201-16722A
TEST PLAN
TABLE OF CONTENTS
Executive Overview ............................................................................ 2
Testing Plan and Rationale................................................................. 4
Testing Plan in Tabular Format....................................................... 5
Introduction ......................................................................................... 6
Physical-Chemical Data...................................................................... 6
Environmental Fate and Pathways ..................................................... 7
Ecotoxicity ........................................................................................................................................................ 8
Mammalian Toxicity ............................................................... 8
A. Acute Toxicity ............................................................................ 8
B. Repeated Dose Toxicity .............................................................. 9
C. Genotoxicity ................................................................................ 12
D. Reproductive Toxicity ................................................................. .13
E. Developmental Toxicity .............................................................. .13
F. Toxicokinetics ............................................................................. 14
Conclusions ........................................................................................ 15
References: ...........................................................................16
APPENDIX:
Substantiation of Closed System Intermediate Status
For Cyclohexanone Oxime........................................................ 18
1
EXECUTIVE OVERVIEW
Cyclohexanone oxime, a white crystalline solid, is used primarily as a
captive intermediate in the synthesis of caprolactam which, in turn, is
polymerized to polycaprolactam (Nylon-6) fibers, resins and plastics. Recent
annual production figures for cyclohexanone oxime are not available.
The Environmental Protection Agency has accepted the Sponsor's claim
that cyclohexanone oxime meets the definition of a "Closed-System
Intermediate" and qualifies for "reduced testing requirements'. Detailed
information in this HPV Test Plan in support of the preceding claim can be found
in an APPENDIX to this Test Plan (See pp. 18-30) entitled "Substantiation of
Closed System Intermediate Status."
Adequate data for cyclohexanone oxime are available relative to
Physical/Chemical properties. This oxime will be a solid below its melting point
(190-196oF) and a liquid above this point. Based on its low vapor pressure
(0.029 mm Hg), high boiling point (406oF), and aqueous solubility (1.5 wt %), it
will tend to remain in water and only slowly volatilize.
Relative to Environmental Fate and Pathways, adequate data exist for
photodegradation but no information is available on biodegradation or transport
and distribution between environmental compartments. In addition, the data on
stability in water (hydrolysis) is limited. Therefore, in order to satisfy HPV/SIDS
requirements for these endpoints, the Sponsor will conduct an OECD TG 111
study to determine stability (hydrolysis) and an OECD TG 301 study to measure
ready biodegradation. In addition, the Sponsor will provide calculated fugacity
values using available measured data from the Physical-Chemical Properties
section.
In the category of Ecotoxicity, limited substantiation data exist for the
fathead minnow (96-Hr LC50 = 208 mg/L) and no aquatic toxicity information was
available for invertebrates or algae. To satisfy Ecotoxicity endpoints, the
Sponsor will conduct an OECD TG 203 study on fish, an OECD TG 202 study on
Daphnia magna, and an OECD TG 201 study on an algal species.
2
Acute toxicity to mammals appears to be relatively low as demonstrated
by oral LD50s in male and female rats of 1765 and 883 mg/kg, respectively, and
a dermal absorption LD50 in rabbits of >5000 mg/kg. On a repeated exposure
basis, several subacute (2-week) and 90-day oral toxicity studies have been
conducted in both rats and mice. In the preceding studies, the major target
organs appear to be the erythrocyte, the spleen, the bone marrow and liver.
Toxicokinetic studies by various routes of administration in rats suggest that
cyclohexanone oxime is readily absorbed, subsequently metabolized, and then
excreted in the urine as glucuronides within a day. Relative to genetic toxicity
potential, cyclohexanone oxime has been thoroughly tested in both in vitro and in
vivo studies. The overall weight of evidence suggests that cyclohexanone oxime
poses no genotoxic hazard. Relative to the HPV Program, adequate studies are
available in the areas of "Acute Toxicity", "Repeated Dose Toxicity", and "Genetic
Toxicity" and no additional testing is needed.
No definitive studies to assess the potential effects of cyclohexanone
oxime on pregnancy or on the reproductive performance of male and female
animals have been conducted. However, the determination by EPA that
cyclohexanone oxime is a "Closed-System Intermediate" will eliminate the need
for any additional reproductive toxicity testing. A developmental toxicity study, on
the other hand, will have to be conducted to fulfill HPV requirements for the
"Reproductive/Developmental Toxicity" category. The Sponsor will conduct such
a study (OECD TG 421) in rats by the oral route.
Overall, cyclohexanone oxime as a "Closed-System Intermediate"
chemical does not appear to represent an unacceptable risk to human health or
the environment. Under the EPA HPV Challenge Program, cyclohexanone
oxime was evaluated, data gaps were identified, and a decision was made to
conduct additional testing in the areas of "Environmental Fate and Pathways",
"Ecotoxicity", and "Developmental Toxicity". Appropriate studies to meet the
HPV requirements will be conducted starting in the 4th quarter of 2008 and take
less than a year to complete.
3
Cyclohexanone Oxime HPV Test Plan
TESTING PLAN AND RATIONALE
4
Testing Plan in Tabular Format
Recommended?
OECD Study?
Acceptable?
GLP Study?
Information
Comments
Estimation
Available?
Cyclohexanol Oxime
Method?
Testing
Study?
Other
HPV Endpoint
Physical/Chemical Properties
Melting Point Y N N N N Y N
Boiling Point Y N N N N Y N
Vapor Pressure Y N N N N Y N
Partition Coefficient Y N N N Y Y N
Water Solubility Y N N N N Y N
Environmental Fate
Photodegradation Y N N N Y Y N
Water Stability Y N N N Y? Y OECD TG 111
Calculated Fugacity
Transport N Y
Values
Biodegradation N Y OECD TG 301
Ecotoxicity
96-Hour Fish Y N N N N Y? Y OECD TG 203
48-Hour Invertebrate N Y OECD TG 202
72-Hour Algae N Y OECD TG 201
MammalianToxicity
Acute Toxicity Y Y/N Y/N Y N Y N
Repeated Dose Y Y? Y N Y N
Genotoxicity (Point Mutation) Y Y? Y N N Y N
Genotoxicity
Y Y Y N N Y N
(Chromosome Aberration)
Y
Reproductive Toxicity N Y Y N N N * No Additional Study
Oral rat; OECD TG
Developmental Toxicity N Y
421 Protocol
*Based on the "Closed-System Intermediate" status of cyclohexanone oxime,
and its very low potential for both occupational exposure and environmental
releases, no additional study is required. See attached APPENDIX (Starting
on p. 18).
5
INTRODUCTION
Cyclohexanone oxime, CAS No. 100-64-1, is a chemical intermediate
used primarily in a closed system in the production of caprolactam. The latter
chemical is subsequently polymerized to produce Nylon-6 (polycaprolactam)
fibers, resins, and plastics.
As part of this HPV Test Plan, DSM Chemicals North America, a primary
producer and the HPV Sponsor of cyclohexanone oxime, has provided detailed
information in support of its claim (accepted by EPA) for reduced testing
requirements for this "Closed- System Intermediate". This information is
contained in an APPENDIX to this Test Plan (See pp. 18-30) entitled:
"Substantiation of Closed System Intermediate Status."
Various studies have already been conducted on the toxicity of
cyclohexanone oxime. Those studies (key and other supporting studies) are
summarized in this document with comments as to whether or not they meet the
requirements of the USEPA High Production Volume (HPV) Program. Robust
summaries, using a SIDS format, have been prepared and include detailed
information on key studies and some supporting studies; these detailed
summaries are contained in a separate document (Tier 1 Screening SIDS
DOSSIER on the HPV Phase....Chemical).
PHYSICAL-CHEMICAL DATA
Physical/chemical properties for cyclohexanone oxime are available from
the literature and from the manufacturer:
190-196oF (1)
Melting Point
406oF (1)
Boiling Point
0.029 mm Hg @ 77oF(1)
Vapor Pressure
Log Pow = 0.84 @ 77oF(2)
Partition Coefficient
1.5 wt% @ 68oF(1)
Water Solubility
6
Cyclohexanone oxime (MW=113.18) is a 6-carbon ring with an "NOH"
group on C1. It is characterized as a white solid at room temperature and as a
clear-to-white crystalline liquid above its melting point of 190-196o F(1). It has a
specific gravity (water=1) of 0.97 and a pungent-to-slightly sweet odor (1).
Cyclohexanone oxime also has a calculated Henry's Law Constant of 8.05E-06
atm-m3/mole (@ 25oC)(2). It also has a lower flammability limit of 1.3%, a flash
point (closed cup) of 181.4oF and autoflammability temperature of 545o F (1).
Recommendation:
No additional studies are recommended to fulfill the HPV required end points for
"Physical/Chemical Properties".
ENVIRONMENTAL FATE AND PATHWAYS
Atmospheric photo-oxidation may be an important removal process for
cyclohexanone oxime. It has a calculated atmospheric OH constant of 7.07E-12
cm3/molecule-sec (2). Relative to stability in water, limited data in a
manufacturer's MSDS states that the chemical is stable and that hydrolysis
occurs only at sustained temperatures (250-300oF)(1). No information was
available on Transport and Distribution between Environmental Compartments
and no information was available on Biodegradation.
Recommendation:
Adequate data exists for Photodegradation and no additional study is planned.
However, the Sponsor agrees to conduct an OECD TG 111 study to determine
stability (hydrolysis) and an OECD TG 301 study to measure ready
biodegradation. In addition, the Sponsor will provide calculated fugacity values
using available measured data from the Physical-Chemical Properties section.
7
ECOTOXICITY
Limited acute aquatic toxicity data are available for cyclohexanone oxime
in fish. In a study following flo-through guidelines, the 96-hr LC50 based on
survival for the fathead minnow (Pimephales promelas) was 208 mg/L (3). No
information was available on invertebrates or algae.
Recommendation:
Since the preceding fish toxicity data (minimal technical detail) may not meet
HPV requirements, and because there is no aquatic toxicity information available
on invertebrates or algae, the Sponsor will conduct an OECD TG 203 study in
fish, an OECD TG 202 study on Daphnia magna, and an OECD 201 study on an
algal species. These ecotoxicity studies will provide appropriate data to satisfy
HPV/SIDS requirements for Ecotoxicity.
MAMMALIAN TOXICITY
A. Acute Toxicity
The acute toxicity potential of cyclohexanone oxime has been
evaluated by several routes of administration. By the intraperitoneal route, its
LD50 in mice was 250 mg/kg (3). By an unspecified route of administration, an
LD50 of 710 mg/kg was reported for male mice (4).
When cyclohexanone oxime was given orally to rats, its LD50 was
1765 mg/kg for males and 883 mg/kg for females (5). These values for oral
toxicity are supported by results from a10-dose subacute oral study at 300 mg/kg
showing no mortality in rats (6).
By the dermal route of administration, the dermal absorption LD50 in
rabbits was >5000 mg/kg, the highest dose tested. Although rabbits showed no
adverse clinical signs, body weight changes, or mortality, various red blood cell
parameters were affected and methemoglobin was elevated at all dose levels
8
(800, 2000 and 5000 mg/kg), suggesting that cyclohexanone oxime may be
absorbed through the skin to a limited extent (7).
There were no reliable data found on inhalation toxicity potential.
However, based on the "Closed-System Intermediate" status of cyclohexanone
oxime, and low occupational exposure potential, inhalation exposure of workers
does not present a significant hazard.
Recommendation:
The preceding acute toxicity studies by the oral, dermal and intraperitoneal
routes are adequate to fulfill HPV/SIDS requirements for "Acute Toxicity".
B. Repeated Dose Toxicity
Several repeated dose toxicity studies on cyclohexanone oxime have
been conducted by the oral route by both gavage and drinking water
administration.
Two 2-week gavage studies were conducted in rats showed dose-related
erythroid hyperphasia in the spleen and bone marrow. In one study (8),
Sprague-Dawley rats that received 1,10, or 1000 mg cyclohexanone oxime per
kg body weight for 2 weeks had hematologic differences including lower
erythrocyte counts, higher platelet counts, lower hemoglobin concentrations and
hematocrit levels, and greater mean red cell hemoglobin and mean red cell
volume values than the control values. Bone marrow smears indicated lower
myeloid, lymphocyte, and monocyte counts concomitant with elevated erythroid
counts. There was also general splenic enlargement with hematopoietic cell
proliferation.
In a second study (6), male and female F344 rats that received 10, 25, 75,
150, or 300 mg cyclohexanone oxime per kilogram body weight by gavage for 2
weeks had adverse hematologic changes similar to those of the Sprague-Dawley
rats. Observations included a dose-related decrease in erythrocyte counts with
9
concomitant increases in the numbers of circulating nucleated erythrocytes and
reticulocytes and reduced hematocrit levels and hemoglobin concentrations.
Methemoglobin concentrations, measured at the highest dose, were significantly
elevated. The rats were observed for another 2 weeks without compound
administration. By Day 28, hematologic values in females had returned to
normal and males displayed only slightly depressed erythrocyte counts and
mildly elevated reticulocyte counts. No significant effects on body weights and
no clinical signs of toxicity were noted in males or females. Splenomegaly and
hepatomegaly were observed in male and female rats on Day 14 and Day 28.
The hematology results suggested that the hematotoxic effects of cyclohexanone
oxime administration were reversible following cessation of exposure. The
authors theorized that cyclohexanone oxime induces oxidative damage to the
erythrocyte resulting in hemolytic anemia compensated by increased
erythropoiesis.
The results of 13-week oral toxicity studies in rats and mice were similar to
those of the two-week oral studies with evidence of splenomegaly and erythroid
hyperplasia in the spleen and bone marrow. In an oral gavage study (7), Fischer
344 rats (20/sex/dose) received doses of 0, 0.25, 2.5, and 25 mg cyclohexanone
oxime per kilogram body weight five times a week for 13 weeks. All males
survived to the end of the study; three of 20 females in the 25 mg/kg group died
before the end of the study. Males were observed with clinical signs of toxicity
that included persistent red nasal discharge (at 25 mg/kg only),
chromodacryorrhea and swollen conjunctiva (at 2.5 and 25 mg/kg), and corneal
opacity (at all dose levels). No significant effects on body weight or feed
consumption were observed in males or females. Hematologic changes similar
to those seen in the 2-week study were noted. Dose-related anisocytosis,
poikilocytosis, elevated osmotic red blood cell fragility, and a greater incidence of
Howell-Jolly bodies were observed. Splenomegaly was noted at necropsy, and
histopathologic examination showed erythroid hyperplasia in the bone marrow
and spleen and increased hemosiderin pigment deposition in the spleen. Data
from satellite groups terminated at 30 and 60 days showed a NOEL at the lowest
10
dose, but results from the end of the study showed a clear cumulative dose-
response down to the 0.25 mg/kg dose level. Other than adverse effects in
spleen and bone marrow, no histopathology was observed in any other rat
organs or tissues, including male and female reproductive systems.
In a second 13-week toxicity study (9), B6C3F1 mice (10/sex/dose) were
given drinking water containing 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm
cyclohexanone oxime. Deaths occurred in the 10,000 ppm groups and weight
gain was depressed in males and females given 10,000 ppm and in females
given 5,000 ppm. There were significant increases in relative spleen weight at
exposure levels of 5,000 and 10,000 ppm and significant increases in the relative
liver weights of males and females that received 10,000 ppm. Microscopically,
hemtopoietic cell proliferation was observed in the spleen of males and females
in the 5,000 and 10,000 ppm groups. Centrilobular cell hypertrophy was
observed in the liver of males in the 2,500, 5,000, and 10,000 ppm groups and in
females in the 5,000 and 10,000 ppm groups. Olfactory epithelial degeneration
was observed in all exposed groups. In summary, the major targets of
cyclohexanone oxime were the erythrocyte, spleen, liver and nasal epithelium.
The NOEL for erythrotoxicity is 2,500 ppm following 13 weeks of exposure. The
NOEL for hematopoietic cell proliferation in the spleen is 2,500 ppm. The NOEL
for hepatotoxicity is 1,250 ppm for males and 2,500 ppm for females following 13
weeks of exposure. Some nasal olfactory epithelial degeneration was observed
at all exposure levels; only at 625 ppm in males was the incidence of this lesion
not significantly different from that in the controls. No other histopathology was
seen in any other mouse organ or tissue, including those involved with male and
female reproduction.
Recommendations:
The subchronic oral toxicity studies on cyclohexanone oxime, supported by
subacute oral studies, meet the HPV requirements for "Repeated Dose Toxicity".
11
C. Genotoxicity
Negative results were obtained in earlier in vitro mutogenicity tests with
several strains of Salmonella tyhimurium, with and without metabolic activation
(10, 11) and with Escherichia coli strain WP2 (10). In a later point mutation
assay (9), cyclohexanone oxime was mutagenic in Salmonella typhimurium
TA1535 with hamster S9 activation but negative in the same strain with rat liver
S9 and negative without any S9 activation. No evidence of mutagenicity was
seen in strains TA97, TA98, or TA100 with or without rat or hamster S9
activation. Under similar experimental conditions (12) the same positive result in
strain TA1537 was reproduced using hamster liver S9; similarly, no evidence of
mutagenicity was seen in strain TA100 with or without hamster liver S9
activation.
In a non-bacterial, in vitro mutagenicity assay (9) with CHO cells,
cyclohexanone oxime tested negative for induction of chromosome aberrations
with S9 activation and equivocal in the absence of rat liver S9. In one other in
vitro assay (11), this oxime was positive in L5178Y mouse lymphoma cells
without metabolic activation; the addition of rat liver S9 eliminated the mutagenic
effect.
Relative to in vivo mutagenicity, cyclohexanone oxime was negative in an
intraperitoneal mouse micronucleus study at doses (3 doses at 24 hour intervals)
as high as 1000 mg/kg. In addition, this oxime was also negative in a
micronucleus assay conducted on mice that were given the chemical at drinking
water doses as high as 10,000 ppm for 90 days (9). In one other in vivo study
(13), there was no increase in the frequency of sex-linked recessive lethal
mutations in germ cells of male Drosophila melanogaster administered
cyclohexanone oxime by feeding.
Based on an overall weight-of-evidence approach, cyclohexanone oxime
is not mutagen.
12
Recommendation:
No additional testing is required. The HPV requirement for genetic testing has
been fulfilled by the preceding in vitro and in vivo studies sensitive to both point
mutations and chromosome aberrations.
D. Reproductive Toxicity
No definitive studies to assess reproductive performance of male and
female experimental animals have been conducted on cyclohexanone oxime.
However, in a 90-day drinking water study (9) on cyclohexanone oxime, mice
receiving drinking water containing as much as 5,000 ppm were given sperm
motility and vaginal cytology evaluations. There were no differences between
treated and control mice. In addition, there were no histophathological effects
seen in the reproductive organs of the male or female mice. Also, in a 90-day
oral gavage study in rats (7) at doses of < 25mg/kg, microscopic examination of
male and female reproductive organs and tissues was unremarkable.
Recommendation:
Although the preceding information may not meet the HPV requirements for
"Reproductive Toxicity", no additional testing is required based on EPA's
acceptance of cyclohexanone oxime as a "Closed-System Intermediate".
E. Developmental Toxicity
No information on the developmental toxicity potential of cyclohexanone
oxime was found in the toxicological literature (published or unpublished).
Recommendation:
Since a "closed-system intermediate" categorization of cyclohexanone oxime
does not eliminate the HPV requirement for an adequate developmental toxicity
study, DSM Chemicals North America will conduct a reproductive/developmental
13
screening study in rats by the oral route following OECD TG 421 guidelines to
satisfy this HPV/SIDS endpoint.
F. Toxicokinetics
A toxicokinetic study (14) of cylochexanone oxime has been conducted in
male Fischer 344 rats by three different routes of administration. The chemical
was found to be rapidly absorbed and cleared within 24 hours after a single oral
administration of 1, 10, or 30 mg/kg of [14 C]-cyclohexanone oxime in aqueous
solution. The majority of the cyclohexanone oxime-derived radioactivity was
excreted in the urine. Three urinary metabolites were identified:
cyclohexylglucuronide and the monoglucuronides of cis- and trans-cyclohexane-
1,2-diol. Low levels of radioactivity (2%-3% of the dose) were retained in the
tissues 24 hours after exposure. After intravenous administration of 1 mg/kg of
[14 C]-cyclohexanone oxime, the oxime was rapidly cleared from plasma, with half
lives of 1.6 minutes (alpha phase) and 18.2 minutes (beta phase). When
cyclohexanone oxime was applied dermally (30 mg/kg), only 4% to 5% of the
dose was recovered in the urine, feces, and tissues. The majority of the dose
volatilized from the skin surface. However, the absorbed radioactivity was readily
distributed and excreted, and its metabolic fate was no different than that
observed after oral administration.
After a 14-day gavage study (8), cyclohexanone oxime has also been
reported to induce increased microsomal activity (aniline hydroxylase and
aminopyrine demethylase) in rats treated at a dose of 100 mg/kg body weight. In
addition, cyclohexanone oxime has been reported to inhibit the oxidative
metabolism of ethanol in rats and mice, an effect similar to that produced in
humans as a result of disulfiram administration (15, 16, 17).
From the preceding animal studies, it is evident that cyclohexanone oxime
can be absorbed by three different routes of administration. Most absorbed
cyclohexanol is metabolized and is subsequently excreted as glucuronides.
14
CONCLUSIONS
Under the EPA HPV Challenge Program, adequate data to meet HPV
requirements are available for cyclohexanone oxime relative to
Physical/Chemical Properties, Acute Toxicity, Repeated Dose Toxicity, and
Genotoxicity. Since the data available for Ecotoxicity and Environmental Fate
and Pathways are limited or non-existent, additional studies in these areas will be
conducted by the Sponsor. Although the"Closed-System Intermediate"
classification of cyclohexanone negates the need for reproductive toxicity testing,
it does not alleviate the need for an adequate developmental toxicity study. Such
a study, following OECD guidelines, will be conducted in rats by the oral route on
cyclohexanone oxime.
15
REFERENCES
1. DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime, July 31, 1996.
2. TOXNET. Search on Cyclohexanone Oxime: Chem ID Advanced Search
?Physical Properties, September 8, 2005.
3. Plzak, V. and J. Doull. National Technical Information Services. No. AD-
691 490, U.S. Department of Commerce, Washington, D.C. 1969.
4. Fridman, A.L., Zalesou, V.S., Dolbilkin, K.V., Sivkova, M.P. and I.K.
Moiseev. Study of antispasmodic and bacteriostatic activities of oximes.
Pharm. Chem. J. 12: 227-230, 1978.
5. Serota, D.G. Acute Oral Administration Study in Rats with Cyclohexanone
Oxime. Hazleton Laboratories Project No.2088-100, May 29, 1979.
6. Derelanko, M.J., Gad, S.C., Powers, W.J., Mulder, S., Gavigan, F. and
P.C. Babich. Toxicity of Cyclohexanone Oxime: Hemotoxicity following
Subacute Exposure in Rats. Fundam. Appl. Toxicol. 5: 117-127, 1985.
7. Gad, S.C., Derelanko, M.J., Powers, W.J., Mulder, S., Gavigan, F. and
P.C. Babich. Toxicity of Cyclohexanone Oxime: Acute Dermal and
Subchronic Oral Studies. Fundam. Appl. Toxicol. 5: 128-136, 1985.
8. Komsta, E., Secours, V.E., Chiu, I., Valli, V.E., Morris, R., Harrison, J.,
Baranowski, E. and D.C. Villeneuve. Short-Term Toxicity of Nine
Industrial Chemicals. Bull. Environ. Contam. Toxicol. 43: 87-94, 1989.
9. Burka, L.T. NTP Technical Report on Toxicity Studies of Cyclohexanone
Oxime, National Toxicology Program Toxicity Report Series, No. 50. NIH
Publication 96-3934, 1996.
10. Araki, A., Takahashi, F. and T. Matsushima. Mutagenicity of oxime
compounds in S. typhimurium TA98, TA100, TA2637 and E. coli WP2
UVRA/PKM101. Mutat. Res. 164: 263, 1986.
11. Rogers-Back, A.M., Lawlor, T.E., Cameron, T.P. and V.C. Dunkel.
Genotoxicity of 6 Oxime Compounds in the Salmonella/Mammalian-
Microsome Assay and Mouse Lymphoma TK+/- Assay. Mutat. Res. 204:
149-162, 1988.
12. Prival, M. J. Anomalous mutagenicity profile of cyclohexanone oxime in
bacteria: cell survival in background lawns. Mutat. Res. 497: 1-9, 2001.
16
13. Vogel, E. and J.L.R. Chandler. Mutagenicity testing of cyclamate and
some pesticides in Drosophila metanogaster. Experientia 30: 621-623,
1974.
14. Parmar, D. and L.T. Burka. Methabolism and Disposition of
Cyclohexanone Oxime in Male F-344 Rats. Drug Metab. Dispos. 19:
1101-1107, 1991.
15. Lewis, W. and L. Schwartz. The occupational disease no one talked
about. A.M.A. Archives of Industrial Health 13: 628-631, 1956.
16. Koe, B.K. and S.S. Tenen. Inhibiting action of n-butyraldoxime on ethanol
metabolism and on natural ethanol preference. J. Pharm. Exp. Ther. 174:
434-449, 1970.
17. Cattanach, B.M. Mutagenicity of cyclamates and their metabolites. Mutat.
Res. 39: 1-28, 1976.
17
APPENDIX
SUBSTANTIATION OF CLOSED SYSTEM INTERMEDIATE
STATUS FOR CYCLOHEXANONE OXIME
DSM Chemicals North America, Inc., initially submitted a claim (March
2006) for reduced SIDS testing based on the "Closed-System Intermediate"
status of cyclohexanone oxime. To support such a claim for reduced testing, the
Company provided the subsequent detailed information on number of
manufacturing sites, process descriptions, monitoring data, presence in products,
and transport (if applicable) in this APPENDIX to the HPV Test Plan. On
November 2007, EPA accepted the classification of cyclohexanone oxime as
as a "Closed-System Intermediate".
The format of this appendix consists of responses (along with diagrams
and tabular data) to a required list of questions (excerpted from the SIDS
manual). Based on these responses reflecting a very low-to-negligible exposure
potential to workers and the environment, DSM Chemicals believes that the
information requirements supporting an exemption claim for reduced SIDS
testing have been satisfied. The information requirements follow on pages 19-30
of this document.
18
Information Requirements Supporting Exemption Claims for Reduced SIDS
Testing Based on Exposure Considerations
I. Information on sites
A. Number of sites: There is only one (1) site - DSM Chemicals
North America, Inc. (DCNA) in Augusta, GA
B. Basis for "closed process" conclusion at each site:
1) process description in enough detail to clarify the basis for
claiming that the process is closed;
See Attachment 1 (p. 22-23) for a process description
of cyclohexanone-oxime. A simplified block flow
diagram of the process is provided in Figures 1 (p.24)
and 2 (p.25).
2) if available, monitoring data showing no detection in any media,
including the limits of detection;
As shown in Figure 1 (p.24), a small portion of
cyclohexanone-oxime does come into contact with
process water, which is discharged to our wastewater
treatment plant (WWTP). Attachment 2 (p.26) is
provided to show the cyclohexanone-oxime
concentration in the combined feed to our on-site
WWTP, including the monthly average and mean
detection limit (MDL). Attachment 3 (p.27) shows the
analysis for cyclohexanone-oxime in the WWTP
effluent (Weir III). The analysis shows cyclohexanone-
oxime at non-detectable (ND) levels, and a limit of
detection is provided also.
3) if monitoring data are unavailable, a statement that no
monitoring has taken place and the basis for believing, in the
absence of data, that the chemical has not been released and that
exposure does not occur.
Monitoring data for vapor emissions is unavailable.
However, based on the low vapor pressure of
19
cyclohexanone-oxime (approximately 25 mmHg at
normal operating temperature), and the fact that the
surge vessel containing this product is heat traced and
insulated, controlled at a fairly constant level, and
equipped with a conservation vent, emissions of
cyclohexanone-oxime are expected to be at de
minimus levels. Tank emission calculation
spreadsheets are provided in Table 1 (pp. 28-30)
showing working losses to the atmosphere from each
surge vessel below 0.4 lb/day.
C. Data on "presence in distributed product" or, in the absence of data, the
basis for believing it is not present at levels above trace concentrations.
Cyclohexanone-oxime is used as an intermediate by DCNA to
manufacture caprolactam. Attachment 4 (p.31) shows
cyclohexanone-oxime analysis performed on our final product
(caprolactam) storage tank year-to-date, including the yearly
average, mean detection limit (MDL), and the internal DCNA
Lab procedure.
II. Information on transport
If transport also occurs, then in addition to the above, the following should be
provided :
?Mode of transport (e.g. water, truck, rail, pipeline)
?Volume (annual)
?Types of consignments (e.g. bulk or drums)
?Controls during transport and transfer at dispatching and receiving sites
(placards, labels, etc.)
Not Applicable
III. Supporting evidence from a data search that the chemical is not present
in other end products
To the best of our knowledge, cyclohexanone-oxime is used as an
intermediate chemical in the manufacture of caprolactam. The
caprolactam manufacturing process at DCNA is similar to that of
our competitors, and as such, we are reasonably confident that
their final product caprolactam will have similar analytical results
showing only trace amounts of cyclohexanone-oxime in the final
product as does DCNA (see Attachment #4 on p. 31).
20
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21
ATTACHMENT 1
Cyclohexanone-oxime, henceforth referred to as oxime, is an intermediate product formed
in the production of caprolactam. Oxime is produced within the 2 HPO sections (Sections
26 & 36) of DCNA by the oximation of hydroxylamine (hyam) and cyclohexanaone
(anone). The hyam is produced by the catalytic reduction of nitrate within the hyam reactor.
Because hyam is unstable in a pure state, an aqueous solution of phosphoric acid,
ammonium phosphate, and ammonium nitrate (referred to as Inorganic Process Liquor, or
IPL) is used as its carrier. The anone is produced within the 2 Oxanone sections (Sections
35 & 45) of DCNA by the air oxidation of cyclohexane.
The oximation reaction takes place in 5 mixer-settler reactors where the hyam rich IPL
stream is contacted with an organic stream of toluene and anone. The oxime produced in
the reaction goes to the organic phase which leaves oximation with an approximate
composition of 73% toluene, 25% oxime and 2% anone. This organic stream is washed
with water and then distilled within two vacuum distillation columns. The oxime product
(see Figure 1), recovered as the bottoms of the section distillation column, is then transferred
to rearrangement where it is completely reacted, using oleum as a catalyst, to form
caprolactam (see Figure 2). There are 2 rearrangement caprolactam purification sections
(Section 27 & 37) at DCNA that further remove impurities and purify the caprolactam to a
strength of ~100%.
The only accumulation points for purified oxime within the caprolactam production facility
are the pumping vessels between distillation and rearrangement. These vessels, not capable
of holding more than 5% of the respective plant's daily production capacity are used to
provide just enough surge capacity to enable the safe shutdown of rearrangement or toluene-
oxime distillation in the event of a process upset in either of the two sections. During
normal operation, the level is controlled at a constant volume in the pumping vessel by
making adjustments in the rearrangement section.
Points of release of oxime during the production of caprolactam include wastewater from
the HPO sections and some vapor emissions, both of which are minimal. The presence of
22
oxime in the wastewater is primarily the result of the wash step of the toluene oxime and
vacuum jet condensate from the toluene/oxime distillation. Prior to discharge, most of the
oxime is removed from the washwater via a toluene extraction step. All of the wastewater is
routed through a steam stripper, which also removes some oxime. This wastewater is
subsequently treated within the site's biological wastewater treatment plant which removes
residual oxime to below detectable limits in the plants effluent. The vapor release is limited
to that coming from the oxime pump vessel which is limited because the vessel is controlled
at a fairly constant level and is equipped with a conservation vent.
23
FIGURE 1
Rearrangement / Purification (27/37)
NH3-Water Benzene
Extraction
Oxime Ammon.
Neutralization
Rearrangement &
Sulfate Stripping
Oleum
Heavies
(CRO) Crude Rearranged
Oxime Benzenic lactam
ExtractionAqueous Ion Distillatio
Exchange n
& Evaporation
Hydrogenation
Lactam
Stripping n
Hydroge
Impurities Impurities 100%
n Water Lactam
WWTP
24
FIGURE 2
Hydroxylamine Phosphate Cyclohexanone Oxime (26/36)
water
H2-gas to Boiler
H2-gas
IPL toluene/oxime
Hyam Prep Washing
water
toluene/oxime
Oximation
IPL cyclohexanone
IPL
toluene
air
NOx IPL
toluene
NH3
NH3-combustion Absorption IPL-purification Toluene/oxime
distillation
water oxime
NH3-gas
NOx-removal Wastewater
Rearrangement
Purification
NOx to
atmosphere
Wastewater
to WWTP
25 1
ATTACHMENT 2
Combined Feed WWTP
Date Oxime wt%
10/31/05 0.0065
11/01/05 0.0081
11/02/05 0.0082
11/03/05 0.0080
11/04/05 0.0090
11/05/05 0.0061
11/06/05 0.0063
11/07/05 0.0096
11/08/05 0.0070
11/09/05 0.0105
11/10/05 0.0058
11/11/05 0.0047
11/12/05 0.0108
11/13/05 0.0097
11/14/05 0.0078
11/15/05 0.0094
11/16/05 0.0062
11/17/05 0.0047
11/18/05 0.0083
11/19/05 0.0101
11/20/05 0.0113
11/21/05 0.0069 Method
11/22/05 0.0068 DCNA-10-GC047
11/23/05 0.0070
11/24/05 0.0081
11/25/05 0.0074
11/26/05 0.0078
11/27/05 0.0072
11/28/05 0.0066
11/29/05 0.0050
11/30/05 0.0048
Average 0.0076
MDL 0.0006
26
ATTACHMENT 3
DSM Chemicals North America, Inc.
DSM Laboratory Special Analysis Request Report
DSMLAB: 9823
SUBMITTED: 11/22/2005 REPORTED: 11/29/200
ORIGINATOR: M. Ray
SAMPLE: Weir III
ANALYSIS: Cyclohexanone oxime
PURPOSE:
PRIORITY:
ANALYST: E. Moe APPROVED: Erin R. Moe
DISTRIBUTION: M. Ray, D. Morris, D. Smith, G. Bowen
cyclohexanone oxime; ppm ND
(limit of detection; 6 ppm)
1
27
TABLE 1 EXPLANATIONS
From: Pocta, John
Sent: Wednesday, December 28, 2005 8:57 AM
To: Morris, Dean
Subject: Oxime losses from V-2608/V-3608
Dean,
The oxime vapor emissions from oxime pump vessels V-2608/V-3608 are minimal for the
following reasons:
1. Oxime has a low vapor pressure (approximately 25 mmHg at normal operating temperature),
2. The vessels are traced and insulated,
3. The vessels are equipped with conservation vents,
4. The vessels are controlled at a fairly constant level
Using the subsequent tables on pp. 28 & 29 (Tank Emission Calculation Forms), the estimated
oxime emissions are less than 150 lb/yr from each vessel.
John
28
2
TANK NO. V-2608
29
3
TANK NO. V-3608
30
4
ATTACHMENT 4
T-2801
Date Oxime ppm
01/04/05 0.5
01/11/05 0.4
01/18/05 0.6
01/25/05 0.3
02/01/05 0.3
02/08/05 0.2
02/15/05 0.2
02/22/05 0.2
03/01/05 0.3
03/08/05 0.3
03/15/05 0.3
03/22/05 0.3
03/29/05 0.5
04/05/05 0.1
04/12/05 0.3
04/19/05 0.2
04/26/05 0.4
05/03/05 0.3
05/10/05 0.2
05/17/05 0.5
05/24/05 0.4
05/31/05 0.2
06/07/05 0.2
06/14/05 0.3
06/21/05 0.1
06/28/05 0.1
07/05/05 0.2
07/12/05 0.1
07/19/05 0.3
07/26/05 0.2
08/02/05 0.3
08/09/05 0.3
08/16/05 0.2
08/23/05 0.2
08/30/05 0.4
09/06/05 0.3
09/13/05 0.5
09/20/05 0.3
09/27/05 0.2
10/04/05 0.4 Method
10/11/05 0.2 DCNA-10-CP009
10/18/05 0.4
10/25/05 0.2
11/01/05 0.3
11/08/05 0.3
11/15/05 0.1
11/22/05 0.2
11/29/05 0.3
Average 0.28
MDL 0.17
Oxime in
lactam
31
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