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EC number: 203-806-2 | CAS number: 110-82-7
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, guideline study, no restrictions, fully adequate for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 000
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:
- Cyclohexane
- EC Number:
- 203-806-2
- EC Name:
- Cyclohexane
- Cas Number:
- 110-82-7
- Molecular formula:
- C6H12
- IUPAC Name:
- cyclohexane
- Details on test material:
- Name of test material (as cited in study report): cyclohexane
- Supplier: Phillips Petroleum Company, Sweeney Refinery, Sweeney, Texas, USA
- Physical state: liquid
- Analytical purity: >99.9%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: Approximately 8 weeks
- Housing: Animals were housed individually in suspended, wire-mesh, stainless steel cages. During the cohabitation period, rats were housed as breeding pairs in stainless steel, wire-mesh cages. Females without evidence of copulation by the end of the cohabitation and assumed-pregnant females from gestation day 14 through delivery, were housed individually in polycarbonate pans with bedding. During the lactation period, adult females were housed with their litters in polycarbonate pans with bedding.
- Diet: Purina "Certified Rodent Checkers" was available ad libitum, except during exposures
- Water: tap water ad libitum, except during exposures
ENVIRONMENTAL CONDITIONS
- Temperature: 23±2°C
- Humidity: 50±10%
- Air changes (per hr): not reported
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: Not reported
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: air
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass exposure chambers with a nominal internal volume of 1.4 m3 (total body volume of the test animals did not exceed 5% of the chamber volume). A tangential feed at the chamber inlet promoted gas mixing and uniform chamber distribution of vapour.
- Cyclohexane atmosphere generation: the liquid cyclohexane was metered into a heated glass Instatherm flask with a Fluid Metering Inc. pump. Nitrogen, introduced into the flask, swept the cyclohexane vapour into the inhalation chamber air supply. The chamber concentration was controlled by varying the amount of the metered liquid evaporated in the chamber air stream. Nitrogen and air were passed through the control chamber at approximately the same flow rates as those used in the exposure chambers.
TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography equipped with a flame ionization (at approximately 15-minute intervals during each 6-hour exposure)
- Samples taken from breathing zone: yes (atmosphere samples were drawn by vacuum pump from representative areas of the chamber where animals were exposed) - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: not reported
- Proof of pregnancy: not reported. The day copulation was confirmed was designated day 0 of pregnancy - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The atmospheric concentration of cyclohexane was determined by gas chromatography at approximately 15 minute intervals during each 6-hour exposure. The results of these determinations indicated the distribution of cyclohexane vapour was sufficiently homogeneous (less than 2% difference in chamber concentration from position to position).
- Duration of treatment / exposure:
- The P1 generation was exposed for at least 10 weeks prior to mating within their respective treatment groups, and allowed to deliver and rear their offspring until weaning (postpartum day 25). Pregnant females were exposed daily during days 0-20 of gestation. They were not exposed from day 21 of gestation until day 4 of lactation. Females resumed their daily exposure regimen from day 5 of lactation until weaning of litters. They were returned to their litters each day after exposure. Males continued to be exposed 5 days/week until sacrifice. Neonates were not exposed to cyclohexane by inhalation during lactation.
At least 11 weeks after weaning, thirty selected F1 rats/sex/ group were bred within their respective treatment groups to produce F2 litters, following the same regime. - Frequency of treatment:
- 6 hours/day, 5 days/week (excluding holidays)
- Details on study schedule:
- At least 11 weeks after weaning 30 F1 rats/sex/group were bred within their respective treatment groups to produce F2 litters
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0 (air), 500, 2000, 7000 ppm
Basis:
other: target concentration
- Remarks:
- Doses / Concentrations:
0 (air), 500, 2000, 7000 ppm
Basis:
other: overall mean measured
- No. of animals per sex per dose:
- 30 /sex/concentration
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- Prior to the initiation of each exposure, during exposure, and during the time required to clear the chambers of test substance, the groups of animals within exposure levels were observed for a normal, diminished, or hyper-responsive alerting behaviour in response to a standardized auditory stimulus. All adult P1 and F1 rats were weighed weekly during the premating, gestation, and lactation periods and clinical signs were recorded at the same time.
- Litter observations:
- F1 and F2 pup body weights and clinical observations were recorded on postpartum days 0, 4, 7, 14, 21 and 25.
- Postmortem examinations (parental animals):
- At day 25 post partum all P1 and F1 parental rats underwent gross postmortem examination. The method of euthanasia was carbon dioxide asphyxiation and exsanguination. Reproductive organs and pituitary gland were collected from each adult animal. Tissues from P1 and F1 adult rats in the control and 7000 ppm groups of both generations were examined microscopically.
- Postmortem examinations (offspring):
- 20 F1 and F2 weanlings/sex/concentration underwent gross postmortem examination. The method of euthanasia was carbon dioxide asphyxiation and exsanguination.
- Statistics:
- For all analyses the level of significance was p < 0.05. The data for each parameter were subject to sequential trend testing. Pair-wise comparisons were used to analyse adult body weight and food consumption data. Continuous data were compared using parametric analyses. The method of analysis was linear contrast of means from One-way Analysis of Variance (ANOVA) followed by Dunnett's test. The nonparametric method, Jonckheere's trend test was used to analyse litter-related continuous data. The litter mean was used as the experimental unit for statistical evaluation of litter parameters. Exact p values were calculated using permutation methodology where the data were tied. Analysis of Covariance (covariates: litter size, sex ratio) followed by a linear contrast of the least square means was used to analyse pup weights. The Cochran-Armitage test for trend was used to evaluate discrete data. Fisher's exact test was used to analyse microscopic observations.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- no effects observed
- 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)
A statistically significant reduction in mean body weight and overall mean body weight gain was present in the P1 and F1 females exposed to 7000 ppm. i.e. at the end of the premating period weight gain was 87% of control for P1 females and 92% of controls for F1 females. There was no effect of 7000 ppm on the bodyweight of males but mean bodyweight was generally statistically significantly reduced throughout the study in the F1 males. Food efficiency was reduced in 7000 ppm females in both generations.
There were no biologically or statistically significant dose-related differences in mating, fertility or gestation indices, implantation efficiency or gestation length in either the P1 or F1 generations.
Effect levels (P0)
- Dose descriptor:
- NOAEC
- Effect level:
- >= 500 - <= 2 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 7 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: 24,080 mg/m3
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEC
- Generation:
- F2
- Effect level:
- 7 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: 24,080 mg/m3
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Mean pup weights (g) selected timepoints
|
Day 0 |
Day 7 |
Day 14 |
Day 21 |
Day 25 |
F1 Generation |
|
|
|
|
|
0 ppm |
6.7 |
16.2 |
30.0 |
48.5 |
67.5 |
500 ppm |
6.7 |
16.2 |
29.9 |
48.5 |
67.8 |
2000 ppm |
6.7 |
16.3 |
29.7 |
48.3* |
68.3 |
7000 ppm |
6.6 |
15.1* |
26.5* |
43.1* |
62.2* |
F2 Generation |
|
|
|
|
|
0 ppm |
6.4 |
16.3 |
31.0 |
50.0 |
69.3 |
500 ppm |
6.6 |
16.0 |
30.2 |
48.3 |
67.1 |
2000 ppm |
6.3 |
15.3 |
28.9 |
46.4 |
65.6 |
7000 ppm |
6.3 |
14.3* |
26.2* |
42.8* |
61.3* |
* Statistically significant difference from control (p 0.05) by Analysis of Covariance with litter size and sex ratio as covariates
Applicant's summary and conclusion
- Conclusions:
- Parental effects were restricted to transient sedation from study day 15-16 (NOAEC 500 ppm) and body weight effects (NOAEC 2000 ppm). There was, however, no adverse effect on reproductive function in male or female rats following exposures up to 7000 ppm.
- Executive summary:
A two-generation reproduction study was conducted to assess the reproductive and developmental toxicity of cyclohexane. Rats of the Crl:CD BR strain were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. Statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency were recorded for the parent P1 and F1 females exposed to 7000 ppm although a statistically significantly lower mean body weight was recorded for parent F1 males only. During exposure, the adult rats exposed to 2000 ppm cyclohexane or more exhibited a transient diminished or absent response to a sound stimulus.
There was a statistically significant lower mean pup weight, from day 7 through to day 25 of lactation, for F1 and F2 litters exposed to 7000 ppm. The no-observed-effect concentration (NOAEC) for systemic toxicity was 500 ppm (1,720 mg/m3) and the NOAEC for reproductive toxicity (based on the decreased pup weights in the F1 and F2 generations) was 2000 ppm. The NOAEC for effects on male and female fertility was 7000 ppm (24,080 mg/m3), the highest concentration tested.
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