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EC number: 905-559-2 | CAS number: -
- 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:
- one-generation reproductive toxicity
- Remarks:
- based on generations indicated in Effect levels (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP-compliant, near-guideline study. Published in peer reviewed literature. No restrictions, fully adequate for assessment.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 994
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- US-NTP Continuous Breeding Protocol. Comprises 4 phases through dose range-finding phase, F0 cohabitation and lactation phase, a F0 crossover mating trial and a F1 fertility assessment phase.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4-vinylcyclohexene
- EC Number:
- 202-848-9
- EC Name:
- 4-vinylcyclohexene
- Cas Number:
- 100-40-3
- Molecular formula:
- C8H12
- IUPAC Name:
- 4-vinylcyclohexene
- Details on test material:
- - Name of test material (as cited in study report): 4-vinylcyclohexene
- Substance type: a dimer of 1,3-butadiene
- Physical state: clear volatile liquid
- Analytical purity: >99%
- Lot/batch No.: A061181/B03
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- other: CD-1 (ICR)BR outbred Swiss albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, NC, USA.
- Age: approximately 9 weeks old upon arrival
- Housing: solid bottom polycarbonate cages with stainless steel wire lids.
- Diet: pelleted food NIH-07 (Zeigler Brothers, Gardners PA, USA) ad libitum
- Water: deionized and filtered water ad libitum
- Acclimation period: Not reported
ENVIRONMENTAL CONDITIONS
- Temperature: 72±0.5°F
- Humidity: 53±6%
- Air changes (per hr): Not reported
- Photoperiod: 10 hrs dark / 14 hrs light
IN-LIFE DATES: Not reported
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 14 weeks - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Aliquots of each dosing formulation analysed at approximately 1-month intervals for concentration of 4-vinylcyclohexene by gas chromatography. Concentrations were acceptable, between 89 and 117% of nominal.
- Duration of treatment / exposure:
- See below
- Frequency of treatment:
- See below
- Details on study schedule:
- See below
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100, 250 or 500 mg/kg/day (F0), 0 and 500 mg/kg/day (F1)
Basis:
other: nominal in corn oil
- No. of animals per sex per dose:
- 40/sex controls, 25/sex 100, 250 and 500 mg/kg test groups (F0)
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CLINICAL OBSERVATIONS: Yes (no details reported)
BODY WEIGHT: Yes
- Time schedule: during weeks 1, 2, 5, 9, 13 and 18 (F0 females).
FOOD CONSUMPTION: Yes
- Time schedule: during weeks 1, 2, 5, 9, 13 and 18 (F0 females), during weeks 1 (breeding), 2, 3, and 4 (F1 male and female).
WATER CONSUMPTION: Yes
- Time schedule: during weeks 1, 2, 5, 9, 13 and 18 (F0 females), during weeks 1 (breeding), 2, 3, and 4 (F1 male and female). - Oestrous cyclicity (parental animals):
- After delivery of the litters, vaginal smears were prepared from F1 females for 12 days.
- Sperm parameters (parental animals):
- Parameters examined in F1 male parental generations:
sperm motility, concentration, morphology and homogenization-resistant spermatid concentration - Litter observations:
- STANDARDISATION OF LITTERS: No
PARAMETERS EXAMINED
Parent (F0) cohabitation parameters included: date of delivery of each litter, number, sex, weight of pups per litter, number of litters per pair, and PND 0 dam body weight. On PND 0, 4, 7, 14, and 21, surviving pups were counted, sexed, and weighed for all dams delivering a litter after week 16.
F1 generation cohabitation parameters included: date of delivery of each litter, number, sex, weight of pups per litter, number of litters per pair, and PND 0 dam body weight. - Postmortem examinations (parental animals):
- At study end, F1 parents were subject to necropsy and body weight, kidney/adrenal weights, liver, testis, prostate, seminal vesicle (+ coagulating gland), ovary/oviduct and uterus weights collected. The ovaries were processed for microscopic assessment.
- Statistics:
- Data were analysed using Williams' modification of Dunn's or Shirley's nonparametric multiple comparison procedures.
- Reproductive indices:
- Mating index = Number of females vaginal plug positive / number cohabitated
Fertility index = Number of females delivering a litter / number cohabitated
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:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Reproductive performance:
- no effects observed
Details on results (P0)
BODY WEIGHT: (PARENTAL ANIMALS): F0 females at 500 mg/kg/day had an 8% reduction in body weight compared to controls during week 18 (data not reported). For F1 animals, there were significantly reduced body weights (7-8%) at 500 mg/kg/day during the F1 breeding phase (PND 77±10 up to and including PND 117±10). At delivery of F2 pups, 500 mg/kg/day dam weights were 7% lower than controls.
FOOD CONSUMPTION (PARENTAL ANIMALS): No effect on F0 parents. For F1 increased relative food consumption in 500 mg/kg/day males during weeks 2 and 4 (19% and 12% respectively) and in 500 mg/kg/day females during weeks 3 and 4 (11% and 29% respectively).
WATER CONSUMPTION: Cohabited pair relative water consumption for F0 was transiently increased at 100 mg/kg/day (7% at 5 weeks of exposure) and 500 mg/kg/day (27% and 17% at 5 and 9 weeks of exposure respectively). F1 relative water consumption was increased by 9% in 500 mg/kg/day females during week 3.
FERTILITY AND REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
F0 parents: 4-vinylcyclohexene at all treatment doses had no effect on reproductive competence including initial fertility, litters per pair, live pups per litter, total pups born alive, proportion of pups born alive, and sex ratio of pups.
F1 parents: 4-vinylcyclohexene at all treatment doses had no effect on reproductive competence including mating index, fertility index, gestation length, live F2 pups per litter, total number of F2 pups born alive, total number of F2 male pups per litter, or live F2 pup weight.
REPRODUCTIVE FUNCTION: F1 SPERM MEASURES (PARENTAL ANIMALS): 4-vinylcyclohexene had no effect on epididymal sperm concentration or morphology, but did cause a statistically significant increase in sperm motility and a statistically significant decrease (16%) in spermatid concentration in the right testis homogenates. No histopathological lesions were noted for the testis.
F1 VAGINAL CYTOLOGY (OESTRUS CYCLICITY): 4-vinylcyclohexene had no effect on normal cyclic patterns of vaginal cytology or mean cycle length following approximately 95 days of exposure to 500 mg/kg bw/day.
F1 ORGAN WEIGHTS (PARENTAL ANIMALS): Statistically significant increase in liver weights in F1 males (55.59±1.2 for controls vs. 60.46±1.37 for treated) and in F1 females (57.52±1.18 for controls vs. 62.08±1.28 for treated) at necropsy compared to controls. All other organ weights assessed were considered normal.
F1 SPERM ANALYSIS: No effect on epididymal sperm concentration or morphology, but did cause a statistically significant increase in sperm motility and a statistically significant decrease (16%) in spermatid concentration in the right testis homogenates. No histopathological lesions were noted for the testis.
F1 SECTIONED OVARY RESULTS: At 500 mg/kg bw/day for approximately 95 days there was a statistically significant reduction in the number of primordial oocytes/follicles by 33%, the number of growing follicles by 55%, and the number of antral follicles by 33%.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- 500 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: no effects on reproductive performance
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
Details on results (F1)
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Generation:
- F1
- Effect level:
- 500 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: no effects on reproductive performance
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 500 mg/kg bw/day (nominal)
- Sex:
- female
- Basis for effect level:
- other: clear ovarian toxicity was apparent in F1 females as evidenced by significant, marked decrements in numbers of primordial oocytes, growing follicles and antral follicles
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 500 mg/kg bw/day (nominal)
- Sex:
- male
- Basis for effect level:
- other: slight, statistically significant reductions in sperm motility in F1 males (concentration and morphology unaffected)
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Parental Effects
Parameter |
Dose (mg/kg/day) |
|||
0 |
100 |
250 |
500 |
|
No. fertile/No. cohabitated |
36/36 |
19/19 |
19/19 |
16/16 |
Litters per pair |
4.8 |
4.7 |
4.8 |
4.6 |
Live pups per litter |
12.2 |
13.5 |
12.5 |
11.5 |
Pups born alive (%) |
97 |
99 |
99 |
99 |
Live males per litter |
49 |
48 |
48 |
49 |
Live pup weight (g) |
1.64 |
1.58 |
1.58 |
1.58* |
Adjusted live pup weight (g) |
1.63 |
1.61 |
1.58 |
1.55 |
* statistically significant
F1 body weights (g)
PND |
Dose (mg/kg/day) |
|||||||
males |
females |
|||||||
0 |
100 |
250 |
500 |
0 |
100 |
250 |
500 |
|
0 |
1.75 |
1.69 |
1.75 |
1.63 |
1.66 |
1.59 |
1.64 |
1.59 |
7 |
4.38 |
4.35 |
1.75 |
4.23 |
4.27 |
4.35 |
4.22 |
4.08 |
21 |
11.07 |
10.98 |
10.79 |
10.94 |
10.3 |
10.93 |
10.2 |
10.56 |
77 |
34.07 |
|
|
31.51* |
28.4 |
|
|
26.20* |
117 |
35.24 |
|
|
32.79* |
30.6 |
|
|
28.00* |
* statistically significant
F2 Fertility and reproductive performance
Parameter |
Dose (mg/kg/day) |
|
0 |
500 |
|
Mating index |
16/20 |
18/20 |
Fertility index |
19/20 |
19/20 |
Number of days to litter |
18.7 |
19.2 |
Live F2 pups per litter |
11.6 |
10.6 |
F2 pups born alive |
99 |
98 |
F2 male pups born alive |
41 |
39 |
Live F2 pup weight |
1.52 |
1.47 |
Sperm analysis
Parameter |
Dose (mg/kg/day) |
|
0 (n=20) |
500 (n=19) |
|
Epididymal sperm concentration |
988 |
876 |
Epididymal sperm motility |
68.9 |
85.5* |
Epididymal sperm morphology |
2.4 |
2.9 |
Testicular sperm concentration |
13.6 |
11.3* |
* statistically significant
F1 sectioned ovary results
Follicular stage |
Dose (mg/kg/day) |
|
0 (n=20) |
500 (n=19) |
|
Primordial oocytes/follicles |
208.9 |
140.6* |
Growing follicles |
51.2 |
23.2* |
Antral follicles |
7.4 |
4.95* |
* statistically significant
Applicant's summary and conclusion
- Conclusions:
- 4-vinylcyclohexene administered at 500 mg/kg bw/day was clearly toxic to ovarian follicles in female offspring and produced a slight but statistically significant effect on spermatogenesis in male offspring, but did not adversely affect reproductive performance in either the F0 or F1 generations. The NOEL for reproductive performance was 500 mg/kg/day.
- Executive summary:
F0male and female CD-1 mice were administered 4-VCH by oral gavage at doses of 0, 100, 250 or 500mg/kg body weight/day for 16 weeks prior to conception of an F1breeding generation. Direct dosing (0 or 500 mg/kg body weight/day, by gavage) of 21-day old weaning F1adults commenced 7-8 weeks prior to conception of an F2generation, therefore, adults were exposed to 4-VCH before and during mating, throughout pregnancy and lactation, with continuous exposure of the foetuses and pups occurring secondary to maternal treatment (i.e. occurring in utero or via milk, respectively).
4-VCH, at doses up to 500 mg/kg body weight/day, which resulted in generalised toxicity, was clearly toxic to ovarian follicles in female offspring (significant reduction in primordial oocytes, growing follicles and antral follicles) and produced a slight but statistically significant effect on sperm motility in F1male offspring (concentration and morphology unaffected). However there were no effects on reproductive performance of the F0or F1generations, including mating and fertility indices, live litter size, sex ratio and pup survival to post-natal day 4.
NOAEL reproductive performance/foetotoxicity/teratogenicity = 500 mg/kg/day
LOAEL gonadal toxicity (F1 males and females) = 500 mg/kg
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