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EC number: 203-894-2 | CAS number: 111-67-1
- 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:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04 July 2013 - 06 March 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study follows the OECD 422 Guidelines and it is GLP compliant. It is classified as reliable without restriction.
- Justification for type of information:
- A discussion and report on the read across strategy is given as an attachment in Section 13.
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 111-66-0
- Molecular formula:
- C8H16
- Test material form:
- other: clear colorless liquid
- Details on test material:
- - Name of test material (as cited in study report): Oct-1-ene
- Cs No.: 111-66-0
- Purity test date: >98%
- Lot/batch No.: 719238
- Expiration date of the lot/batch: 29 April 2014
- Label: Alpha Olefin C8 Lot 719238
- Data received: 29 April 2013
- Storage condition of test material: room temperature in the dark under nitrogen
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Oct-1-ene
- Cs No.: 111-66-0
- Purity test date: >98%
- Lot/batch No.: 719238
- Expiration date of the lot/batch: 29 April 2014
- Label: Alpha Olefin C8 Lot 719238
- Data received: 29 April 2013
- Storage condition of test material: room temperature in the dark under nitrogen
Oct-1-ene, CAS# 111-66-0 used in this study was a typical production sample, according to the details included in the boundary composition in IUCLID section 1.2. Oct-1-ene was chosen in the Higher Olefins category testing strategy because it represents a substance with high alpha olefin content (category range 0 - 98%). Please see the testing strategy attached in section 13 for further details.
Test animals
- Species:
- rat
- Strain:
- other: Wistar Han™:RccHan™:WIST
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Blackthorn, Bicester, Oxon, UK.
- Age at study initiation: 12 weeks old
- Weight at study initiation: males: 312 to 357g; females: 194 to 234g
- Fasting period before study:
- Housing:
Beginning: all animals were housed in groups of four in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK).
Pairing phase: animals were transferred to polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male: one female basis within each dose group.
Evidence of successful mating: the males were returned to their original cages and mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
- Diet (e.g. ad libitum): Pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK.)
- Water (e.g. ad libitum): free access
- Acclimation period: eight days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 55 ± 15% respectively
- Air changes (per hr): at least fifteen air changes per hour
The in-life phase of the study was conducted between 04 July 2013 (first day of treatment) and 21 August 2013 (final day of necropsy).
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): the test item was prepared at the appropriate concentrations as a solution in Arachis oil BP.
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: The volume of test and control item administered to each animal was based on the most recent scheduled body weight and was adjusted at weekly intervals.
Storage vehicle: approximately 4°C - Details on mating procedure:
- - M/F ratio per cage: 1/1 (pairing period)
- Length of cohabitation: minimum 14 days
- Proof of pregnancy: The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation)
- After successful mating each pregnant female was caged: males were returned to their original holding cages (unless required for additional pairing). Mated females were housed individually during the period of gestation and lactation. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Formulations were therefore prepared weekly and stored at approximately 4 °C in the dark under nitrogen. The analytical results indicate that the prepared formulations were within ± 4% of the nominal concentration.
- Duration of treatment / exposure:
- The test item was administered by gavage to three groups (12/sex) for up to eight weeks (including a two-week pre-pairing phase, pairing, gestation and early lactation for females).
- Frequency of treatment:
- daily
- Details on study schedule:
- Twelve male and twelve female animals per dose group were treated daily (except for females during parturition where applicable).
The first day of dosing was designated as Day 1 of the study.
Prior to the start of treatment and once weekly thereafter, all animals were observed for signs of functional/behavioural toxicity.
On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.
Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.
On completion of the pairing phase (during Week 6), five selected males per dose group were evaluated for functional/sensory responses to various stimuli.
Pregnant females were allowed to give birth and maintain their offspring until Day 5 post partum. Litter size, offspring weight and sex, surface righting and clinical signs were also recorded during this period.
At Day 4 post partum, five selected females per dose group were evaluated for functional/sensory responses to various stimuli.
Blood samples were taken from five males from each dose group for hematological and blood chemical assessments on Day 42. The male dose groups were killed and examined macroscopically on Day 43.
Blood samples were taken from five randomly selected females from each dose group for hematological and blood chemical assessment on Day 4 post partum. At Day 5 post partum, all females and surviving offspring were killed and examined macroscopically. Any female which did not produce a pregnancy was also killed and examined macroscopically.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were examined for overt signs of toxicity, ill-health and behavioural change
immediately before dosing, soon after dosing, and one hour after throughout the treatment period (except for females during parturition where applicable).
BODY WEIGHT: Yes
- Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until mating was evident. Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum. Body weights were also recorded at terminal kill.
DOOD CONSUMPTION:Yes
Pre-pairing period and after (male): weekly
Females showing evidence of mating: post coitum Days 0-7, 7-14 and 14-20.
Females with live litters: Days 1 and 4 post partum.
FOOD EFFICIENCY:Yes
Males (throughout the study period-with the exception of the mating phase, and females during the pre-pairing phase
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Water intake was measured daily during the pre-pairing phase of the
BEHAVIORAL, FUNCTIONAL OBSERVATIONS and SENSORY REACTIVITIES were observed and recorded. - Litter observations:
- Number of offspring born
Number of offspring alive recorded daily and reported on Days 1 and 4 post partum
Sex of offspring on Days 1 and 4 post partum
Clinical condition of offspring from birth to Day 5 post partum
Individual offspring weights on Days 1 and 4 post partum (litter weights were calculated retrospectively from this data)
- Postmortem examinations (parental animals):
- Pathology Females: Uterus (for signs of implantation and the number of uterine implantations in each horn), the corpora lutea.All adult animals and offspring: full external and internal examination. All macroscopic abnormalities were recorded. - Organ Weights- Histopathology: Tissues from 5 selected male and female animals/group were preserved. Histopathological examination was undertaken on tissues from control and high dose animals. Since there were indications of possible treatment-related changes in the forestomach, examination was subsequently extended to include similarly prepared sections of the stomach from animals in the low and intermediate groups.
- Postmortem examinations (offspring):
- All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
- Statistics:
- Data were analysed using the decision tree from the Provantis Tables and Statistics Module. The homogeneity of variance from mean values was analysed using Bartlett’s test. Intergroup variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covarities. Any transformed data were analysed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for nonparametric data. If no dose response was found but the data shows non-homogeneity of means, the data were analysed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the MannWhitney U test (non-parametric).
- Reproductive indices:
- Mating Performance and Fertility
i. Pre-coital Interval
ii. Fertility Indices (Mating Index and Pregnancy Index)
Gestation and Parturition Data
i. Gestation Length
ii. Parturition Index - Offspring viability indices:
- Parturition Index (%)
Litter Responses
i. Implantation Losses (%)
ii. Live Birth and Viability Indices
iii. Sex Ratio (% males)
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg bw/day showed increased salivation from Day 1 (males) and Day 3 (females) onwards. Males treated with 300 mg/kg bw/day also showed episodes of increased salivation between days 16 and 29. No such effects were detected infemales treated with 300 mg/kg bw/day or animals of either sex treated with 100 mg/kg bw/day. One male treated with 1000 mg/kg bw/day, one female treated with 1000 mg/kg bw/day and three control females had generalised fur loss during the treatment period. Observations of this nature are commonly observed ingroup housed animals and is considered not to be of toxicological significance.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects detected in body weight development. Statistical analysis of the data did not reveal any significant intergroup differences.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study. Statistical analysis of female data during gestation and lactation did not reveal any significant intergroup differences.
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg bw/day showed an increase in overall water consumed when compared to the control group.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No toxicologically significant effects were detected in the haematological parameters examined.
The following intergroup differences were detected however they were considered not to be toxicologically significant. Females treated with 1000 mg/kg bw/day showed an increase in hemoglobin levels whilst males from this treatment group showed a reduction in activated partial thromboplastin time. The majority of individual values were within the normal background range for these parameters. Females from all treatment groups showed an increase in erythrocyte count however a true dose related response was not evident and all of the individual values were within the normal background range for this parameter. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No toxicologically significant effects were detected in the blood chemical parameters examined.
The following intergroup differences were detected however they were considered not to be toxicologically significant. Males treated with 1000 and 300 mg/kg bw/day showed a reduction in alkaline phosphatase. Females treated with 1000 mg/kg bw/day showed an increase in albumin. All of the individual values were within the normal background range for these parameters. Males from all treatment groups showed an increase in creatinine however a true dose related response was not evident and the majority of individual values were within the normal background range for this parameter. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Behavioral Assessments
Weekly open field arena observations did not reveal any treatment-related effects for treated animals when compared to controls. All inter and intra group differences in behavioural scores were considered to be a result of normal variation for rats of the strain and age used, and the differences were of no toxicological importance.
Functional Performance Tests
There were no toxicologically significant changes in functional performance. Males from all treatment groups showed a statistically significant increase (p<0.05) in mean forelimb grip strength whilst females from all treatment groups showed a statistically significant (p<0.05) reduction in overall activity. The intergroup differences for males were confined to one out of the three tests and in the absence of a true dose related response in either sex was considered not to be of toxicological importance. Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in overall activity. In the absence of any associated clinical signs to suggest a neurotoxic effectthe intergroup difference was considered not to be of toxicological importance.
Sensory Reactivity Assessments
There were no treatment-related changes in sensory reactivity. - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Stomach
Epithelial hyperplasia in the forestomach was evident in four out of the five males examined and in three out of the five females examined at 1000 mg/kg bw/day. Of the affected animals, two males and two females had minimal severity, two males had moderate severity and one female had slight severity. These findings detected in the forestomach were consistent with local irritation. Humans do not have a rat forestomach counterpart therefore the macroscopic stomach changes detected have limited relevance to human toxicity. No such effects were detected in animals of either sex treated with 300 or 100 mg/kg bw/day. - Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating
There were no treatment-related effects on mating performance.
Fertility
No treatment-related effects on fertility were detected for treated animals, when compared to controls. One control female and one female treated with 100 mg/kg bw/day did not achieve pregnancy following evidence of mating. No histopathological correlates were evident in the reproductive organs for these animals and in the absence of any similar infertility effects detected at 1000 mg/kg bw/day the intergroup differences were considered not to be related to test item toxicity.
Gestation Length
There were no differences in gestation lengths. The distribution for treated females was comparable to controls. The gestation lengths were between 22 and 23½ days.
Details on results (P0)
Animals of either sex treated with 1000 mg/kg bw/day showed increased salivation from Day 1 (males) and Day 3 (females) onwards. Males treated with 300 mg/kg bw/day also showed episodes of increased salivation between days 16 and 29. No such effects were detected infemales treated with 300 mg/kg bw/day or animals of either sex treated with 100 mg/kg bw/day. One male treated with 1000 mg/kg bw/day, one female treated with 1000 mg/kg bw/day and three control females had generalised fur loss during the treatment period. Observations of this nature are commonly observed ingroup housed animals and is considered not to be of toxicological significance.
Water Consumption
Animals of either sex treated with 1000 mg/kg bw/day showed an increase in overall water consumed when compared to the control group.
Hematology
No toxicologically significant effects were detected in the haematological parameters examined.
The following intergroup differences were detected however they were considered not to be toxicologically significant. Females treated with 1000 mg/kg bw/day showed an increase in hemoglobin levels whilst males from this treatment group showed a reduction in activated partial thromboplastin time. The majority of individual values were within the normal background range for these parameters. Females from all treatment groups showed an increase in erythrocyte count however a true dose related response was not evident and all of the individual values were within the normal background range for this parameter.
Clinical Biochemistry
No toxicologically significant effects were detected in the blood chemical parameters examined.
The following intergroup differences were detected however they were considered not to be toxicologically significant. Males treated with 1000 and 300 mg/kg bw/day showed a reduction in alkaline phosphatase. Females treated with 1000 mg/kg bw/day showed an increase in albumin. All of the individual values werewithin the normal background range for these parameters. Males from all treatment groups showed an increase in creatinine however a true dose related response was not evident and the majority of individual values were within the normal background range for this parameter.
Behavior: Functional Performance Tests
There were no toxicologically significant changes in functional performance. Males from all treatment groups showed a statistically significant increase (p<0.05) in mean forelimb grip strength whilst females from all treatment groups showed a statistically significant
(p<0.05) reduction in overall activity. The intergroup differences for males were confined to one out of the three tests and in the absence of a true dose related response in either sex was considered not to be of toxicological importance. Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in overall activity. In the absence of any associated clinical signs to suggest a neurotoxic effectthe intergroup difference was considered not to be of toxicological importance.
Organ Weights
No toxicologically significant effects weredetected in the organ weights measured.
Males treated with 1000 mg/kg bw/day showed an increase in liver and kidney weight both absolute and relative to terminal body weight. Males from all treatment groups also showed an increase in absolute and relative adrenal weight. Females treated with 1000 mg/kg bw/day showed an increase in absolute and relative thyroid weight. The majorityof individual values for adrenal, kidney and thyroid weights were within the normal background ranges. Although the majority of liver weights were outside the background range, in the absence of any associated histology correlates all the intergroup differenceswere considered not to be of toxicological significance.
Necropsy
One female treated with 1000 mg/kg bw/day had a thickened stomach at necropsy. This female showed epithelial hyperplasia in the stomach at microscopic examination.
No such effects were detected in males treated with 1000 mg/kg bw/day or animals of either sex treated with 300 or 100 mg/kg bw/day.
One male treated with 1000 mg/kg bw/day had enlarged and mottled kidneys. One female treated with 300 mg/kg bw/day had reddened lungs atnecropsy. In the absence of any histology correlates, the intergroup differences were considered not to beof toxicological importance.
Histopathology
Stomach - Epithelial hyperplasia in the forestomach was evident in four out of the five males examined and in three out of the five females examined at 1000 mg/kg bw/day. Of the affected animals, two males and two females had minimal severity, two males had moderate severity and one female had slight severity. These findings detected in the forestomach were consistent with local irritation. No such effects were detected in animals of either sex treated with 300 or 100 mg/kg bw/day.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- systemic toxicity
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on irritant effects in the fore stomach
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The findings were not considered to reflect true systemic toxicity
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- reproductive toxicity
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No reproductive effects at 1000 mg/kg/day
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No obvious clinical signs of toxicity were detected for offspring from treated females when compared to controls. The incidental clinicalsigns detected throughout the control and treated groups, consisting of small size, no milk in stomach, a physical injury, found dead or missing, were considered to be low incidence findings observed in offspring in studies of this type and were considered unrelated to test item toxicity.
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects detected.
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects detected.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects detected.
- Histopathological findings:
- not examined
Details on results (F1)
No significant differences were detected for corpora lutea, implantation counts, implantation losses, litter size or litter viability for treated animals when compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences.
OFFSPRING GROWTH and DEVELOPMENT
There were no treatment related effects detected. No obvious clinical signs of toxicity were detected for offspring from treated females when compared to controls. The incidental clinical signs detected throughout the control and treated groups, consisting of small size, no milk in stomach, a physical injury, found dead or missing, were considered to be low incidence findings observed in offspring in studies of this type and were considered unrelated to test item toxicity.
NECROPSY
No treatment-related macroscopic abnormalities were detected for interim death or terminal kill offspring. The incidental findings observed were those occasionally observed in reproductive studies of this type and were considered to be unrelated to toxicity of the test item.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No Developmental effects seen at 1000 mg/Kg/day
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Table 1. Summary of Reproductive Performance - Groups Values |
||||
|
Dose Group (mg/kg bw/day |
|||
0 (Control) |
100 |
300 |
1000 |
|
Males |
|
|||
Initial group size |
12 |
12 |
12 |
12 |
Paired |
12 |
12 |
12 |
12 |
Failed to induce pregnancy in female partner |
1 |
1 |
0 |
0 |
Induced pregnancy in female partner |
12 |
12 |
12 |
12 |
Surviving to terminal necropsy |
12 |
12 |
12 |
12 |
|
||||
Females |
|
|||
Initial group size |
12 |
12 |
12 |
12 |
Paired |
12 |
12 |
12 |
12 |
Total litter loss |
0 |
0 |
0 |
2 |
Non-pregnant |
1 |
1 |
0 |
0 |
Rearing young to Day 5 of age |
11 |
11 |
12 |
10 |
Table 2. Group Mean Functional Test Values and Standard Deviations - Males |
|||||||||||
Group (sex) |
|
Test 1 Forelimb (g) |
Test 1 Hindlimb (g) |
Test 2 Forelimb (g) |
Test 2 Hindlimb (g) |
Test 3 Forelimb (g) |
Test 3 Hindlimb (g) |
Overall Activity |
Overall Mobile |
Last 20% Activity |
Last 20% Mobile |
1 (M) |
Mean |
853.0 |
408.6 |
536.8 |
281.6 |
783.2 |
377.6 |
383.2 |
0.4 |
19.4 |
0.2n |
S.D. |
168.8 |
91.6 |
191.1 |
86.5 |
264.2 |
116.1 |
157.6 |
0.5 |
24.5 |
0.4 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
2 (M) |
Mean |
909.8 |
436.0 |
934.8* |
505.2 |
925.8 |
515.8 |
367.2 |
0.8 |
2.4 |
0.0n |
S.D. |
149.8 |
109.3 |
251.6 |
132.7 |
223.0 |
218.8 |
85.5 |
1.3 |
2.9 |
0.0 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
3 (M) |
Mean |
964.0 |
349.8 |
824.6* |
482.6 |
950.6 |
560.0 |
285.0 |
1.0 |
11.6 |
0.0n |
S.D. |
227.4 |
102.7 |
198.9 |
223.2 |
154.9 |
145.4 |
94.1 |
1.4 |
24.8 |
0.0 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
4 (M) |
Mean |
887.4 |
375.4 |
795.0* |
425.4 |
815.4 |
442.0 |
220.6* |
0.2 |
31.2 |
0.0n |
S.D. |
176.1 |
101.9 |
162.0 |
137.3 |
143.9 |
54.6 |
106.1 |
0.4 |
57.7 |
0.0 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
General Footnote: Unit = Time (seconds) for Motor Activity Assessments
Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day
* Significantly different from control group p<0.05
n Data not appropriate for statistical analysis
Table 3. Group Mean Functional Test Values and Standard Deviations - Females |
|||||||||||
Group (sex) |
|
Test 1 Forelimb (g) |
Test 1 Hindlimb (g) |
Test 2 Forelimb (g) |
Test 2 Hindlimb (g) |
Test 3 Forelimb (g) |
Test 3 Hindlimb (g) |
Overall Activity |
Overall Mobile |
Last 20% Activity |
Last 20% Mobile |
1 (F) |
Mean |
847.8 |
478.0 |
960.0 |
502.6 |
877.4 |
450.8 |
693.2 |
5.2 |
77.4 |
1.2n |
S.D. |
163.5 |
131.8 |
87.0 |
139.4 |
132.6 |
87.1 |
149.6 |
4.3 |
49.3 |
1.8 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
2 (F) |
Mean |
859.8 |
468.6 |
745.0 |
422.4 |
748.0 |
476.6 |
513.2* |
5.2 |
87.2 |
1.8n |
S.D. |
148.0 |
153.0 |
220.6 |
154.4 |
201.0 |
98.7 |
45.0 |
3.0 |
73.5 |
2.2 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
3 (F) |
Mean |
803.4 |
383.4 |
679.2 |
309.2 |
827.8 |
369.0 |
586.2* |
4.2 |
67.6 |
0.4n |
S.D. |
220.7 |
126.6 |
99.9 |
73.8 |
262.4 |
99.3 |
77.7 |
3.8 |
62.1 |
0.9 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
|
|||||||||||
4 (F) |
Mean |
809.8 |
463.2 |
763.8 |
405.2 |
718.8 |
377.2 |
519.8* |
3.4 |
69.0 |
0.0n |
S.D. |
184.3 |
96.5 |
252.6 |
118.8 |
191.1 |
120.5 |
115.5 |
1.5 |
74.1 |
0.0 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
General Footnote: Unit = Time (seconds) for Motor Activity Assessments
Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day
* Significantly different from control group p<0.05
n Data not appropriate for statistical analysis
Table 4. Group Mean Hematological Values - Males |
||
Group |
|
APTT (Seconds) |
Group 1 (0 – Control) |
Mean |
16.14 |
S.D. |
0.79 |
|
N |
10 |
|
|
||
Group 2 (100 mg/Kg bw/day) |
Mean |
15.50 |
S.D. |
2.21 |
|
N |
10 |
|
|
||
Group 3 (300 mg/Kg bw/day) |
Mean |
14.26 |
S.D. |
2.71 |
|
N |
10 |
|
|
||
Group 4 (1000 mg/Kg bw/day) |
Mean |
13.04* |
S.D. |
1.38 |
|
N |
10 |
* Significantly different from control group p<0.05
Table 5. Group Mean Hematological Values - Females |
|||
Group |
|
Hb (g/dL) |
RBC (1012/L) |
Group 1 (0 – Control) |
Mean |
12.76 |
6.778 |
S.D. |
0.38 |
0.318 |
|
N |
5 |
5 |
|
|
|||
Group 2 (100 mg/Kg bw/day) |
Mean |
13.26 |
7.344* |
S.D. |
0.53 |
0.383 |
|
N |
5 |
5 |
|
|
|||
Group 3 (300 mg/Kg bw/day) |
Mean |
13.28 |
7.212* |
S.D. |
0.96 |
0.426 |
|
N |
5 |
5 |
|
|
|||
Group 4 (1000 mg/Kg bw/day) |
Mean |
13.66* |
7.278* |
S.D. |
0.48 |
0.272 |
|
N |
5 |
5 |
* Significantly different from control group p<0.05
Table 6. Group Mean Blood Chemical Values - Males |
|||
Group (sex) |
|
AP (IU/L) |
Creat (mg/dL) |
Group 1 (0 – Control) |
Mean |
244.2 |
0.660 |
S.D. |
77.3 |
0.046 |
|
N |
5 |
5 |
|
|
|||
Group 2 (100 mg/Kg bw/day) |
Mean |
212.6 |
0.756* |
S.D. |
48.5 |
0.071 |
|
N |
5 |
5 |
|
|
|||
Group 3 (300 mg/Kg bw/day) |
Mean |
166.4* |
0.888* |
S.D. |
44.4 |
0.288 |
|
N |
5 |
5 |
|
|
|||
Group 4 (1000 mg/Kg bw/day) |
Mean |
131.0** |
0.714* |
S.D. |
42.3 |
0.043 |
|
N |
5 |
5 |
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
Table 7. Group Mean Blood Chemical Values - Females |
||
Group |
|
Albumin (g/dL) |
Group 1 (0 – Control) |
Mean |
3.38 |
S.D. |
0.19 |
|
N |
5 |
|
|
||
Group 2 (100 mg/Kg bw/day) |
Mean |
3.06 |
S.D. |
0.96 |
|
N |
5 |
|
|
||
Group 3 (300 mg/Kg bw/day) |
Mean |
3.66 |
S.D. |
0.15 |
|
N |
5 |
|
|
||
Group 4 (1000 mg/Kg bw/day) |
Mean |
3.76* |
S.D. |
0.23 |
|
N |
5 |
* Significantly different from control group p<0.05
Table 8. Summary Incidence of Necropsy Findings - Males |
||||
|
Males |
|||
0 Control |
100 mg/Kg bw/day |
300 mg/Kg bw/day |
1000 mg/Kg bw/day |
|
Number of animals examined |
12 |
12 |
12 |
12 |
Kidneys |
|
|||
Submitted |
(12) |
(12) |
(12) |
(12) |
No Visible Lesions |
12 |
12 |
12 |
11 |
Enlarged |
0 |
0 |
0 |
1 |
Mottled Appearance |
0 |
0 |
0 |
1 |
Table 9. Summary Incidence of Necropsy Findings - Females |
||||
|
Females |
|||
0 Control |
100 mg/Kg bw/day |
300 mg/Kg bw/day |
1000 mg/Kg bw/day |
|
Number of animals examined |
12 |
12 |
12 |
12 |
Lungs (With Bronchi) |
|
|||
Submitted |
(12) |
(12) |
(12) |
(12) |
No Visible Lesions |
12 |
10 |
11 |
12 |
Reddened |
0 |
2 |
1 |
0 |
|
||||
Stomach |
|
|||
Submitted |
(12) |
(12) |
(12) |
(12) |
No Visible Lesions |
12 |
12 |
12 |
11 |
Thickened |
0 |
0 |
0 |
1 |
Table 10. Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights |
|||||||||
|
|
Males |
Females |
||||||
0 Control |
100 mg/Kg bw/day |
300 mg/Kg bw/day |
1000 mg/Kg bw/day |
0 Control |
100 mg/Kg bw/day |
300 mg/Kg bw/day |
1000 mg/Kg bw/day |
||
Adrenals |
Mean (g) |
0.05670 |
0.07550* |
0.07714* |
0.07736* |
|
|
|
|
S.D. |
0.00630 |
0.01491 |
0.01091 |
0.01645 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Mean (%) |
0.014 |
0.018* |
0.019* |
0.019* |
|
|
|
|
|
S.D. |
0.002 |
0.003 |
0.003 |
0.003 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Kidneys |
Mean (g) |
2.31488 |
2.37080 |
2.51686 |
2.69416* |
|
|
|
|
S.D. |
0.26047 |
0.24924 |
0.17059 |
0.26830 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Mean (%) |
0.569 |
0.583 |
0.602 |
0.656* |
|
|
|
|
|
S.D. |
0.031 |
0.088 |
0.041 |
0.074 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Liver |
Mean (g) |
13.0518 |
12.8470 |
13.4033 |
15.5767** |
|
|
|
|
S.D. |
1.62501 |
0.47524 |
1.39447 |
0.31896 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Mean (%) |
3.205 |
3.151 |
3.196 |
3.792** |
|
|
|
|
|
S.D. |
0.266 |
0.215 |
0.211 |
0.209 |
|
|
|
|
|
N |
5 |
5 |
5 |
5 |
|
|
|
|
|
|
|||||||||
Thyroid/Parathyroid |
Mean (g) |
|
|
|
|
0.01646 |
0.01892 |
0.01566 |
0.02124** |
S.D. |
|
|
|
|
0.00178 |
0.00255 |
0.00217 |
0.00313 |
|
N |
|
|
|
|
5 |
5 |
5 |
5 |
|
|
|||||||||
Mean (%) |
|
|
|
|
0.006 |
0.007 |
0.006 |
0.008** |
|
S.D. |
|
|
|
|
0.001 |
0.001 |
0.001 |
0.002 |
|
N |
|
|
|
|
5 |
5 |
5 |
5 |
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
Table 11. Group Mean Implantation Losses and Survival Indices Values |
||||||
Group |
|
Pre-Implantation Loss (%) |
Post-Implantation Loss (%) |
Live Birth Index (%) |
Viability Index (%) |
|
Control (0 mg/Kg bw/day) |
Mean |
2.7 |
11.7 |
100.0 |
97.5 |
|
S.D. |
5.0 |
11.9 |
0.0 |
8.2 |
||
N |
11 |
11 |
11 |
11 |
||
|
||||||
100 mg/Kg bw/day |
Mean |
6.7 |
9.0 |
98.5 |
99.1 |
|
S.D. |
11.9 |
9.9 |
5.0 |
3.0 |
||
N |
11 |
11 |
11 |
11 |
||
|
||||||
300 mg/Kg bw/day |
Mean |
2.3 |
13.1 |
100.0 |
98.0 |
|
S.D. |
4.6 |
15.0 |
0.0 |
5.1 |
||
N |
12 |
12 |
12 |
12 |
||
|
||||||
1000 mg/Kg bw/day |
Mean |
5.5 |
6.5 |
99.3 |
95.4 |
|
S.D. |
17.2 |
7.7 |
2.1 |
7.1 |
||
N |
10 |
10 |
10 |
10 |
Applicant's summary and conclusion
- Conclusions:
- The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was considered to be 300 mg/kg bw/day, based on irritation in the forestomach at 1000 mg/kg/day. The NOAEL was however considered to be 1000 mg/kg bw/day because the findings were not evidence of true systemic toxicity. The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.
- Executive summary:
An Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422) was performed on the test material Oct-1 -ene CAS 111 -66 -0.
After eight weeks treatment clinical signs were detected in animals of either sex treated with 1000 mg/kg bw/day and in males treated with 300 mg/kg bw/day. Increased salivation was evident throughout the treatment period, but no alteration of the physical condition was observed. No difference between animals treated and controls were detected in body weight development and food consumption. In contrast, the water consumption was increased in animals of either sex treated with 1000 mg/kg bw/day. Increased salivation and increased water consumption might be related to unpalatability problems and irritancy of the stomach. Microscopic investigations of the stomachs showed epithelial hyperplasia in animals of either sex treated with 1000 mg/kg bw/day and thickening of the stomach in one female treated with 1000 mg/kg bw/day at necropsy. The findings are considered a result of local irritation rather than any adverse systemic toxicity of the test item. All parameters related to blood and chemistry examinations and reproductive system showed no treatment-related effects.
No significant differences were detected for corpora lutea, implantation counts, implantation losses, litter size or litter viability for treated animals when compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences
In view of these results, the NOAEL for systemic toxicity was considered to be 1000 mg/Kg bw/day. The 'No Observed Effect Level' (NOEL) for reproductive toxicity was considered to be 1000 mg/Kg bw/day.
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