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EC number: 204-435-9 | CAS number: 120-92-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- from 05 sep 1984 to 19 mar 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well described and GLP, but performed on an analogue
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
- Report date:
- 1986
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Cyclohexanone
- EC Number:
- 203-631-1
- EC Name:
- Cyclohexanone
- Cas Number:
- 108-94-1
- Molecular formula:
- C6H10O
- IUPAC Name:
- cyclohexanone
- Details on test material:
- Test material identity: Cyclohexanone from Allied Fiber and Plastics Company (CAS 108-94-1)
Details on test material:
* Name of test material: cyclohexanone
* Molecular formula: C6H10O2
* Molecular weight: 98.14 g
* physical state: liquid
* Substance type: pure active substance
* Analytical purity: 99.9+%
* Impurities: 0.01% water, 0.02% cyclohexanol, 0.058% esters (as cyclohexylformate), 0.003% acidity (as formic acid)
* Purity test date: data not available
* Lot/batch No: 403102 and 506241
* Expiration date of the lot/batch: data not available
* Stability under test conditions: data not available
* Storage condition of test material: stored under nitrogen
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS:
- Species: rat
- Strain: RAT STRAINS: Sprague-Dawley
- Sex: male/female
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: (P) 40 days of age ; (F1) were 29-43 days of age at the initiation of the F1 generation
- Weight at study initiation: (P) Males: ca. 156 +/- 12 g; Females: ca. 130 +/- 8 g; (F1) Males: ca. 55-63 g; Females: ca. 50-56 g
- Fasting period before study: data not available
- Housing: animals were housed in one of 2 types of cages:
* stainless steel, open mesh cage bank units, each containing 10 individual cubicles, were used during acclimation and all study phases, excluding mating, gestating, and lactating periods ;
* hanging, wire-bottom, galvanized steel caging was used during the mating trials.
- Diet: certified Purina Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 25.5°C
- Humidity: 30 - 70%
- Air changes: at least 12 per hr
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: no data
Administration / exposure
- Route of administration:
- inhalation
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- - Generation of test atmosphere / Chamber description:
Airflow rates through the flasks were 80-100 L/minute and column and flask temperatures were maintained below 105°C (flask, column and chamber temperatures were recorded hourly). Flask air flow, column and flask temperature and FMI pump rate were adjusted to achieve the target concentrations. The pressure drop was measured by minihelic gauge that calibrated against a mass flowmeter. Chamber airflow was recorded hourly.
- Test atmosphere:
* Brief description of analytical method used: gas chromatography (detector: photoionization)
* Samples taken from breathing zone: yes - Details on mating procedure:
- - M/F ratio per cage: monogamous cohabitation, whenever possible, was used
- Length of cohabitation: 5 days
- Proof of pregnancy: vaginal plug or sperm-positive results of vaginal smears referred to as day 0 of pregnancy
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged: individually - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- (P) Males: 5 days/weeks before mating (at least 10 weeks), 5 days/week during mating (15-day maximum duration) and until initiation of the F1a weanings
(P) Females: 5-7 days/weeks before mating (at least 7+3 weeks), 7 days/weeks during mating (15-day maximum duration), 7 days/weeks during resulting pregnancies, 7 days/weeks through weaning of their F1 offspring.
(F1) Males: 5 days/weeks before mating (at least 15 weeks), 5 days/week during mating (15-day maximum duration) and until sacrifice
(F1) Females: 5-7 days/weeks before mating (at least 12+3 weeks), 7 days/weeks during mating (15-day maximum duration) and until sacrifice
Duration of test: 2 generations - Frequency of treatment:
- 6 hours per day, 5 days per week (for males and females pre-mating) or 7 days per week (for females only 3 weeks prior to the mating trial, during gestation days 0-20 and on lactation days 5-28).
- Details on study schedule:
- no data
Doses / concentrations
- Remarks:
- Doses / Concentrations:
F0: 250, 500 or 1000 ppm (1.0, 2.0 or 4.0 mg/L).|F1: 250, 500 or 1400 ppm (1.0, 2.0 or 5.6 mg/L).
Basis:
other: daily time-weighed average concentrations
- No. of animals per sex per dose:
- 30 males and 30 females in the F0 and the F1a generation
- Control animals:
- other: conditioned air only
- Details on study design:
- no data
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- * Cage side observations: Yes
- Time schedule: one a week (each animal was removed from its cage and thoroughly examined
* Detailed clinical observations: Yes
- Time schedule for examinations of morbidity and mortality: at least twice each day
* Body weight: Yes
- Time schedule for examinations: once a week
- Estrous cyclicity (Parental animals): no
- Sperm parameters (Parental animals): no - Litter observations:
- - Standardisation of litters:
* Performed on day 4 postpartum: yes
* If yes, maximum of 8 pups/litter (4/sex/litter); excess pups were killed and discarded.
- Parameters examined: the sexes and numbers of pups delivered, delivered viable, delivered stillborn, and found partially cannibalized were recorded for each litter of progeny on the day of parturition. The number of pups surviving to lactation days 1, 4, 7, 14 and 28 were determined. Individual pup weights and sexes were determined on lactation days 0, 4, 7, 14, 21 and 28 for all surviving progeny. Each litter of progeny was examined daily for mortality and behavioural anomalies. Each pup was also examined thoroughly for developmental anomalies at birth, at each body weight interval, and again at weaning. Assessment for neurotoxicological effects were conducted on 1 pup from each F1a litter delivered. Ophtalmologic examination was performed on all F1a progeny and all F2a and F2b weanlings
- Gross examination of dead pups: data not available - Postmortem examinations (parental animals):
- - Sacrifice:
* Male animals: All surviving animals
* Maternal animals: All surviving animals
- Gross necropsy: Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- Histopathology / organ weights: The tissues indicated in Table 1 (attached document) were prepared for microscopic examination and weighed, respectively - Statistics:
- Quantitative continuous variables, i.e. body weights, food consumption, were analyzed by Analysis of Variance with significant differences described by that treatment further studied by multiple comparison. Progeny body weight data were additionally studied using Analysis of Covariance (with the litter size as the covariate) and Dunnett's T-test. Reproductive data and neurotoxicologic data were analyzed using Chi-square analysis and Fisher's exact test.
All statistical analyses were interpreted using the untreated control group for comparison. Differences were considered significant at the p<0.05 and p<0.01 confidence levels. - Reproductive indices:
- Mating index = [ Number of copulations X 100 ] / [ Number of estrus cycles* utilized ]
Fertility index = [ Number of pregnancies X 100 ] / [ Number of copulation ]
Gestation index = [ Number of parturitions X 100 ] / [ Number of pregnancies ]
Female fertility index = [ Number of pregnancies X 100 ] / [ Number of female mated ]
Male fertility index = [ Number of sires X 100 ] / [ Number of males mated ]
* Five days equals 1 estrus cycle - Offspring viability indices:
- Born viable = [ No. pups delivered alive X 100 ] / [ Total No. pup delivered ]
Born dead = [No. stillbirths X 100 ] / [ Total No. pup delivered ]
Born and cannibalized = [ No. pups found partially cannibalized X 100 ] / [Total No. pup delivered ]
1 day = [ No. pups viable at lactation day 1 X 100 ] / [ No. pups born alive ]
4 day = [ No. pups viable at lactation day 4 X 100 ] / [ No. pups born alive ]
7 day = [ No. pups viable at lactation day 7 X 100 ] / [ No. pups retained at lactation day 4 ]
14 day = [ No. pups viable at lactation day 14 X 100 ] / [ No. pups retained at lactation day 4 ]
21 day = [ No. pups viable at lactation day 21 X 100 ] / [ No. pups retained at lactation day 4 ]
28 day = [ No. pups viable at lactation day 28 X 100 ] / [ No. pups retained at lactation day 4 ]
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
No deaths were noted for treated F0 parental animals.
In F0 parental animals, following the first 2 exposures to 1000 ppm, lacrimation, ataxia and irregular breathing were noted.
- BODY WEIGHT AND FOOD CONSUMPTION:
Body weight data of F0 treated animals were comparable to the untreated control animals.
- REPRODUCTIVE PERFORMANCE:
In F0 parental animals, statistical analyses of the mating indices calculated for the treated animals revealed no significant differences.
See table 2 in the attached document.
- OTHER FINDINGS:
Urinalysis was performed in 5 randomly selected F0 parental females from each treatment level post-lactation. The overnight urine volumes collected from these females revealed an increase in the volume of urine from the 1000 ppm females ; however, no qualitative differences were noted that corresponded with this increase. All other urinalysis parameters obtained were comparable to the untreated control females.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- Remarks on result:
- other:
- Remarks:
- Clinical signs were observed in P0 animals at 1000 ppm
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
Details on results (P1)
In F1 parental animals, irregular breathing, urine soaked fur, prostration, lacrimation and ataxia were the predominant observation noted post-exposure to 1400 ppm. During week 16, these animals appeared to acclimate to treatment with lethargy being the predominant post-exposure observation. Pre-exposure, 27/60 of the 1400 ppm animals had yellow/brown stained fur, and 2 males exhibited a staggering gait during week 30.
Body weight:
in F1 parental animals, the body weight data revealed significant reductions for the 1400 ppm males up the the 33th week and for the 500 ppm males only during the first week, when compared to the untreated control males.
Effect levels (P1)
- Dose descriptor:
- other: NOAEL Parental F1
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- Remarks on result:
- other:
- Remarks:
- Clinical signs and body weight reduction were seen at 1400 ppm
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
During the 1st generation, F1a litter, progeny delivery and population data were similar for treated groups and the untreated control group. Progeny survival during the F1a litters was not altered by maternal exposure to cyclohexanone.
See table 3 in the attached document.
- BODY WEIGHT:
Body weight data obtained for F1a progeny were not considered to be affected by maternal cyclohexanone exposure.
- GROSS PATHOLOGY:
The examinations for progeny development generally revealed findings/anomalies which were sporadic in occurrence and which have been seen among control progeny. During the F1a litter, 1 pup from the 500 ppm groups and 1 pup from the 1000 ppm group exhibited eye opacity.
Examination of the specified tissues of the nervous system of untreated and 1000 ppm F1a progeny selected for neurotoxicologic testing did not reveal lesions in any of the tissues.
- HISTOPATHOLOGY:
Microscopic examination of the eyes from the F1a progeny revealed lenticular vacuolation for 2/115 of the 500 ppm progeny and 3/111 of the 1000 ppm progeny. The examining pathologist concluded that based on the low incidence and minimal nature of these changes, they were not treatment-related.
- OTHER FINDINGS:
Evaluation of behavioural/neurotoxicologic development of selected F1a progeny revealed no consistent statistical differences between treated and control groups. On lactation day 15, 31-56% fewer test progeny had open eyelids than the untreated control progeny ; however no dose-response pattern was apparent.
The ophthalmologist's interpretation of the examinations of the eyes was that the test substance did not increase the incidence of cataracts in the progeny. The lens and other ocular abnormalities appeared to be within the range of type and incidence expected in the number of animals examined.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 1 000 ppm
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other: No effect
- Remarks on result:
- other:
- Remarks:
- The NOAEL is higher than 1000 ppm. No effect was noted.
Results: F2 generation
Details on results (F2)
Statistical analysis of the F2a and F2b progeny data revealed significant reductions for the mean number of 1400 ppm progeny viable during the lactation period. Progeny delivery and population data for the 250 and 500 ppm groups were comparable to the untreated control group. The % of 1400 ppm F2a and F2b progeny delivered viable and surviving to lactation days 1 and 4 (but not at lactation days 14, 21 and 28) were significantly less than seen for the untreated control. Progeny survival indices calculated for the 250 and 500 ppm groups during the F2a and F2b litters were similar to the untreated control group.
Statistical analysis of the 1400 ppm F2a and F2b progeny body weights revealed significant reduction when compared to the untreated control progeny. Because the statistical weight differences noted for the 250 and 500 ppm F2a progeny were minimal (5 to 17%) and were not seen for the F2b progeny, maternal exposure to 250 or 500 ppm cyclohexanone was not considered to adversely affect pup body weights.
See table 4 in table 4 in the attached document.
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 500 ppm
- Sex:
- not specified
- Basis for effect level:
- viability
- body weight and weight gain
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1: Gross necropsy and tissue preparation of parent (checked (X) collected (column C), weighed (column W) and examined for histopathology (column H with X = all groups, # = control and top dose animals)
F0 parental |
F1 parental |
||||||
C |
W |
H |
SYSTEM |
C |
W |
H |
SYSTEM |
|
|
|
digestive |
|
|
|
digestive |
|
|
|
Liver |
X |
|
# |
Liver |
|
|
|
Stomach |
|
|
|
Stomach |
|
|
|
reticulo- endothelial |
|
|
|
reticulo- endothelial |
|
|
|
Bone marrow§ |
|
|
|
Bone marrow§ |
|
|
|
Lymph nodes |
|
|
|
Lymph nodes |
|
|
|
Peyer’s patch |
|
|
|
Peyer’s patch |
|
|
|
Spleen |
|
|
|
Spleen |
|
|
|
Thymus |
|
|
|
Thymus |
|
|
|
urogenital |
|
|
|
urogenital |
X |
|
# |
Epididymis |
X |
|
# |
Epididymis |
|
|
|
Kidneys |
X |
|
# |
Kidneys |
X |
|
# |
Ovaries |
X |
|
# |
Ovaries |
|
|
|
Primordial follicles, growing follicles, and large Corpora lutea of lactation from the post-lactation ovary |
|
|
|
Primordial follicles, growing follicles, and large Corpora lutea of lactation from the post-lactation ovary |
X |
|
# |
Prostate |
X |
|
# |
Prostate |
X |
|
# |
Seminal Vesicle with Coagulating Gland (if present) |
X |
|
# |
Seminal Vesicle with Coagulating Gland (if present) |
X |
|
# |
Testes |
X |
|
# |
Testes |
X |
|
# |
Uterus (with oviducts) |
X |
|
# |
Uterus (with oviducts) |
X |
|
# |
Vagina |
X |
|
# |
Vagina |
|
|
|
neurologic |
|
|
|
neurologic |
|
|
|
Brain |
X |
|
# |
Brain |
|
|
|
Peripheral nerve tissue |
|
|
|
Peripheral nerve tissue |
|
|
|
Spinal cord (at least 2 different locations) |
|
|
|
Spinal cord (at least 2 different locations) |
|
|
|
glandular |
|
|
|
glandular |
|
|
|
Adrenal glands |
|
|
|
Adrenal glands |
|
|
|
Pituitary gland |
|
|
|
Pituitary gland |
|
|
|
other |
|
|
|
other |
|
|
|
Target organ: |
X |
|
# |
Eyes |
|
|
|
|
|
|
|
|
Applicant's summary and conclusion
- Executive summary:
A reproduction study was conducted to ascertain the potential effects of inhalation exposure to cyclohexanone vapor upon reproductive performance, growth, and development of 2 consecutive generations of CD Sprague-Dawley albino rats. Groups of 30 males/30 females were exposed to either 0, 250, 500 or 1000 ppm during the 1st (F0) generation. 30 males/30 females were selected from the F1a litters of each group to continue on test as second (F1) generation animals. The F1 generation animals were exposed to 0, 250, 500 or 1400 ppm cyclohexanone. Assessment for potential neurotoxicologic/neuropathologic effects were conducted pre-weaning and post-weaning in each F1a litter.
The daily time-weighted average concentrations during the F0 generation were 0, 253.2, 499.2 and 1008.9 ppm and during F1 generation the daily time-weighted average concentrations were 0, 249.8, 496.9 abd 1387.2 ppm of cyclohexanone.
Inhalation exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through 2 consecutive generations did not adversely affect the growth, development, and reproductive performance of the CD Sprague-Dawley derived albino rats. Evaluation for behavioral/neurotoxicologic development of selected F1a progeny revealed no consistent differences betwwen treated groups and the control group.
Inhalation exposure of the CD rat (progeny from parental animals exposed to 1000 ppm) to 1400 ppm cyclohexanone through one generation resulted in exposure-related male body weight depressions, reduced progeny survival, and progeny body weight depressions.Based on this study cyclohexanone induce in the F2 generation a reduction on the viability and on the body weight. However the fertility is not impacted and no developmental effect was seen.
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