201-16722B
CONTENTS
Page
SIDS PROFILE ...................................................................................................................................... 1
SIDS SUMMARY ................................................................................................................................. 2
1.0 GENERAL INFORMATION................................................................................................................ 3
1.01 SUBSTANCE INFORMATION................................................................................................. 3
A. CAS-NUMBER ..................................................................................................................... 3
C. OECD NAME........................................................................................................................ 3
D. CAS DESCRIPTOR .............................................................................................................. 3
G. STRUCTURAL FORMULA ................................................................................................ 3
1.5 QUANTITY ................................................................................................................................. 3
1.7 USE PATTERN ........................................................................................................................... 3
A. GENERAL USE PATTERN................................................................................................. 3
B. USES IN CONSUMER PRODUCTS ................................................................................... 3
1.9 SOURCES OF EXPOSURE........................................................................................................ 3
2.0 PHYSICAL-CHEMICAL DATA ......................................................................................................... 3
2.1 MELTING POINT .......................................................................................................................... 3
2.2 BOILING POINT............................................................................................................................ 4
2.3 DENSITY (RELATIVE DENSITY).............................................................................................. 4
2.4 VAPOR PRESSURE ...................................................................................................................... 5
2.5 PARTITION COEFFICIENT n-OCTANOL/WATER ................................................................. 5
2.6 WATER SOLUBILITY.................................................................................................................. 5
2.7 FLASH POINT ............................................................................................................................... 6
2.8 AUTO FLAMMABILITY.............................................................................................................. 6
2.12 OXIDATION:REDUCTION POTENTIAL ................................................................................. 6
2.13 ADSORPTION:DESORPTION REDUCTION TO SELL .......................................................... 6
3.0 ENVIRONMENTAL FATE AND PATHWAYS ................................................................................ 6
3.1 STABILITY ................................................................................................................................ 6
3.1.1 PHOTODEGRADATION ........................................................................................................... 6
3.1.2 STABILITY IN WATER ............................................................................................................ 6
3.2 TRANSPORT AND DISTRIBUTION ....................................................................................... 7
3.5 BIODEGRADATION.................................................................................................................. 7
4.0 ECOTOXICOLOGICAL DATA........................................................................................................... 7
4.1 ACUTE TOXICITY TO FISH....................................................................... 7
4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES (e.g., Daphnia).................... 8
4.3 ACUTE TOXICITY TO AQUATIC PLANTS e.g., ALGAE.................................... 8
5.0 TOXICITY ............................................................................................................................................. 8
5.1.1 ACUTE ORAL TOXICITY ........................................................................................................ 8
5.1.2 ACUTE INHALATION TOXICITY ............................................................... 10
5.1.3 ACUTE DERMAL TOXICITY.. 10
5.1.4 ACUTE INTRAPERITONEAL TOXICITY...................................................... 10
5.4 REPEATED DOSE TOXICITY (general) .................................................................................................. 11
5.5 GENETIC TOXICITY IN VITRO ........................................................................................................... 14
A. BACTERIAL TEST .............................................................................................................. 14
B. NON-BACTERIAL IN VITRO TEST ................................................................................. 15
5.6 GENETIC TOXICITY IN VIVO............................................................................................................. 16
5.7 TOXICITY TO REPRODUCTION......................................................................................................... 17
5.8 DEVELOPMENTAL TOXICITY........................................................................................................... 18
5.11 EXPERIENCE WITH HUMAN EXPOSURE (WORKPLACE) .......................................................... 18
6.0 REFERENCES....................................................................................................................................... 18
SIDS PROFILE
DATE: July 29, 2008
1.01 A. 108-93-0
CAS No.
CYCLOHEXANONE OXIME
1.01 C. CHEMICAL NAME
1.01 D. Not applicable
CAS DESCRIPTOR
1.01 G. C6H120
=N-O-H
FORMULA & STRUCTURE
No current production information available
1.5 QUANTITY
Primarily used in a closed process system in the
1.7
synthesis of caprolactam which, in turn, is used
USE PATTERN
to produce polycaprolactam (Nylon-6) fibers
and resins.
Process leaks during manufacture of
1.9 SOURCES AND LEVELS OF
caprolactam
EXPOSURE
Based on EPA's acceptance of a claim of Closed-System Intermediate (CSI) Status
TEST PLAN
for CHO, the need to meet HPV requirement for "Reproductive toxicity" is waived.
JUSTIFICATION
However, testing will be still needed to satisfy the "Developmental Toxicity"
/ISSUES FOR
endpoint, Also, since little or no data is available, "Ecotoxicity" and
DISCUSSION
"Environmental Fate and Pathways" testing will be required. No additional testing,
based on adequate available data, will be needed for the categories of "Physical
Chemical Properties," "Acute and Repeated-Dose Toxicity" and "Genotoxicity."
1
Tier 1
SIDS SUMMARY
DATE: July 29, 2008
CAS NO: 100-64-1
STUDY Y/N Y/N Y/N Y/N Y/N Y/N Y/N
PHYSICAL-CHEMICAL DATA
N
Y
N
N
Y
Melting Point
2.1
N
Y
N
N
Y
Boiling Point
2.2
N
Y
N
N
Y
Density
2.3
N
Y
N
N
Y
Vapour Pressure
2.4
N
Y
N
N
Y
Partition Coefficient
2.5
N
Y
N
N
Y
a. Water Solubility
2.6
b. pH and pKa values
N
Y
N
N
Y
Flash Point
2.7
N
Y
N
N
Y
Flammability
2.8
N
N
Oxidation: Reduction Potential
2.12
N
N
Adsorption/Desorption to Soil
2.13
ENVIRONMENTAL FATE and PATHWAY
N
N N Y Y?
3.1.1 Photodegradation Y
N Y
N N N
Y
3.1.2 Stability in water
Y
3.3 Transport and Distribution N
Y
Biodegradation N
3.5
ECOTOXICITY
N Y
N
4.1 Acute toxicity to Fish Y N
Y
4.2 Acute toxicity to Daphnia N
Toxicity to Algae1 Y
4.3 N
TOXICITY
Acute Toxicity:
5.1
N
Y
N
N
Y
Acute Oral
5.1.1
N
Y?
Y
Acute Inhalation
5.1.2
N
Y
Y
N
Y
Acute Dermal
5.1.3
N
Y
N
N
Y
Acute intraperitoneal
5.1.4
N
Y
Y
N
Y
Repeated Dose (General)
5.4
Genetic Toxicity in vitro
5.5
N
Y
Y
N
Y
. Gene mutation
N
Y
Y
N
Y
. Chromosomal aberration
N
Y
Y
N
Y
Genetic Toxicity in vivo
5.6
N*
Y?
N
Reproduction Toxicity
5.7
Y
N
Developmental Toxicity/Teratogenicity
5.8
*Decision based on the accepted claim for "closed system intermediate" status for cyclohexanol oxime based on low
occupational exposure potential and negligible environmental release potential; the result of such a status
is reduced SIDS testing for this oxime (See APPENDIX (pp. 18-30) of HPV Test Plan document).
2
GENERAL INFORMATION
1.
1.01 SUBSTANCE INFORMATION
A. CAS-Number 100-64-1
C. OECD Name Cyclohexanone oxime
D. CAS Descriptor Not applicable
G. Structural Formula C6H11NO
=N-O-H
1.5 QUANTITY
Remarks: Cyclohexanone oxime is primarily consumed in a closed system during the production
of caprolactam.
1.7 USE PATTERN
Remarks: Most of the cyclohexanone oxime produced is used in the production of caprolactam
during the manufacture of Nylon-6 polymer.
1.9 SOURCES OF EXPOSURE
Process leaks during manufacture of caprolactam are remotely possible. However,
engineering controls and recommended protective equipment/clothing will assure
low exposure potential via inhalation, dermal and eye routes of administration.
PHYSICAL-CHEMICAL DATA
2.
2.1 MELTING POINT
Value: 190 - 196癋
Decomposition: No Data
Sublimation: No Data
Method: No Data
GLP: Yes [ ] No [ ] ? [X]
3
Remarks: None
[4] Not assignable because limited study information was available.
Reliability:
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. July 31, 1996.
2.2 BOILING POINT
Value: 406癋
Pressure: Not available
Decomposition: No Data
Method: No Data
GLP: Yes [ ] No [ ] ? [X]
Remarks: No additional data
[4] Not assignable because limited study information was available.
Reliability:
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. Julu 31, 1996.
2.3 DENSITY
Type: Bulk density [ ]; Density [ ]; Relative Density [x]
Value: 0.97
Temperature: Not given
Method: No Data
GLP: Yes [ ] No [ ] ? [X]
Remarks: No additional data
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. Julu 31, 1996.
2.4 VAPOR PRESSURE
4
Value: 0.029 mmHg
Temperature: 77癋
Method: calculated [ ]; measured [ ]
GLP: Yes [ ] No [ ] ? [X]
Remarks: No additional data
Reliability: [4] Not assignable because limited study information was available.
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. Julu 31, 1996.
PARTITION COEFFICIENT log10Pow
2.5
log10Pow: 0.84
Temperature: 25癈
Method: calculated [ ]; measured [X]
Result: Cyclohexanone oxime log Pow = 0.84
Remarks: No other information available
Test Substance:Cyclohexanone oxime (? purity)
GLP: Yes [ ] No [ ] ? [x]
Reliability: [4] Not assignable because limited study information was available.
Reference: TOXNET Search on Cyclohexanone Oxime. ChemID Plus Advanced
Search: Physical Properties, September 8, 2005.
2.6 WATER SOLUBILITY
Value: 1.5 wt%
Temperature: 68癋
Description: [ ]Of very high solubility
[ ]Of high solubility
[ ]Soluble
[X]Slightly soluble
[ ]Of very low solubility
[ ]Not soluble
Method: No information
GLP: Yes [ ] No [ ] ? [X]
5
Remarks: No additional data
Reliability: [4] Not assignable because limited study information was available
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. Julu 31, 1996.
2.7 FLASH POINT: 181.4癋 (SF Closed Cup)
2.8 AUTO FLAMMABILITY: 545癋
2.9 flammability limits: lfl = 1.3%
2.12 OXIDATION:REDUCTION POTENTIAL ?No information available
2.13 ADSORPTION/DESORPTION TO SOIL ?No information available
ENVIRONMENTAL FATE AND PATHWAYS
3.
3.1 STABILITY ?No information available
3.1.1 PHOTODEGRADATION
Type: Air [X]; Water [ ]; Soil [ ]; Other [ ]
7.07E-12 (cm3/molecules-sec)
Rate constant:
Method: Calculated (method unknown)
Remarks: No additional information was available.
Reliability: [4] Not assignable because limited study information was available
Reference: TOXNET Search on Cyclohexanone Oxime. ChemID Plus Advanced
Search: Physical Properties, September 8, 2005.
3.1.2 STABILITY IN WATER
Summary: No specific study to measure hydrolysis in water was found.
However, a manufacturer's MSDS states that cyclohexanone
oxime is stable in water and undergoes hydrolysis only at
sustained temperatures (250 - 300癋). Since cyclohexanone oxime
contains a potentially hydrolyzable oxime group, and no data acceptable to
EPA is available to demonstrate that hydrolysis will be negligible, the
Sponsor will conduct an OECD TG 111 study to provide adequate
information for this endpoint.
6
Reliability
(Klimisch Code): [4] Not assignable because limited study information was available
Reference: DSM Chemicals North America, Inc. Material Safety Data Sheet:
Cyclohexanone Oxime. July 31, 1996.
3.2 TRANSPORT AND DISTRIBUTION BETWEEN ENVIRONMENTAL COMPARTMENTS
INCLUDING ESTIMATED ENVIRONMENTAL CONCENTRATIONS AND
DISTRIBUTION PATHWAY ?No information available
The Sponsor agrees to provide calculated fugacity values using available measured data from
Physicochemical Properties.
3.5 BIODEGRADATION ?No information available
The Sponsor agrees to conduct an OECD TG 301 study to provide measured ready biodegradation
data to satisfy this endpoint.
ECOTOXICOLOGICAL DATA
4.
4.1 ACUTE TOXICITY TO FISH
A. Preferred Result
Type of Test: static [ ]; semi-static [ ]; flow-through [ X ]; other [ ]
Species: Fathead Minnow
Exposure Period: 96 Hours
LC50 = 208 mg/L (189 mg/L min to 230 mg/L max)
Results:
Analytical monitoring: Yes [X] No [ ]
Method: No information available
Test substance: Cyclohexanone oxime (purity unknown)
GLP: Yes [ ] No [ X ]
Remarks: Reported as "not acutely toxic"
Reliability: [4] Not assignable because limited study information was available
Reference: Geiger, D.L., et al. Acute Toxicity of Organic Chemicals to Fathead
Minnows. Volume 5. Center for Lake Superior Environmental Studies,
University of Wisconsin ?Superior, WI I: 332, 1990.
B. Supporting Data
7
One other aquatic toxicity reference which has limited information is the following:
Applegate, V.C. et al. Toxicity of 4346 Chemicals to Larval Lampreys and Fishes.
Spec. Sci. Rep. Fish No. 207, Fish Wildlife Service, U.S.D.I., Washington, D.C., 1957.
C. Comment
Since no additional detail on test method, deviation from test method, test parameters and
results could be found for the preferred fish toxicity study, the Sponsor plans to satisfy
this endpoint by conducting an OECD TG 203 Study to provide adequate acute ecotoxicity
data on fish.
4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES ?No information available
The Sponsor plans to conduct an OECD TG 202 Study on Daphnia magna to satisfy the
endpoint for acute ecotoxicity data on invertebrates.
4.3 ACUTE TOXICITY TO AQUATIC PLANTS (e.g. Algae) ?No information available
The Sponsor plans to conduct an OECD TG 201 Study on an algal species to satisfy this
ecotoxicity endpoint.
TOXICITY
5.
5.1.1 ACUTE ORAL TOXICITY
A. Preferred Result
Type of Test: Oral LD50
Species: Rat (Fischer 344; male and female)
Value: Males: 1765 mg/kg (1632 ?1909 mg/kg; 95% C..L.)
Females: 883 mg/kg (726 ?1074 mg/kg; 95% C.L.)
Method: The study report states that "According to proposed EPA guidelines for
hazard evaluation", cyclohexanone oxime was administered by oral
intubation (following an overnight fast) to 7 groups of 10 male rats at doses
of 562, 794, 1000, 1410, 1590, 2000, and 5000 mg/kg of body weight, and
to 5 groups of 10 female rats at doses of 398, 631, 1000, 2000, and 5000
mg/kg of body weight. Rats were weighed and observed over a 14-day
post-dosing period. Necropsies were performed on rats dying during the
study and on rats sacrificed at termination (14 days P.E.). Oral LD50s were
subsequently calculated for both male and female rats based on the
mortality data.
Test substance: The study report states "Cyclohexanone oxime, a white crystalline powder,
was received (at Hazleton Labs) from the sponsor (Industrial Health
Foundation) and was stored at room temperature." Percent purity was not
specifically stated in the report.
GLP: Yes [ X?] No [ ] ? [ ]
8
In the Introduction of the study report (May 1979), it states that this study
was conducted "according to proposed Environmental Protection Agency
guidelines for hazard evaluation." This suggests that prevailing "GLP"
practices were utilized.
Remarks: Clinical observations during the study consisted of slight-to-marked
depression, rough hair coat, salivation, urine stains, ataxia, labored
respiration and prostration. Gross pathology showed spleen discoloration
in most male rats at the 794 and 1590 mg/kg dose levels.
Reliability: [2] Valid with restrictions
Purity of the test substance was not specifically stated.
Reference: Serota, D.G. Acute Oral Administration Study in Rats with Cyclohexanone
Oxime. Hazleton Laboratories Project No. 2088-100, May 29, 1979.
B. Supporting Data:
Type: LD
Species: Fischer 344 Rats (5/sex/dose)
Value: > 300 mg/kg
Method: Subacute oral gavage study (10 doses at 300 mg/kg bw)
Test substance: Purity (>99.5%)
GLP: Yes [ X ] No [ ] ? [ ]
No compound-related mortality after 10 doses at <300 mg/kg. No
Remarks:
Significant signs of gross toxicity attributable to CHO were observed.
At gross autopsy, splenomegaly and hepatomegaly were seen at the
300 mg/kg dose level. Abnormally dark cervical lymph nodes were also
seen in all rats. No other remarkable findings were apparent at autopsy.
Reliability: [2] Valid with restrictions
A dose of 300 mg/kg was the highest dose tested in this subacute study.
Reference: Derelanko, M.J., et al. Toxicity of Cyclohexanone Oxime: Hemotoxicity
Following Subacute Exposure in Rats. Fundam. Appl. Toxicol. 5 :
117 ?127, 1985.
5.1.2 ACUTE INHALATION TOXICITY ?No reliable information
5.1.3 ACUTE DERMAL TOXICITY
Type: LD50; dermal absorption toxicity
Species: New Zealand albino rabbits (5/sex/dose)
9
Value: > 5000 mg/kg
Method: Cyclohexanone oxime was applied to the shaved backs of rabbits for 24
hours at dose levels of 0 (distilled water), 0.8, 2 or 5 g/kg under an occluded
patch and then observed for 14 days after dosing. Clinical signs and body
weights were recorded. Blood samples were taken on days 1, 4 and 7 post-
dosing and various hematological and chemical parameters were measured.
Animals were terminated after 14 days, spleen weights were taken, and all
rabbits were given gross autopsies.
Test substance: cyclohexanone oxime (99.5% purity)
GLP: Yes [X] No [ ] ? [ ]
Remarks: No rabbits died at any dose level during the 24-hour dosing period or the
14-day post-dosing period. There were no adverse clinical signs, body
weight or organ weight changes associated with treatment. However,
reticulocyte counts were elevated on Day 1 in a dose-related manner in
males; a similar but not statistically significant elevation occurred in
females. Hemoglobin values were depressed in a dose-related manner in
females; the depression was statistically significant only at the highest dose
at 7 days after dosing. Methemoglobin levels were increased in both sexes
in a dose-related manner at 4 days post-dosing, but not at either 1 or 7 days
post-dosing. These results suggest that cyclohexanone oxime may be
absorbed through the skin in toxicologically significant amounts.
Reliability: [2] valid with restrictions
No mortality occurred at the highest dose tested ?5000 mg/kg, an
exceptionally high dose for an acute dermal absorption study.
Reference: 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.
5.1.4 ACUTE INTRAPERITONEAL TOXICITY
: Type of Test: LD50
Species: Male mice (strain unknown)
Value: 250 mg/kg
Method: No information available
Test Substance:Cyclohexanone Oxime (unknown purity)
GLP: Yes [ ] No [ X ] ? [ ]
Remarks: Limited information available; have not yet located full reference.
Reliability: [4] Not assignable because limited study information was available
Reference: Plzak, V. and J. Doull. National Technical information Services,
No. AD-691490. US Department of Commerce, Washington, D.C., 1969.
10
5.4 REPEATED DOSE TOXICITY
A. Preferred Result
Type: A 90-Day Oral Gavage Study in Rats
Species/strain: Fischer 344 Male and Female rats (15/sex/exposure level)
Route of Administration: Oral Gavage
Exposure period: 10 rats/sex/dose for 30 days
10 rats/sex/dose for 60 days
20 rats/sex/dose for 90 days
Frequency of treatment: 5 days/week
Post-dosing
observation period: None
Dose Levels: 0, 0.25, 2.5 and 25 mg/kg bw
Control group: Yes (distilled water)
Method: Groups of rats were dosed by oral gavage with cyclohexanol oxime for
5 days/week for 30 days (10 rats/sex/dose), 60 days (10 rats/sex/dose)
or 90 days (20 rats/sex/dose) at doses of 0, 0.25, 2.5 or 25 mg/kg body
weight. All rats were observed for adverse clinical signs daily and for
neurobehavioral effects, body weight changes, and food consumption
on a weekly basis. At dosing termination, hematology, blood chemistry
and urinalysis measurements were conducted, as well as a complete
histopathological examination of tissues.
Test Substance: Cyclohexanone Oxime (>99.5% purity)
GLP; Yes [X] No [ ] ? [ ]
Results: There were no significant effects of cyclohexanone oxime on either
body weight or food consumption; a slight mortality occurred at the
highest dose (3 female rats) which may or may not have been
treatment-related. In males, treatment-related effects occurred during
the first 9 weeks of dosing and included red nasal discharge (highest
dose only), chromodacryorrhea and swollen conjunctiva (high and mid
doses), and corneal opacity (all doses). These observations gradually
subsided and disappeared by the end of the study. In females, there
were no adverse clinical signs during the first 2 weeks of dosing. After
that time, adverse signs included chromodacryorrhea (high dose) and
corneal opacity (high and mid dose), both of which gradually subsided
but never completely disappeared by study termination. Relative to
haematology, after 90 days of dosing, there was a dose-related
decrease in erythrocytes, hemoglobin and hematocrit, accompanied by
an increase in circulating reticulocytes and nucleated erythrocytes,
suggesting an increased erythropoeisis in the spleen and bone marrow.
11
The latter changes were confirmed by gross autopsy (splenomegaly)
and by histopathological examination. Other than histopathology in
spleen and bone marrow, no other organs or tissues were adversely
affected, including reproductive organs (See Section 5.7 Toxicity to
Reproduction). Since the major hematological effects were not severe
(no evidence of anemia, e.g.), recovery would be expected upon
removal from exposure.
Conclusion: When rats were exposed repeatedly by oral gavage for up to 90 days,
the primary effect of cyclohexanone oxime was increased destruction
of erythrocytes with a compensatory increase in erythropoeisis without
a noticeable anemia. The bone marrow was able to respond in a
sufficient manner to keep up with the added needs. These effects were
seen at all dose levels. Since these effects after 90 days of dosing
were not severe, recovery would be expected.
Data Quality
(Klimisch Code): [1] Valid without restrictions
Reference: 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.
B. Supporting Results
Type; A 90-Day Drinking Water Study in Mice
Species/Strain: B6C3F1 Male and Female Mice
Route of Administration: Oral (via drinking water)
Frequency of Treatment: Daily
Dosing Period: 90 Days
Post-Dosing
Observation Period: None
Dose Levels: 0, 625, 1250, 2500, 5000 and 10000 ppm cyclohexanone oxime in the
drinking water
Control Group: Yes (water alone)
Method: Mice (10/sex/dose) were given drinking water containing 0, 625, 1250,
2500, 5000 and 10000 ppm cyclohexanone oxime daily for 90 days.
Mice were observed twice daily for mortality and adverse clinical
signs. Clinical observations and body weights were recorded weekly
and water consumption was recorded twice weekly. Complete gross
and histopathological examinations were conducted at study
termination. Sperm motility and vaginal cytology evaluations were
performed on mice in the 0, 1250, 2500 and 5000 ppm dose groups.
Males were evaluated for necropsy body weight and reproductive
organ weights, and epididymal spermatozoal data. Females were
evaluated for necropsy body weights, estrous cycle length, and the
percent of cycle spent in the various stages.
12
Test Substance: Cyclohexanone Oxime (>99% purity)
GLP: Yes [X] No [ ] ? [ ]
Results: Deaths occurred in the 10000 ppm groups and weight gain was
depressed in males and females given 10000 ppm and also in females
given 5000 ppm. There were significant increased in the relative
spleen weights at both 5000 and 10000 ppm, and in the relative liver
weights of male and female mice dosed at 10000 ppm.
Microscopically, hematopoeitic cell proliferation was seen in the
spleens of males and females in both the 5000 and 10000 ppm groups.
In the liver, centrilobular cell hypertrophy was seen in males at 2500,
5000 and 10000 ppm and in females at 5000 and 10000 ppm.
Olfactory epithelial degeneration was seen in all dose groups. No
other histopathology was seen in any other organs or tissues, including
those involved with reproduction (See Section 5.7 Toxicity to
Reproduction). In addition, there were no significant differences in
sperm motility or vaginal cytology parameters between dosed and
control male and female mice.
Conclusion: The major targets of cyclohexanone oxime administered in the
drinking water for 90 days to mice were the erythrocyte, spleen, liver
and nasal epithelium. The NOEL for erythrotoxicity and
hematopoeitic cell proliferation in the spleen was 2500 ppm. The
NOEL for hepatotoxicity was 1250 ppm for males and 2500 for
females following 13 weeks of dosing. Some nasal olfactory epithelial
degeneration was observed at all dose levels; only at 625 ppm in males
was the incidence of this lesion not significantly different from
controls. There were no effects on sperm motility or vaginal cytology
parameters at doses as high as 5000 ppm (highest dose evaluated).
Data Quality
(Klimisch Code): [1] Valid without restrictions
Reference: Burka, L.T. NTP Technical Report on Toxicity Studies of
Cyclohexanone Oxime. NTP Report Series No. 50, NIH Publication
No. 96-3934, 1996.
5.5 GENETIC TOXICITY IN VITRO
A. Bacterial In Vitro Test
(1) Type: Bacterial reverse mutation assay
System of testing: Preincubation protocol
13
cyclohexanone oxime concentrations ranged from 33 g/plate to 3333
Concentration:
g/plate (with metabolic activation) and from 333 to 6666 g/plate (without
metabolic activation); at least 5 doses tested
Method of Activation: With [ ]; Without [ ]; With and Without [X]; No data [ ]
Results: Not mutagenic in Salmonella typhimurium strains TA97, TA98, and
TA100, with or without S9 activation. Positive evidence of mutagenicity
only in strain TA1535 with hamster S9 activation but negative in same
strain with rat liver S9 and negative without any S9 activation.
Test Substance:Cyclohexanone Oxime (>99% purity)
Cytotoxicity
>3333 g/plate with S9 activation; >6666 礸/plate without S9 activation
Concentration:
Precipitation
Concentration: No data
Testing was performed as reported by Zeiger (Environ. Mol. Mutagen. 19
Method:
(Suppl. 21): 2-14, 1992). Cyclohexanone oxime was incubated with
Salmonella typhimurium tester strains (TA97, TA98, TA100 and TA1535)
either in buffer (without activation) or S9 mix (metabolic activation
enzymes and cofactors from Aroclor 1254-induced male Sprague-Dawley
rats or Syrian hamster liver) for 20 minutes at 37癈. Top agar supplemented
with l-histidine and d-biotin was added and the contents of all tubes were
mixed and poured onto the surfaces of minimal glucose agar plates.
Histidine-independent mutant colonies arising on these plates were counted
following incubation for 2 days at 37癈. Each trial consisted of triplicate
plates of concurrent positive and negative controls and of at least
5 doses of cyclohexanone oxime. All positive assays were repeated under
the conditions that elicited a positive response; all negative assays were
also repeated.
GLP: Yes [X] No [ ] ? [ ]
Reliability: [2] valid with restrictions
This oxime was positive in TA1535 but not in TA100, a more sensitive
strain for the same kind of mutation.
Reference: Burka, L.T. NTP Technical Report on Toxicity Studies of Cyclohexanone
Oxime. NTP Report Series No. 50, NIH Publication No. 96-3934, 1996.
(2) Type: Other Point Mutation Assays (Supporting Data)
Summary:
Under similar experimental conditions, Prival (2001) reproduced the preceding positive result in
strain TA1535 using hamster liver S9, without evidence of mutagenicity in strain TA 100.
However, negative results with cyclohexanone oxime were obtained in mutagenicity tests with
several strains of Salmonella typhimurium, with and without metabolic activation (Araki 1986;
Rogers-Back 1988) and with Escherichia coli strain WP2 (Araki 1986). The only other
mutagenic activity reported for cyclohexanol oxime was noted in L5178Y mouse lymphoma
14
cells treated in the absence of S9 activation; the addition of rat liver S9 eliminated the
mutagenic effect (Rogers-Back 1988).
References:
Araki, A., et al. Mutagenicity of Oxime Compounds in the S. typhimurium TA98, TA100,
TA2637, and E. coli WP2 uvrA/pKM101. Mutat. Res. 164: 263, 1986.
Prival, M.J. Anomalous mutagenicity profile of cyclohexanone oxime in bacteria: cell survival in
background lawns. Mutat. Res. 497: 1-9, 2001.
Rogers-Back, A.M. et al. Genotoxicity of 6 Oxime Compounds with Salmonella-Mammalian-
Microsome Assay and Mouse Lymphoma TK Assay. Mutat. Res. 204: 149-162, 1988.
B. Non-Bacterial In VitroTest
Type: Cytogenetic assay (chromosome aberration)
System of testing: Chinese hamster ovary (CHO) cells
Concentration: Doses of cyclohenanone oxime ranging from 500 to 5000 礸/ml
Metabolic activation: With [ ]; Without [ ]; With and Without [ X ]; No data [ ]
Results: Negative
Cytotoxicity Concentration: >>5000 礸/ml
Precipitation Concentration: 5000 礸/ml
Genotoxic effects: None
Method: Testing was performed as reported by Galloway (Environ. Mol.
Mutagen. 10 (Suppl. 10): 1-175, 1987). Cyclohexanone oxime was
tested in cultured CHO cells for induction of chromosome aberrations
(Abs), both in the presence and absence of Aroclor 1254-induced male
Sprague-Dawley rat liver S9 and cofactor mix. Each test consisted of
concurrent solvent and positive controls and of at least 3 doses of
cyclohexanone oxime. In the absence of toxicity, 5000 礸/ml was
selected as the high dose. A single flask per dose was used; tests
yielding equivocal or positive results were repeated. In the ABS test
without S9, cells were incubated in McCoy's 5A medium with
cyclohexanone oxime for 10 hours; Colcemid was added and
incubation was continued for 2 hours. The cells were then harvested
by mitotic shake-off, fixed, and stained with Giemsa. For the Abs test
with S9, cells were treated with cyclohexanone oxime and S9 for 2
hours, the treatment medium was removed, and the cells were then
incubated for 10 hours in fresh medium. Colcemid was added for the
final 2 hours. Cells were then harvested in the same manner as for
treatment without S9. For scoring, cells were selected on the basis of
good morphology and completeness of karyotype(21+2 chromosomes)
and all slides were scored blind. Two hundred first-division metaphase
cells were scored at each dose level.
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GLP: Yes [X ] No [ ] ? [ ]
Test substance: Cyclohexanone Oxime (>99% purity)
Remarks: None
Reliability: [2] Valid with restrictions
Reference: Burka, L.T. NTP Technical Report on Toxicity Studies of Cyclohexanone
Oxime. NTP Report Series No. 50, NIH Publication No. 96-3934, 1996.
5.6 GENETIC TOXICITY IN VIVO
(A) Type: Micronucleus Assay
Species/strain: B6C3F1 Mice
Sex: Female [ ]; Male [ ]; Male/Female [X]; No data [ ]
Route of Administration: Oral (drinking water); intraperitoneal injection
Dosing Period: 90 Days; over 3 days at 24-hour intervals ......
16, 24 and 48 hours for the high dose group; 24 hours for the lower doses
Doses: 0, 625, 1250, 2500, 5000, and 10000 ppm in the water;
400, 600, 800 and 1000 mg/kg (ip).
Negative in 5 mice/sex dose (oral study) and in 5 male mice (ip study)
Results:
Effect on mitotic
index or P/N ratio: No information
Genotoxic effects: Not an in vivo mutagen
Method: A detailed discussion of this micronucleus assay on peripheral blood has
been presented by MacGregor (Fundam. Appl.Toxicol. 14: 513-522,
1990). At the end of a 90-day drinking water study on cyclohexanone
oxime, peripheral blood samples were taken from 5 mice/sex/dose
(highest dose in the drinking water was 10000 ppm), smears were
immediately prepared and fixed in absolute methanol, and the slides were
then stained with a chromatin-specific fluorescent dye and coded. Two
thousand normochromatic erythrocytes were scored in each of 5 mice/sex
in each of the 5 dose groups. The criteria of Schmid (In "Chemical
Mutagens: Principles and Methods for their Detection", Vol. 4,
A.Hollander (Ed.), pp. 31-53, Plenum Press, New York, 1976) were
used in defining micronuclei.
For the intraperitoneal micronucleus test, after preliminary rangefinding, 5
male mice/dose were injected (ip) over 3 days at 24-hour intervals with
cyclohexanone oxime dissolved in corn oil (total dose volume of 0.4 ml) at
doses of 0, 400, 600, 800 and 1000 mg/kg bw. Solvent control animals
16
received 0.4 ml of corn oil only and positive control mice got injections of
cyclophosphamide. Twenty-four hours after the third injection, the mice
were sacrificed and smears of the bone marrow cells (from the femur) were
prepared. Air-dried smears were fixed and stained; 2000 polychromatic
erythrocytes were scored for frequency of micronucleated cells in each of 5
mice at each of 4 doses.
GLP: Yes [X] No [ ] ? [ ]
Test substance: Cyclohexanone Oxime (>99% purity)
Remarks: In micronucleus tests conducted in mice by two different routes of
administration (oral and ip), cyclohexanone oxime showed no
evidence of in vivo mutagenicity.
Reliability: [1] Valid without restrictions
Reference: Burka, L.T. NTP Technical Report on Toxicity Studies of Cyclohexanone
Oxime. NTP Report Series No. 50, NIH Publication No. 96-3934, 1996
(B) Type: Gene Mutation In Vivo (Supporting Data)
Summary: When male fruit flies (Drosophila melanogaster) were administered
cyclohexanone oxime (8.8 mM) by feeding, there was no increase in the
frequency of sex-linked recessive mutations in germ cells.
Reference: Vogel, E. and J.L.R. Chandler. Mutagenicity Testing of Cyclamate and
Some Pesticides in Drosophila Melanogaster. Experientia 30: 621-623,
1974.
5.7 TOXICITY TO REPRODUCTION
Although no specific experimental studies were conducted to evaluate the potential effects of
cyclohexanone oxime (CHO) on male and female reproductive performance, results from two CHO
subchronic oral studies in rodents are worthy of mention. In the 90-day oral gavage study (Gad et
al. 1985) in rats at doses of < 25 mg/kg bw, and in the 90-day drinking water study (Burka 1996) in
mice at doses of < 10,000 ppm, gross and microscopic examinations were conducted on male and
female reproductive organs and tissues ?testis with epididymis, prostate, ovaries, uterus and
mammary glands. No evidence of toxicity was seen grossly (organ weights, e.g.) or
microscopically in male or female reproductive tissue following 90 days of oral dosing with
cyclohexanone oxime. Since the Closed-System Intermediate (CSI) status for CHO has been
accepted by EPA, no additional testing for the reproductive endpoint is required.
5.8 DEVELOPMENTAL TOXICITY: No data available
The Sponsor agrees to provide data for the developmental toxicity endpoint by conducting
a reproductive/developmental screening study in rats following OECD TG 421.
5.11 EXPERIENCE WITH HUMAN EXPOSURE (WORKPLACE)
No definitive studies on human exposure to cyclohexanone
oxime were found. No occupational exposure limits(OSHA PEL
17
or ACGIH TLV?have been established. In one older
reference(Finkel, A.J. in Hamilton and Hardy's Industrial
th
Toxicology, 4 Edition, John Wright PSG, Boston, MA, 1983),
hematological disorders were reported in humans exposed to
cyclohexanone oxime. It was also stated that dermatitis
and skin sensitization may also be potential effects of
occupational exposure. No other details were given.
REFERENCES
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