 34(7): 28-32. (In Russian with English
translation)
Khadzhleva, E.D. 1969b. Effect of caprolactam on the sexual cycle. Gig.
Tr. Prof. Zabol. 13: 22. (Cited 1n Gross, 1984)
Khadzhleva, E.D. 1972. Effects of caprolactam on female reproductive func-
tions. Vopr. Gig. Norm1rovan1ya Izuch Otdalennykh Pusledstvll Vozde1sn1ya.
p. 68. (Cited In Gross, 1984)
Kool, H.3., C.F. Van Kreljl and B.C.J. Zoeteman. 1982. Toxicology assess-
ment of organic compounds 1n drinking water. Cr1t. Rev. Env. Cont. 12:
207-357.
Kopfler, F.C., R.G. Helton, 3.L. Mullaney and R.G. Tardlff. 1977. Human
exposure to water pollutants. Adv. Environ. Sc1. Technol. 8: 419-433.
Llllard, D.A. and J.J. Powers. 1975. Aqueous odor threshold of organic
pollutants In Industrial effluents. U.S. EPA, Off. Res. Dev., Athens, GA.
20 p. EPA 660/4-75-002.
0065d -55- 01/20/88
-------
Loewengart, G. 1984. Aquatic toxlclty and environmental fate studies —
Caprolactam. In;. Proc. Symp. Ind. Approach Chem. Risk Assess.: Caprolactam
Relat. Compd. Case Study, 35-52. Ind. Health Found., Pittsburgh, PA. [CA
103(l):1681e]
Lomonova, G. 1966. Toxlclty of Caprolactam. G1g. Tr. Prof. Zabol. 10:
54-57. (CHed In IARC, 1979b)
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 4-9, 5-5,
7-4.
Martynova, A.P., V.M. Lotls, E.D. Keadzhlfua and P.S. Galdova. 1972.
Occupational health of women In the production of caprolactam fibres. G1g.
Tr. Prof. Zabol. 16: 9. (Cited In Gross, 1984)
McGregor, 0., J. Ashby, C. Barrett, et al. 1985. Summary report on the
performance of the cell transformation assays. Jji: Progress In Mutation
Research. Evaluation of Short-term Tests for Carcinogens, Vol. 5., D.
Ashby, et al., Ed. WHO, Elesvler Science Publishing, Amsterdam, p. 103-115.
Nadezhdlna, L.Z. and E.I. Talaklna. 1971. Status of the menstrual and
child-bearing function of pregnant female workers 1n the caprolactam
Industry. G1g. Tr. Prof. Zabol. 15: 43. (Cited In Gross, 1984)
NTP (National Toxicology Program). 1982. Carcinogenic bloassay of capro-
lactam (CAS No. 105-60-2) F344 rats and B6C3F1 mice (feed study). NTP Tech.
Rep. Ser. No. 214. [Also publ. as NIH Publ. NIH-81-1770]
0065d -56- 01/20/88
-------
Pagga, U. and W. Guenthner. 1982. B1odegradat1on and toxldty studies with
microorganisms: A comparison of laboratory tests with a treatment plant
model system. Com. Eur. Comm., Environ. Qual. Life. p. 498-504.
Parry, J.M., P. Arn1, T. Brooks, et al. 1985. Summary report on the per-
formance of the yeast and Asperglllus assays. Prog. Hutat. Res. 5: 25-46.
Pestrl, Yu. N. 1970. State of the nervous system of workers producing
caprolactam. G1g. Tr. Prof. Zabol. 14: 37. (Cited 1n Gross, 1984)
Peterson, J.C., D.F. Clark and P.S. Sleevl. 1986. T1re fire oil monitor-
Ing: A new environmental pollutant. Anal. Chem. 58(1): 70A-72A, 74A.
Petrov, N.Y. 1975. Health status of women working In the chemical fiber
Industry according to data of medical examinations. Vrach. Delo. 10: 145.
(Cited In Gross, 1984)
PHter, P. 1976. Determination of biological degradablllty of organic
substances. Water Res. 10: 231-235.
Powers, W.J., Jr., J.C. Peckham, K.H. Sllno and S.C. Gad. 1984. Effects of
subchronlc dietary caprolactam on renal function. In.: Proc. Symp. Ind.
Approach Chem. Risk Assess.: Caprolactam Relat. Compd. Case Study. 77-96
Ind. Health Found., Pittsburgh, PA. [CA 103(l):1681e]
R1dd1ck, J.A., W.K. Bunge and T.K. Sakano. 1986. Organic solvents: Physi-
cal properties and methods of purification. Ln: Techniques of Chemistry,
Vol. 2, 4th ed. Wlley-Intersclence, New York. p. 1325.
0065d -57- 01/20/88
-------
Serota, D.G., A.M. Hoberman and S.C. Gad. 1984. A three generation repro-
duction study with caprolactam 1n rats. In.: Proc. Symp. Ind. Approach Chem.
Risk Assess.: Caprolactam Relat. Compel. Case Study, 191-204. Ind. Health
Found., Pittsburgh, PA.
Shackelford, H.M. and L.H. Keith. 1976. Frequency of Organic Compounds
Identified 1n Water. U.S. EPA, Athens, GA. EPA 600/4-76-062.
Shama, G. and D.A.J. Wase. 1981. B1odegradat1on of e-caprolactam and
some related compounds: A review. Int. B1odeter1or. Bull. 18(1): 1-9.
Spath, P. 1967. An accidental poisoning with perchlorocuprlc phthalocya-
mlne and e-caprolactam. Int. Arch. Gewerbepathol. Gewerbe Hyg. 24: 183.
(Cited In Gross, 1984)
Stuplna, V.V. and H.M. Blleka. 1973. Effect of e-caprolactam on biochem-
ical composition of some chlorococcal algae. UKR Bot ZH. 30(6): 751-756.
(Taken from HEEP/74-11884)
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Thorn, N.S. and A.R. Agg. 1975. The breakdown of synthetic organic com-
pounds 1n biological processes. Proc. R. Soc. Lond. B. 189: 347-357.
0065d -58- 01/20/88
-------
Tuma, S.N., F. Orson, F.V. Fossella and W. Waldhofer. 1981. Seizures and
dermatitis after exposure to caprolactam. Arch. Intern. Hed. 141(11):
1544-1545.
Unger, P.O., A.3. Salerno and M.A. Friedman. 1981. Disposition of
[14C]caprolactam 1n the rat. Food Cosmet. Toxlcol. 19(4): 457-462.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Haste and Emergency Response,
Washington, DC.
U.S. EPA. 1985. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986a. Methodology for Evaluating Potential Carclnogenlclty 1n
Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, for the Office of Solid Waste and Emergency Response,
Washington, DC.
0065d -59- 01/20/88
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U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). Fate of Atmo-
spheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA, Washington,
DC.
U.S. EPA. 1987b. STORET Water Quality Database. Online: February, 1987.
USITC (U.S. International Trade Commission). 1984. Imports of Benzenold
Chemicals and Products. 1983. USITC Publ. 1548, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals. United States Production and Sales, 1985. USITC Publ. 1745,
Washington, DC.
VenHt, S., R. Baker, H. Liber, T. Matsushlma, G. Probst and E. Zelger.
1985. Summary report on the performance of the bacterial mutation assays.
In: Progress 1n Mutation Research. Evaluation of Short-term Tests for
Carcinogens, Vol. 5., D. Ashby, et al., Ed. WHO, Elesvler Science Publish-
ing, Amsterdam, p. 11-23.
Vogel, E.W., H. Fre1, K. Fujikawa, et al. 1985. Summary report on the
performance of the Drosophlla assays. Prog. Mutat. Res. 5: 47-57.
Waddell, W.J., C. Marlowe and M.A. Friedman. 1934. The distribution of
[14C]caprolactam 1n male, female and pregnant mice. Food Chem. Toxlcol.
22(4): 293-303.
0065d -60- 01/20/88
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Wljnands, W.C. and F.J. Feron. 1969. Range-finding (28-day) Toxldty Study
with Caprolactam 1n Rats. Central Institute for Nutrition and Food
Research, Netherlands. (Cited 1n Gross, 1984)
Williams, G.M., R. Barratt, H. Bradley, et al. 1985. Summary report on the
performance of the assays for DNA damage. Prog. Hutat. Res. 5: 59-67.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 243.
Zahn, R. and U. Huber. 1975. Ring test for biological degradation of
products. Tenslde Deterg. 12: 266-270. (Ger.)
Zahn, R. and H. Wei lens. 1980. Examination of biological degradabUHy
through the batch method — Further experience and new possibilities of
usage. Z. Wasser Abwasser Forsch. 13: 1-7. (Ger.)
0065d -61- 01/20/88
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
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 February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be 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).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances 1n
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey 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 Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0065d -62- 01/20/88
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer 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, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. MHO, IARC, Lyons, France.
Jaber, H.M., U.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
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, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. .Menlo Park, CA. .
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards 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). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
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.
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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 H.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 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.
0065d -64- 01/20/88
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0
9*
a.
i
i
APPENDIX B
Summary Table for Caprolactam
Species Exposure Effect RfD or qj*
Inhalation Exposure
Subchronlc NA .,. NA NA NA
Chronic NA NA NA NA
Carclnogenlclty NA NA NA NA
Oral Exposure
Subchrontc , rat 0.1X of diet for 90 days at 0.5X of diet, elevated BUN 0.5 mg/kg/day or
35 mg/day for a
70 kg human
Chronic rat 1000 ppm of diet In a at 5000 ppm of diet, reduced 0.5 mg/kg/day or
3-generatlon reproduction body weight of offspring 35 mg/day for a
study 70 kg human
Carclnogenlclty NA NA NA NA
REPORTABLE QUANTITIES
Based on Chronic Toxlclty: 1000
Based on Carclnogenlclty: NA
Reference
NA
NA
NA
Powers
et al.. 1984
Serota
et al.. 1984
NA
NTP. 1982
NA
NA = Not applicable
rvi
00
CO
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