Registration Dossier
Registration Dossier
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EC number: 618-143-8 | CAS number: 883233-93-0
Endpoint summary
Administrative data
Description of key information
Four read-across 28-day oral exposure
studies (OECD 407/422) and three 90-day oral exposure studies (OECD
408/OECD 415) were identified either within category or from a
structural analogue. There were no key dermal or inhalation repeated
dose studies identified.
Overall, the 28-day exposure studies found
no toxicity when the respective poly alpha olefins were administered
orally. Results were as follows.
· The NOAEL is 6245 mg/kg/day in male rats and 6771 mg/kg/day in female rats for the 28-day oral repeated dose study from 1-decene, homopolymer, hydrogenated.
· The NOAEL is 1000 mg/kg/day in male and female rats for the 28-day oral repeated dose study from 1-dodecene dimer with 1-decene, hydrogenated.
· The NOAEL is 1000 mg/kg/day in male and female rats for the 28-day oral repeated dose study from 1 -dodecene, trimer.
· The NOAEL is 1000 mg/kg/day in male and female rats for the 28-day oral repeated dose study from 1-dodecene, dimer.
For the 90-day oral exposure studies,
results were as follows.
• The NOAEL is 4145.4 mg/kg bw in male rats and 4619.9 mg/kg bw in
female rats for the 90-day exposure study from 1-decene, homopolymer,
hydrogenated.
• The NOAEL is 1000 mg/kg bw in male and female rats for the 91-day
exposure study from 1-decene, homopolymer, hydrogenated.
• The NOAEL is 1000 mg/kg bw in male and female rats for the 90-day
one-generation reproduction study with subchronic toxicity from 1
-dodecene, trimer.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2021-AUG-04 to TBD
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- July 2016
- Deviations:
- yes
- Remarks:
- None of the deviations impacted the overall integrity of the study or the interpretation of the study results and conclusions.
- Qualifier:
- according to guideline
- Guideline:
- other: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- July 2000
- Deviations:
- yes
- Remarks:
- None of the deviations impacted the overall integrity of the study or the interpretation of the study results and conclusions.
- GLP compliance:
- yes
- Limit test:
- yes
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: Higher Olefins & Poly Alpha Olefins vzw; Batch No. DBA0146456
- Purity, including information on contaminants, isomers, etc.: 100% (UVCB)
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: Stable in the vehicle when prepared and stored under the same conditions.
FORM AS APPLIED IN THE TEST (if different from that of starting material): Clear colourless liquid
OTHER SPECIFICS
- Expiration date: 2023-MARCH-01 - Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl: WI(Han)
- Details on species / strain selection:
- The Wistar Han rat was chosen as the animal model as it is an accepted rodent species for toxicity testing by regulatory agencies. The CRO (Charles River Den Bosch) has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland (Sulzfeld, Germany)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Males: 10-11 weeks old (at dosing); Females: 13-14 weeks old (at dosing)
- Weight at study initiation: Males: 281 to 345 grams; Females: 204 to 247 grams
- Fasting period before study: Not specified
- Housing:
On arrival; during the pretest (females only); and pre-mating period: animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon, MIV type, height 18 cm).
Mating phase: males and females were cohabitated on a 1:1 basis in Makrolon plastic cages (MIII type, height 18 cm).
Post-mating phase: males were housed in their home cage (Makrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 males/cage. Females were individually housed in Makrolon plastic cages (MIII type, height 18 cm).
Lactation phase: females were housed in Makrolon plastic cages (MIII type, height 18 cm). Pups were housed with the dam, except during locomotor activity monitoring of the dams.
Locomotor activity monitoring: F0-animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cage-enrichment, bedding material, food and water.
- Diet (e.g. ad libitum): SM R/M-Z pelleted diest (SSNIFF® Spezialdiäten GmbH, Soest, Germany) ad libitum except during designated procedures. During motor activity measurements, animals did not have access to food for a maximum of 2 hours.
- Water (e.g. ad libitum): Municipal tap water via water bottles. During motor activity measurements, animals did not have access to water for a maximum of 2 hours.
- Acclimation period: 8 days prior to start of the pretest period (females) or 8 days before the commencement of dosing (males).
DETAILS OF FOOD AND WATER QUALITY: Analysis for nutritional components and environmental contaminants were provided by the supplier. It was considered that there were no known contaminants in the feed that would interfere with the objectives of the study. Periodic analysis of the water was performed it was considered that there were no known contaminants in the water that could interfere with the outcome of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C to 22°C
- Humidity (%): 32% to 57%
- Air changes (per hr): Ten or more air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 2021-SEP-29 To: 2021-DEC-24 - Route of administration:
- oral: gavage
- Details on route of administration:
- The oral route of exposure was selected because this is the intended route of human exposure this is a possible route of human exposure during manufacture, handling or use of the test material.
- Vehicle:
- corn oil
- Remarks:
- Sigma-Aldrich (Steinheim, Germany)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared weekly and formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. Dosing formulations were filled out in daily portions and stored in the refrigerator protected from light. The dosing formulations were removed from the refrigerator, stirred at room temperature for at least 30 minutes before dosing and dosed within 24 hours after removal. Dosing formulations were kept at room temperature until dosing and continuously stirred until and during dosing. Adjustment was made for specific gravity of the vehicle and test material. No correction was made for the purity/composition of the test material.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil; Corn oil selected based on trial preparations were performed to select the suitable vehicle and to establish a suitable formulation procedure. These trials were not performed as part of this study and were not used for dosing.
- Concentration in vehicle: 0, 25, 75, or 250 mg/mL for the control, 100, 300, and 1000 mg/kg/day dose groups, respectively
- Amount of vehicle (if gavage): 4 mL/kg
- Lot/batch no. (if required): Not specified
- Purity: Not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulation samples (duplicate) were collected for analysis as follows: Concentration analysis - week 1 of treatment; sample collected from approximately middle of dosing container for all dose groups; Homogeneity analysis - week 1 of treatment; sample collected from approximately top, middle, and bottom of the dosing container for dose groups 2 (100 mg/kg/day) and 4 (1000 mg/kg/day). Samples to be analyzed were transferred at room temperature under normal laboratory light conditions to the analytical laboratory and analyses were performed using a validated analytical procedure (Test Facility Study No. 20296615).
Concentration analysis: Temperature was set to maintain 18 - 22°C and the acceptance criteria set as: mean sample concentration results within or equal to ± 15% of theoretical concentration.
Homogeneity analysis: Temperature was set to maintain 18 - 22°C and the acceptance criteria set as: relative standard deviation (RSD) of concentrations of ≤10% for each dose group.
Stability analysis: Stability analyses was performed previously in conjunction with the method development and validation study (Test Facility Study No. 20296615) and demonstrated that the test material was stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study. - Duration of treatment / exposure:
- Males: 7 days a week for a minimum of 28 days, including at least 2 weeks of treatment prior to mating and during the mating period up to and including the day before scheduled necropsy.
Females: 7 days a week for at least 14 days prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy. - Frequency of treatment:
- Once daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1 - Control (corn oil)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Group 2 - Low dose
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Group 3 - Intermediate dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4 - High dose
- No. of animals per sex per dose:
- 10/sex/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose levels were selected based on the results of a 10 Day Dose Range Finder (DRF) with oral administration of 1-Dodecene, dimers in rats (Test Facility Reference No. 20296616) and in an attempt to produce graded responses to the test material.
- Rationale for animal assignment: Animals were randomly assigned to groups at arrival. Males and females were randomized separately.
- Fasting period before blood sampling for clinical biochemistry: F0-males: Yes (overnight with a maximum of 24 hours); F0-females: No
- Dose range finding studies:
A Dose Range Finder (DRF) (Test Facility Reference No. 20296616) was conducted to select dose levels for the Main study (Test Facility Study No. 20286618), and to determine the peak effect of occurrence of clinical signs after dosing. For the DRF, all animal activities and necropsy were performed
The test material with vehicle was administered to the appropriate animals by once daily oral gavage for 10 consecutive days at dose levels of 600 or 1000 mg/kg/day. Based on the results of the DRF, dose levels selected for the Main study were 100, 300 and 1000 mg/kg/day.
Since no clinical signs were observed in the DRF, clinical observations were conducted and functional observations were started in the Main study after dosing at no specific time point, but within a similar time period after dosing for the respective animals. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day (except on days of receipt and necropsy where frequency was at least once daily). Arena observations were conducted once before the first administration of the test material and weekly during the Treatment Period.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily, beginning during the first administration of the test material and lasting throughout the Dosing Periods up to the day prior to necropsy. During the Dosing Period, observations were performed after dosing at no specific time point, but within a similar time period after dosing for the respective animals.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights of all animals were recorded on Day 1 of treatment (prior to dosing) and weekly thereafter.
Mated females: on Days 0, 4, 7, 11, 14, 17, and 20 post coitum and during lactation on PND 1, 4, 7, and 13.
A terminal weight was recorded on the day of scheduled necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Mated females: on Days 0, 4, 7, 11, 14, 17, and 20 post coitum and during lactation on PND 1, 4, 7, and 13
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: On a regular basis throughout the study by visual inspection of the water bottles. However, no quantitative investigation was introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On the day of scheduled necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (F0-males: fasted overnight with a maximum of 24 hours; F0-females: No)
- How many animals: Selected F0-animals (5/sex/group)
- Parameters checked in table [No.2] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On the day of scheduled necropsy
- Animals fasted: Yes (F0-males: fasted overnight with a maximum of 24 hours; F0-females: No)
- How many animals: Selected F0-animals (5/sex/group)
- Parameters checked in table [No.3] were examined.
SERUM HORMONES: Yes
- Time of blood sample collection: On the day of scheduled necropsy
- Animals fasted: Yes Yes (F0-males: fasted overnight with a maximum of 24 hours; F0-females: No)
- How many animals: Selected F0-animals (5/sex/group)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Males: Week 4 of treatment; Females: last week of lactation (PND 6-13)
- Dose groups that were examined: All dose groups
- Battery of functions tested: Hearing ability; Pupillary reflex; Static righting reflex; Fore- and hind-limb grip strength; Locomotor activity
IMMUNOLOGY: No
OTHER:
COAGULATION
Blood samples were processed for plasma, and plasma was analyzed for Prothrombin time (PT) and Activated partial thromboplastin time (APTT). - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see Table 4 and 5)
Unscheduled Deaths/Euthanasia
Females with total litter loss (No. 78) were weighed and deeply anesthetized using isoflurane and subsequently exsanguinated within 24 hours after the last pup was found dead or missing. They underwent necropsy, and specified tissues were retained and weighed.
Scheduled Euthanasia
Animals surviving until scheduled euthanasia (Males: after a minimum of 28 days of administration ; Females: PND 14-16, or after total litter loss, or failure to deliver) were weighed, and deeply anesthetized using isoflurane and subsequently exsanguinated and subjected to a full post mortem examination. Scheduled necropsies were conducted as follows:
- Males (which sired or failed to sire): Following completion of the mating period (a minimum of 28 days of administration).
- Females which delivered: PND 14-16.
- Females which failed to deliver: With evidence of mating (No. 56): Day 25 post-coitum.
- Without evidence of mating (No. 68): 25 days after the last day of the mating period.
All males surviving to scheduled necropsy were fasted overnight (water was available) for approximately 24 hours before necropsy. F0 females were not fasted.
Organ Weights – F0 Generation
The organs identified in the tables 5 and 6 were weighed at necropsy for all scheduled euthanasia animals and females with total litter loss. Organ weights were not recorded for animals euthanized in poor condition or in extremis. Paired organs were weighed together. In the event of gross abnormalities, in addition to the combined weight, the weight of the aberrant organ was taken and recorded in the raw data. Organ to body weight ratios (using the terminal body weight) were calculated.
HISTOPATHOLOGY: Yes (see Table 7 and 8)
Histopathology: F0 Generation
Representative samples of the tissues identified in table 7 and 8 below were collected from all animals and preserved in 10% neutral buffered formalin (neutral phosphate buffered 4% formaldehyde solution, Klinipath, Duiven, The Netherlands).
The following tissues were embedded in paraffin, sectioned, mounted on glass slides, and stained with hematoxylin and eosin:
- Selected animals and unscheduled deaths (sacrificed in extremis): Tissues identified in Table 7 (except animal identification, aorta, nasopharynx, esophagus, harderian gland, lacrimal gland, salivary gland, larynx, optic nerve, pancreas, skin and tongue).
- Males that failed to sire, females that failed to deliver pups and females with total litter loss: Cervix, epididymis, coagulation gland, prostate gland, seminal vesicles, ovaries, testes, uterus and vagina.
- Females with total litter loss: Mammary gland
- Remaining animals: Gross lesions/masses.
For the testes of all selected males of Groups 1 and 4 and all males that failed to sire, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle. - Statistics:
- For information on statistics please see 'Any other information on materials and methods incl. tables'.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical signs were observed either during daily detailed clinical or during the weekly arena observations.
Incidental findings observed included scabs, wounds, and alopecia. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were not considered to be treatment-related. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No treatment-related mortality was observed in the F0 animals.
One control female (No. 43) was sacrificed in extremis on Day 23 post coitum. The female had a pale appearance and piloerection and at the point 3 pups were born of which 1 was alive and 2 were found dead. As no more pups were born and the condition of the animal deteriorated, the animal was sacrificed in extremis. At necropsy, the uterus of this female contained 3 alive and 5 dead fetuses. No other macroscopic or microscopic findings were observed. Based on this, the condition of this female was considered to be related to delivery difficulties.
One female in the 100 mg/kg/day (No. 60) dose group was sacrificed in extremis on Day 1 of lactation. The animal was found with a pale appearance and piloerection. Due to the deteriorating condition of this animal, it was sacrificed in extremis. Additionally, all 11 delivered pups were found to be dead. At necropsy, a pale liver was observed corresponding to microscopic moderate multifocal necrosis in the liver which likely contributed to the moribundity. Based on the single incidence of this event in the low dose group, the condition of this animal was not considered to be treatment-related. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weights and body weight gain were considered to be unaffected by treatment.
Females at 1000 mg/kg/day displayed slightly lower (6% lower than control) absolute body weight on Day 4 of lactation was. As body weight gain was similar over this period and as this was only an incidental occurrence, this temporary lower body weight was not considered to be treatment-related. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption before or after correction for body weight was not affected by treatment.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Description (incidence and severity):
- Water consumption was monitored on a regular basis throughout the study by visual inspection of the water bottles. However, no quantitative investigation was introduced as no effect was suspected.
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Hematological parameters of rats were unaffected by treatment.
A reduction of large unstained cell (LUC) counts was observed in male rats at 300 mg/kg/day. However, in the absence of a dose-related trend, this was considered to be unrelated to treatment.
Coagulation parameters of rats were unaffected by treatment. A shorter prothrombin time (PT) observed in male rats at 100 mg/kg/day was considered to be unrelated to treatment in the absence of a dose-related trend. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical chemistry parameters of male rats were unaffected by treatment. In female rats, a reduction in total bilirubin levels (TBIL) was observed at 100, 300, and 1000 mg/kg/day (0.69x, 0.71x and 0.66x of control, respectively). In the absence of corroborative histopathological findings, this was considered not adverse. Increased sodium levels were observed in female rats at 300 mg/kg/day but this considered to be minor and in the absence of a dose-related trend, unrelated to treatment.
- Endocrine findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Serum levels of thyroxine (T4) and thyroid-stimulating hormone (TSH) in male and female rats were unaffected by treatment.
Serum total triiodothyronine (T3) levels in F0 males at 100 mg/kg/day were increased (Group mean values were 1.29x of control; however, an increase in the SD was also observed). Mean values were within the historical control data range and values at 300 mg/kg/day and 1000 mg/kg/day were comparable with the control group. Therefore, although treatment-related, this increase was not considered as adverse.
Serum total T3 levels were increased in F0 females at 1000 mg/kg/day (1.26x of control). No historical control data for total T3 in lactating females was available at the Testing Facility. However, since only 1/10 individual females displayed a T3 value above the highest individual control value, the mean increase of T3 at 1000 mg/kg/day was considered unrelated to treatment. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Hearing ability, pupillary reflex, static righting reflex and grip strength of the fore legs (males and females), and motor activity (females only) were considered unaffected by treatment at 100 and 300 mg/kg/day.
Females at 1000 mg/kg/day displayed decreased grip strength of the hind legs (0.63x of control). In the absence of clinical signs and corroborative histopathological findings, this was not considered as adverse.
An apparent upward trend in motor activity (total movements and ambulations) observed in male rats of all treatment groups was considered to have arisen as a result of slightly low control values and therefore not considered treatment-related.
All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related effects or alterations in organ weights were observed. Any differences, including those that reached statistical significance (males; heart at 100 mg/kg/day (absolute and relative to body weight) and 1000 mg/kg/day (absolute only); liver at 1000 mg/kg/day (absolute only)), were not considered to be treatment-related due to the direction of the change and/or a lack of dose-related trend.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross necropsy did not reveal any remarkable treatment-related findings.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Histopathology did not reveal any microscopic observations related to treatment with the test material. All of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no treatment-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Systemic Toxicity
- Key result
- Critical effects observed:
- no
- Conclusions:
- Based on the lack of adverse treatment-related effects observed through the study period, the systemic toxicity No Observed Adverse Effect Level (NOAEL) for 1-Dodecene, dimers was determined to be≥1000 mg/kg/day in the rat.
- Executive summary:
A key OECD Guideline 422 combined 28-Day repeated dose toxicity study with the Reproduction / Developmental Toxicity Screening Test was conducted to evaluate the potential toxic effects of the test material (1-Dodecene, dimers; CAS# 62132-67-6) when given orally to Wistar Han rats.
The test material Wistar Han rats (10/sex/dose) were administered once daily via oral gavage in a corn oil vehicle at doses of 0, 100, 300, or 1000 mg/kg/day for a minimum of 28 days for males (including at least 2 weeks of treatment prior to mating and during the mating period up to and including the day before scheduled necropsy). Female rats were dosed 7 days a week for at least 14 days prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy.
Parameters were evaluated in this study included mortality/ moribundity, clinical signs, functional observations, body weight and food consumption, clinical pathology, measurement of thyroid hormones T3, T4 and TSH (F0 males and females), gross necropsy findings, organ weights and histopathologic examinations.
No treatment-related mortality was observed in the F0 animals.
One control female (No. 43) was sacrificed in extremis on Day 23 post coitum. The female had a pale appearance and piloerection and at the point 3 pups were born of which 1 was alive and 2 were found dead. As no more pups were born and the condition of the animal deteriorated, the animal was sacrificed in extremis. At necropsy, the uterus of this female contained 3 alive and 5 dead fetuses. No other macroscopic or microscopic findings were observed. Based on this, the condition of this female was considered to be related to delivery difficulties.
One female in the 100 mg/kg/day (No. 60) dose group was sacrificedin extremison Day 1 of lactation. The animal was found with a pale appearance and piloerection. Due to the deteriorating condition of this animal, it was sacrificedin extremis. Additionally, all 11 delivered pups were found to be dead. At necropsy, a pale liver was observed corresponding to microscopic moderate multifocal necrosis in the liver which likely contributed to the moribundity. Based on the single incidence of this event in the low dose group, the condition of this animal was not considered to be treatment-related.
No treatment-related clinical signs were observed either during daily detailed clinical or during the weekly arena observations.
Incidental findings observed included scabs, wounds, and alopecia. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were not considered to be treatment-related.
Body weights and body weight gain were considered to be unaffected by treatment. Females at 1000 mg/kg/day displayed slightly lower (6% lower than control) absolute body weight on Day 4 of lactation was. As body weight gain was similar over this period and as this was only an incidental occurrence, this temporary lower body weight was not considered to be treatment-related.
Food consumption before or after correction for body weight was not affected by treatment.
Hearing ability, pupillary reflex, static righting reflex and grip strength of the fore legs (males and females), and motor activity (females only) were considered unaffected by treatment at 100 and 300 mg/kg/day.
Females at 1000 mg/kg/day displayed decreased grip strength of the hind legs (0.63x of control).In the absence of clinical signs and corroborative histopathological findings, this was not considered as adverse.
An apparent upward trend in motor activity (total movements and ambulations) observed in male rats of all treatment groups was considered to have arisen as a result of slightly low control values and therefore not considered treatment-related.
All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period.
Hematological parameters of rats were unaffected by treatment. A reduction of large unstained cell (LUC) counts was observed in male rats at 300 mg/kg/day. However, in the absence of a dose-related trend, this was considered to be unrelated to treatment.
Coagulation parameters of rats were unaffected by treatment. A shorter prothrombin time (PT) observed in male rats at 100 mg/kg/day was considered to be unrelated to treatment in the absence of a dose-related trend.
Clinical chemistry parameters of male rats were unaffected by treatment. In female rats, a reduction in total bilirubin levels (TBIL) was observed at 100, 300, and 1000 mg/kg/day (0.69x, 0.71x and 0.66x of control, respectively). In the absence of corroborative histopathological findings, this was considered not adverse. Increased sodium levels were observed in female rats at 300 mg/kg/day but this considered to be minor and in the absence of a dose-related trend, unrelated to treatment.
Serum levels of thyroxine (T4) and thyroid-stimulating hormone (TSH) in male and female rats were unaffected by treatment.
Serum total triiodothyronine (T3) levels in F0 males at 100 mg/kg/day were increased (Group mean values were 1.29x of control; however, an increase in the SD was also observed). Mean values were within the historical control data range and values at 300 mg/kg/day and 1000 mg/kg/day were comparable with the control group. Therefore, although treatment-related, this increase was not considered as adverse.
Serum total T3 levels were increased in F0 females at 1000 mg/kg/day (1.26x of control). No historical control data for total T3 in lactating females was available at the Testing Facility. However, since only 1/10 individual females displayed a T3 value above the highest individual control value, the mean increase of T3 at 1000 mg/kg/day was considered unrelated to treatment.
Gross necropsy did not reveal any remarkable treatment-related findings and no treatment-related effects or alterations in organ weights were observed. Any differences, including those that reached statistical significance (males; heart at 100 mg/kg/day (absolute and relative to body weight) and 1000 mg/kg/day (absolute only); liver at 1000 mg/kg/day (absolute only)), were not considered to be treatment-related due to the direction of the change and/or a lack of dose-related trend.
Histopathology did not reveal any microscopic observations related to treatment with the test material. All of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no treatment-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Based on the lack of adverse treatment-related effects observed through the study period, the systemic toxicity No Observed Adverse Effect Level (NOAEL) for 1-Dodecene, dimers was determined to be≥1000 mg/kg/day in the rat.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1989-03-08 to 1989-06-15
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restrictions because it closely followed OECD 407 guidelines and was GLP compliant.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories (Portage, Michigan)
- Age at study initiation: 41 days old
- Weight at study initiation: Males: 161 to 204 grams; Females: 133 to 169 grams
- Housing: Individually in hanging stainless steel wire-bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23
- Humidity (%): 46 to 76%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light
IN-LIFE DATES: From:1989-04-06 To:1989-06-14 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Test compound was mixed weekly by weight per volume in peanut oil.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: Not reported
- Amount of vehicle (if gavage): Adjusted weekly to body weight
- Lot/batch no. (if required): Not reported
- Purity: Not reported - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were found to be stable and homogeneous. Doses were generally within 10% of the nominal concentration.
- Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0, 200, 500, or 1000 mg/kg/day
Basis:
other: nominal in oil - No. of animals per sex per dose:
- 6 animals per sex per dose
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Based on a pilot 2 week repeat dose toxicity study
- Rationale for selecting satellite groups: Not reported
- Post-exposure recovery period in satellite groups: 2 weeks - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included viability checks.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily for changes in skin, fur, eyes, mucus membrane, respiratory system, autonomic and central nervous system, somatomotor activity, and behavioural patterns; Pupil response was checked on day 0 and then weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, twice weekly, and once weekly during recovery period
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Terminal sacrifice
- Anaesthetic used for blood collection: Yes (sodium pentabarbitol)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in Table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Terminal sacrifice
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in Table 2 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: Overnight prior to study termination
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
- Parameters checked in Table 3 were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, included external surfaces; all orifices; the cranial, thoracic, and abdominal cavities
HISTOPATHOLOGY: Yes (see table 4) - Other examinations:
- The following organs were weighed: Brain, kidneys, adrenals, and testes/ovaries.
- Statistics:
- A one-way analysis of variance and Dunnett's test on continuous variables in the main study. An analysis of variance followed by a Student's t-test was used on the data from the recovery groups. Differential white blood cell counts were analysed using a non-parametric Kruskal Wallis ANOVA followed by Mann-Whitney U test.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Critical effects observed:
- not specified
- Conclusions:
- The test compound did not cause any toxicologically significant or treatment-related results. Therefore, the NOAEL is 1000 mg/kg/day.
- Executive summary:
In a repeated dose oral toxicity study, 1-Dodecene, dimer with 1-decene, hydrogenated was administered to 6 Sprague-Dawley rats/sex/dose at dose levels 0, 200, 500, or 1000 mg/kg bw/day for 29 days. A recovery group (6 rats), dosed with 0 or 1000 mg/kg/day of the test substance, was observed for two weeks post-dosing. Each animal was observed daily for toxicological changes one hour post-dosing. Blood analysis, urinalysis, and necropsies were conducted post-sacrifice. The test conditions complied with the guideline requirements for this study type and the statistical methods used were appropriate.
No mortality, compound-related systemic toxicity or pathological changes were observed in the study or recovery groups at the limit dose of 1000 mg/kg 1-Dodecene, dimer with 1-decene, hydrogenated. Statistically significant changes occurred in food consumption, haematology, serum chemistry, and organ weights; however, none of the changes were considered to be of toxicological significance. No LOAEL could be determined due to lack of any affects. The NOAEL is 1000 mg/kg/day.
This study received a Klimisch score of 1 and is classified as reliable without restrictions because it closely followed OECD 407 guidelines and was GLP compliant.
This study will influence the DNEL.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-12-05 to 1995-01-31
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restrictions because it was GLP compliant and was conducted according to OECD 407 guidelines
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Animals not fasted prior to blood collection
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (U.K.) Ltd
- Age at study initiation: 6 weeks
- Weight at study initiation: Male - 149-179 grams; Female - 125-170 grams
- Fasting period before study: Not fasted
- Housing: Groups of 5 by sex in polypropylene grid floor cages
- Diet (e.g. ad libitum): Rat and Mouse SQC Expanded Diet No. 1 (Special Diets Services Limited, Essex, U.K.) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 15 per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
IN-LIFE DATES: From: 1994-12-05 To: 1995-01-31 - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The test material was administered daily by gavage using a stainless steel cannula attached to a disposable plastic syringe.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
0 mg/kg bw
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
0 mg/kg bw (Satellite)
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
1000 mg/kg bw (Satellite)
Basis:
actual ingested - No. of animals per sex per dose:
- 5/sex/dose
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): Random assignment
- Rationale for selecting satellite groups: Not reported
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): Not reported - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Work week - Prior to dosing and one to five hours post-dosing; Weekend - Prior to dosing and 1 hour post-dosing; Satellite groups - Twice daily on weekdays and once daily on weekends
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 7, 14, 21, and 28 and for satellite groups on days 35 and 42 as well.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption was recorded for each cage group at weekly intervals throughout the study.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
FOOD EFFICIENCY: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination (Day 28) for animals in dose groups 1 and 2 and on day 42 for satellite groups
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: All animals
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination (Day 28) for animals in dose groups 1 and 2 and on day 42 for satellite groups
- Animals fasted: No
- How many animals: All animals
- Parameters checked in table [No.2] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: Organ weights for adrenals, brain, gonads, heart, kidneys, liver, pituitary, and spleen were determined post termination - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
HISTOPATHOLOGY: Yes. Although the required tissues were preserved only the adrenals, heart, kidneys, liver, spleen, testes, and macroscopic lesions were examined histologically. - Statistics:
- Data were processed t o give group mean values and standard deviations where appropriate. Absolute and relative organ weights, haematological and blood chemical data were analyzed by one way analysis o f variance incorporating 'F-max' test for homogeneity of variance. Data showing heterogeneous variances were analyzed using Kruskal-Wallis non-parametric analysis of variance and Mann Whitney U-Test.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality or clinically observable signs of toxicity was observed in male or female rats in the control or treatment groups through the study period.
BODY WEIGHT AND WEIGHT GAIN
All animals showed normal gain in body weight throughout the study period. Body weight gain in test animals was comparable with that seen
in controls.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There was no adverse effect on food consumption during the study. Food efficiency in test animals was comparable with that seen in controls.
FOOD EFFICIENCY
Not determined
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Daily visual inspection of water bottles revealed no overt intergroup differences.
OPHTHALMOSCOPIC EXAMINATION
Not determined
HAEMATOLOGY
There were no treatment-related changes in the haematological parameters measured. A statistically significant increase in group mean neutrophil and eosinophil count was detected for treated females in comparison with controls. Individual values were within the normal range for rats of this strain and age, with the exception of one female. This animal showed a general increase in leukocyte fractions but, as an isolated finding, this was considered to be unrelated to test material toxicity.
CLINICAL CHEMISTRY
There were no treatment-related changes in the blood chemical parameters measured. No statistically significant differences were detected between test or control groups.
URINALYSIS
Not determined
NEUROBEHAVIOUR
Not determined
ORGAN WEIGHTS
There were no changes in the organ weights measured which could be considered attributable to treatment with the test material. Treated females showed a statistically significant reduction in group mean relative liver weight in comparison with controls. All values were within the normal range for rats of this strain and age and with no morphological changes to support an effect in this organ the reduction was considered to be of no toxicological significance.
GROSS PATHOLOGY
No treatment-related macroscopic abnormalities were detected.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related changes were observed.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: Based on the lack of systemic toxicity or adverse clinical effects observed at this dose level.
- Critical effects observed:
- not specified
- Conclusions:
- There were no indications of toxicity based on clinical findings, mortality rates, change in food and water consumption, body weight changes, clinical chemistry examination, haematology, necropsy, change in organ weights, or histopathology. Therefore, the NOAEL for this study is 1000 mg/kg/day.
- Executive summary:
In a repeated dose oral toxicity study, 1 -dodecene, trimer was administered to 5 Sprague-Dawley CD rats/sex/dose at dose levels 0 or 1000 mg/kg bw/day for 28 consecutive days. An additional 2 satellite groups (0 and 1000 mg/kg/bw/day) were also maintained without treatment for a further fourteen days following the end of the dosing period.
There were no compound related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, or gross and histologic pathology. Thus the NOAEL is 1000 mg/kg/day.
This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was GLP compliant and was conducted according to OECD 407 guidelines.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-12-05 to 1995-01-31
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified reliable without restriction. The study was conducted according to OECD 407 Guidelines and followed GLP recommendations.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd., Kent, U.K.
- Age at study initiation: 6 weeks
- Weight at study initiation: Male: 134-173 grams; Female: 127-153 grams
- Fasting period before study: No
- Housing: In groups of 5 by sex in polypropylene cages
- Diet (e.g. ad libitum): Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, U.K. ad libitum
- Water (e.g. ad libitum): Mains water ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2˚C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
IN-LIFE DATES: From: 1994-12-05 To: 1994-01-31 - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: For the purpose of this study the test material was used undiluted as supplied by the sponsor.
DIET PREPARATION
The test material was then administered daily, for twenty-eight consecutive days, by gavage using a stainless steel cannula attached to
a disposable plastic syringe. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test material was assessed by gas chromorography (GC) using control samples of test material maintained at approximately -18°C and 4°C.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- 5/sex/dose
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Not reported
- Rationale for animal assignment: Random
- Rationale for selecting satellite groups: Not reported
- Post-exposure recovery period in satellite groups: 14 days - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:prior to dosing and one and five hours after dosing during the working week
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior dosing and one and five hours after dosing during the working week. Animals were observed immediately before dosing and one hour after dosing at weekends and public holiday. During the treatment-free period satellite group animals were observed twice daily, morning and afternoon (once daily at weekends).
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 (the day before the start of treatment) and on Days 7, 14, 21, 28 and in the case of satellite group animals on Days 35 and 42.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, Food consumption was recorded for each cage group at weekly intervals throughout the study.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes, weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Daily
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: groups 1 and 2 at the end of the treatment period (Day 28) and in satellite animals (groups 3 and 4) at the end of the treatment-free period (Day 42).
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: All animals (n = 20)
- Parameters checked in table [No. 1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: groups 1 and 2 at the end of the treatment period (Day 28) and in satellite animals (groups 3 and 4) at the end of the treatment-free period (Day 42).
- Animals fasted: No
- How many animals: All animals (n = 20)
- Parameters checked in table [No. 2] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3): On completion of the dosing period or, in the case of satellite group animals at the end of the treatment-free period; all animals were killed by intravenous overdose of sodium pentobarbitone (Sagatal, 60 mg/ml; May and Baker Limited, Dagenham, Essex, U.K.)
followed by exsanguination. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
HISTOPATHOLOGY: Yes (see table 4): Samples of the tissues indicated in Table 4. were removed from all animals and preserved in buffered 10% formalin. - Statistics:
- Data were processed to give group mean values and standard deviations where appropriate. Absolute and relative organ weights, haematological and blood chemical data were analysed by one way analysis of variance incorporating 'F-max' test for homogeneity of variance. Data showing heterogeneous variances were analysed using Kruskal-Wallis non-parametric analysis of variance and Mann Whitney U-Test.
Probability values were calculated as:
p < 0.001***
p < 0.01 **
p < 0.05 *
p > 0.05 (not significant) - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY: No clinically observable signs of toxicity were detected in test or control animals throughout the study period. One treated male developed a wound on the right shoulder from Day 17 but this healed rapidly and was no longer apparent by Day 25. Minor
injuries of this nature are occasionally seen in group housed rats and are not indicative of test material toxicity.
BODY WEIGHT AND WEIGHT GAIN: All animals showed normal gains in bodyweight throughout the study period.- Bodyweight gain in test animals was comparable with that seen in controls.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): There was no adverse effect on food consumption during the study. Food
efficiency in test animals was comparable with that seen in controls.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Daily visual inspection of water bottles revealed no overt intergroup
differences.
HAEMATOLOGY: There were no treatment-related changes in the haematological parameters measured. The only statistically significant differences detected between test and control groups were confined to a reduction in haemoglobin and increase in leucocyte count, specifically in the lymphocyte fraction, for satellite treated females at the end of the recovery period. No such changes were apparent in main group animals after twenty-eight days of treatment and these were, therefore, considered to be fortuitous.
CLINICAL CHEMISTRY: There were no blood chemical changes which could be considered toxicologically significant. Group mean alkaline phosphatase showed a statistically significant reduction for treated females in comparison with controls. All individual values were within the normal range for rats of this strain and age and a reduction in this parameter cannot be regarded as toxicologically important. The remaining statistically significant differences detected between test and control groups were confined to an increase in alanine aminotransferase and reduction in plasma creatinine for treated satellite females. No such changes were detected for main group animals and the differences were, therefore, considered to be fortuitous.
ORGAN WEIGHTS: There were no changes in the organ weights measured which could be considered attributable to treatment with the test material. A statistically significant increase in absolute ovary weight was detected for treated females in comparison with controls. Relative weights were unaffected and, as such, the increase was considered not to be toxicologically significant. Statistically significant increases in relative heart, brain and ovary weight for treated satellite females and an increase in relative testes weight for treated satellite males were detected at the end of the recovery period. These changes were not apparent in main group animals after twenty-eight days of treatment and were, therefore, considered to be unrelated to test material toxicity.
GROSS PATHOLOGY: No treatment-related macroscopic abnormalities were detected. The incidental findings recorded at necropsy were consistent with those normally expected in laboratory maintained rats.
HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related changes were observed. All morphological changes were those commonly observed in
laboratory maintained rats of the age and strain employed and, since there were no differences in incidence or severity between control and treatment groups, all were considered to be without toxicological significance. - Dose descriptor:
- NOEL
- Effect level:
- ca. 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on absence of treatment-related adverse effects observed in male and female rats.
- Critical effects observed:
- not specified
- Conclusions:
- Oral administration of the test material, 1-dodecene dimer, hydrogenated, to rats for a period of twenty-eight consecutive days at a dose level of 1000 mg/kg/day produced no treatment-related changes in the parameters measured. The "No Observed Effect Level" (NOEL) is therefore, considered to be 1000 mg/kg/day.
- Executive summary:
In a 28-day oral toxicity study (Coles, L. J., and Brooks, P. N., 1995; Klimisch score = 1), the test material (1-dodecene dimer, hydrogenated) was administered by gavage to a group of five male and five female Sprague-Dawley CD strain rats, for twenty-eight consecutive days, at a dose level of 1000 mg/kg/day. A control group of five males and five females remained untreated throughout the study period but was otherwise handled in an identical manner to the test animals. Two satellite groups, each of five males and five females were similarly treated at 1000 mg/kg/day or remained untreated respectively; satellite groups were maintained without treatment for a further fourteen days following the end of the dosing period. Clinical signs, bodyweight, food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all main groups animals during the final week of dosing and for satellite group animals at the end of the treatment-free period. All animals were subjected to a gross necropsy examination and a limited histopathological evaluation of tissues from main test and control animals was performed.
No mortality or signs of adverse clinical toxicity were observed through the study period. Food consumption, water consumption, and body weight gain remained unaffected. No treatment-related effects were observed on hematology and blood chemistry parameters. Organ weights were not affected either by treatment with 1-dodecene dimer, hydrogenated. Necroscopy and histopathology did not reveal any remarkable findings at termination.
Based on the lack of adverse effects observed in this 28-day study, the NOEL for 1-dodecene dimer, hydrogenated, is considered to be >1000 mg/kg bw/day.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993-09-29 to 1993-10-28
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable with restriction because although the study closely adhered to OECD 407 guidelines, haematology, clinical biochemistry, and neurobehavioral assessments were not conducted.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Haematology, clinical chemistry, and neurobehavioural tests were not performed
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Olac Limited, England
- Age at study initiation: 35 to 42 days old
- Weight at study initiation: Not reported, but stated to weight between 59 and 76 grams the day after arrival
- Housing: Five per stainless steel cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55%
- Air changes (per hr): At least 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light
IN-LIFE DATES: From:1993-09-29 To: 1993-10-28 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with ground diet
- Storage temperature of food: 21 degrees Celsius
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity was tested on the lowest and highest concentration by taking 6 samples from different positions in the mixer. The dose formulation was determined to be homogeneous. Stability was determined on the highest and lowest concentrations after 1 and 2 weeks. The dose formulation was determined to be stable for at least 2 weeks. Dietary concentrations were analysed during week 1 and 4. Dose formulations were within 10% of nominal dose.
- Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0; 8000; 20,000; or 50,000 ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- Five per sex per dose
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Based on studies performed using similar materials
- Rationale for animal assignment (if not random): Random - Positive control:
- None
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included overt signs of toxicity and faecal examination.
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Study initiation, twice weekly during treatment, and at study termination
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: Yes
- Time schedule for examinations:No quantitative measurement was made, but water bottles were observed daily to check for any changes that might indicate a treatment-related change in fluid balance
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, detailed necropsy was performed.
HISTOPATHOLOGY: Yes, although numerous tissues and organs were preserved, only the liver and mesenteric lymph nodes were examined histologically. - Other examinations:
- Organs provided in table 1 were weighed.
- Statistics:
- A Bartlett's test was used to test for homogeneity of the data. Depending on the results a Behrens-Fisher or Dunnett's test were performed. Fischer's exact test was used on microscopic and macroscopic findings.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: There were no treatment-related effects.
BODY WEIGHT AND WEIGHT GAIN: High-dose females had a marginal increase in body weight gain. However, this was related to increased food consumption so was considered due to individual variability and not treatment-related.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): High-dose females had a slight increase in food consumption. Compound intake in males was 1030, 2538, and 6248 mg/kg/day for the 8000 ppm; 20,000 ppm; and 50,000 ppm dose groups, respectively. Compound intake in females was 995, 2481, and 6771 mg/kg/day, respectively.
FOOD EFFICIENCY: There were no treatment-related effects.
ORGAN WEIGHTS: There was a slight, but dose-related, decrease in absolute and relative mandibular weight in males and females that reached statistical significance in high-dose females only.
GROSS PATHOLOGY: There were no treatment-related effects.
HISTOPATHOLOGY: There were no treatment-related effects. - Dose descriptor:
- NOAEL
- Effect level:
- 6 245 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: Overall effects
- Dose descriptor:
- NOAEL
- Effect level:
- 6 771 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: Overall effects
- Critical effects observed:
- not specified
- Conclusions:
- The systemic NOAEL for dec-1-ene, homopolymer, hydrogenated in the diet is 50,000 ppm, which is equivalent to a daily intake of 6245 mg/kg/day in males and 6771 mg/kg/day in females.
- Executive summary:
In a repeated dose oral toxicity study, dec-1 -ene, homopolymer,hydorgenated was administered to F-344 rats (5 sex/dose) in the diet for four weeks at nominal concentrations of 0, 8000; 20,000; or 50,000 ppm (equivalent overall mean daily intakes were 1039, 2538, or 6245 mg/kg/day for males and 995, 2481, or 6771 mg/kg/day for females).
There was no overt toxicity or mortality observed in male or female rats during the study. Overall body weight gain and food consumption of females in the 50,000 ppm dose group was higher than the corresponding controls. A dose-dependent decrease in mandibular lymph node weights (absolute and relative to body weight) was observed in males and females; however, these results were statistically significant only for 50,000 pm females. Gross necroscopy, histopathology, and microscopic findings did not reveal any significant treatment-related findings in either male or female rats. Dietary administration of dec-1 -ene, homopolyer, hydrogenated to male and female F-344 rats at levels up to 50,000 ppm for 4 weeks did not produce toxicologically significant effects. Therefore, the subacute oral NOAEL for dec-1 -ene, homoopolymer, hydrogenated is 6245 mg/kg/day in males and 6771 mg/kg/day in females.
This study received a Klimisch score of 2 and is classified as reliable with restrictions because although the study closely adhered to OECD 407 guidelines, haematology, clinical biochemistry, and neurobehavioral assessments were not conducted. This study will influence the DNEL.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restriction because it was conducted according to GLP, is scientifically acceptable and appears to have adhered to the OECD guideline recommendations.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Source: Charles River (U.K.) Limited
- Age at study initiation: (P): 6 to 8 weeks; (F1): 3 weeks
- Weight at study initiation: (P) Males: 205 to 280 grams; Females: 148 to 205 grams
- Fasting period before study: No
- Housing: Groups of four in polypropylene cages prior to mating; one male to one female during mating; Post-mating, males returned to original cages and females housed individually during gestation and lactation
- Diet (e.g. ad libitum): Rodent PMI 5002 (Certified) diet (BCM IPS Limited, London, UK) ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2ºC
- Humidity (%): 55 ±15%
- Air changes (per hr): At least 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
IN-LIFE DATES: From: 2005-06-22 To: 2005-10-20 - Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Test material was prepared on a weekly basis at the appropriate concentrations as a solution in Arachis oil BP and stored at 4ºC in the dark.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: 0, 12.5, 62.5, or 250 mg/mL depending on the dosage
- Amount of vehicle (if gavage): 4 mL/Kg
- Purity: Not reported - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of Dosing formulations at 250 mg/ml were also analysed for achieved concentration on a weekly basis during the study. The results indicatethat prepared high dose formulations were within ± 12% of the nominal concentration.
- Duration of treatment / exposure:
- 10 weeks
- Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
0, 50, 250, 1000 mg/kg/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10/sex/dose
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: The dose levels were chosen by the Sponsor based on available toxicological data
- Rationale for animal assignment (if not random): Animals were allocated to dose groups using a randomisation procedure based on stratified
bodyweights(Table No. 1)
- Rationale for selecting satellite groups: Ten animals of either sex from the control and 1000 mg/kg/day dosage groups were selected for the ophthalmoscopic examination - Positive control:
- Not utilized in the study design
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Prior to dosing and at weekly intervals before pairing, ten animals/sex from each dose group were observed cage-side for functional and behavioural changes.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Immediately prior to dosing and then 1 to 5 hours post-dosing from Monday through Friday. On the weekend, animals were observed prior to dosing, immediately after dosing and at 1 hour post dosing.
BODY WEIGHT: Yes
- Time schedule for examinations: Males: Day 0 and once a week thereafter; Females: Weekly during maturation
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, During the maturation period, weekly food consumption was recorded for each cage of adults
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes, weekly food conversation efficiency(bodyweight gain/food intake) was calculated for both sexes for the pre-pairing maturation phase of the study.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water intake was observed daily by visual inspection of water bottles for any overt change.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Once during week 10 of the study
- Dose groups that were examined: Control and high-dose group (10 rat/sex)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Once during week 10
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: 10/sex
- Parameters checked in Table No.2 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Once during week 10 of the study
- Animals fasted: No
- How many animals: 10/sex
- Parameters checked in Table No. 3 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once/week for the first 10 weeks
- Dose groups that were examined: 10 rats/sex from each dose groups
- Battery of functions tested: Sensory activity / grip strength / motor activity
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, see Table No. 4
HISTOPATHOLOGY: Yes, see Table 5 - Statistics:
- Data were processed to give group mean values and standard deviations where appropriate. Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dennett’s test. Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test. Chi-squared analysis was used for differences in the incidence of lesions occurring with an overall frequency of 1 or greater while the Kruskal-Wallis one-way non-parametric analysis of variance was utilized for the comparison of severity grades for the more frequently observed graded conditions.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY: There were two unscheduled deaths during the study, neither of which were considered treatment-related. No clinically observable signs of toxicity were detected in test or control animals throughout the study period.
BODY WEIGHT AND WEIGHT GAIN: Bodyweight and bodyweight gain of males and females (including the gestation and lactation phases) at dosages of up to 1000 mg/kg/day were unaffected by treatment throughout the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Food consumption of males during the pre-pairing and post pairing phases of the study was unaffected by treatment at dosages of up to 1000 mg/kg/day. Food consumption of females during the pre-mating, gestation and lactation periods of the study was also not adversely affected by treatment at dosages up to 1000 mg/kg/day.
FOOD CONVERSION EFFICIENCY: Food conversion efficiency of both sexes during the pre-pairing phase of the study were unaffected by treatment at dosages of up to 1000 mg/kg/day.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No treatment-related effect on water consumption was observed in the treatment group when compared with controls
OPHTHALMOSCOPIC EXAMINATION: No treatment-related ocular effects were detected at the end of the pre-pairing phase (following 10 weeks of treatment).
HAEMATOLOGY: Intergroup differences in haematological parameters were considered not to indicate any adverse effect of treatment.
CLINICAL CHEMISTRY: Intergroup differences in blood chemistry parameters were considered not to indicate any adverse effect of treatment.
NEUROBEHAVIOUR: There were no treatment-related changes in the functional performance parameters measured. Statistical analysis of the data revealed no significant intergroup differences. Additionally, there were no treatment-related changes in sensory reactivity.
ORGAN WEIGHTS: Intergroup differences in absolute and bodyweight-relative organ weights for either sex were not indicative of any adverse effect of treatment.
GROSS PATHOLOGY: Neither the type, incidence nor distribution of macroscopic finding observed at necropsy for decedent animals or for animals killed at scheduled termination indicated any adverse effect of treatment for either sex.
HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related changes were observed. - Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: Based on the lack of systemic toxicity effects observed at this dose level
- Critical effects observed:
- not specified
- Conclusions:
- The oral administration of 1-dodecene, trimer to rats by gavage at a maximum dose level of 1000 mg/kg/day resulted in no treatment-related effects. The ‘No Observed Effect Level’ for adult toxicity was therefore considered to be 1000 mg/kg/day.
- Executive summary:
In a oral subchronic study, 1 -dodecene, trimer was administered orally, once daily, by gavage to three groups each of 10 male and 10 female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, at dose levels of 1000, 250 and 50 mg/kg/day. A further group of 10 male and 10 female rats received the vehicle alone to serve as a control.
There were two unscheduled deaths on the study, occurring in the control and 250 mg/kg/day dosage groups, neither of which was associated with treatment. There were no signs of clinical toxicity observed in either sex at any of the doses tested. Behavioural and functional performance remained unaffected in male and female rats treated with 1 -dodecene, trimer. Sensory reactivity, body weight, food and water consumption were unaffected. Haematological and clinical chemistry assessments revealed no significant treatment-related effects on male and female rats.
The oral administration of 1 -dodecene, trimer, hydrogenated to rats by gavage at a maximum dose level of 1000 mg/kg/day resulted in no treatment related effects. Thus, the NOAEL for adult toxicity was considered to be 1000 mg/kg/day.
This study received a Klimisch score of 1 and is classified as reliable without restriction because it was conducted according to GLP, is scientifically acceptable and appears to have adhered to the OECD guideline recommendations.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-04-20 to 1994-08-17
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restrictions because it was GLP compliant and was conducted according to OECD 408 guidelines.
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Not all tissues were examined histologically
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles river Limited, England
- Age at study initiation: 35 to 42 days old
- Weight at study initiation: 86 to 106 grams
- Housing: Five per sex per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 55%
- Air changes (per hr): At least 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
IN-LIFE DATES: From: 1994-04-20 To: 1994-08-17 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with ground diet
- Storage temperature of food: Room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity was tested on the lowest and highest concentration by taking 6 samples from different positions in the mixer. The dose formulation was determined to be homogeneous. Stability was determined on the highest and lowest concentrations after 1 and 2 weeks. The dose formulation was determined to be stable for at least 2 weeks. Dietary concentrations were analysed during weeks 1 and 13. Dose formulations were within 10% of nominal dose.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0; 1000; 7000; or 50,000 ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- Ten animals per sex per dose
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Doses were selected based on a 4 week study
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: Satellite groups were selected to examine the reversibility of any effects.
- Post-exposure recovery period in satellite groups: 4 weeks
- Section schedule rationale (if not random): Random - Positive control:
- None
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included mortality and overt signs of toxicity.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: At study initiation, weekly throughout the treatment and reversibility periods, and at study termination
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to study initiation and during week 12
- Dose groups that were examined: Control and high-dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 12 weeks of treatment or 3 weeks of reversibility
- Anaesthetic used for blood collection: Yes (halothane/nitrous oxide)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in Table No.1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 12 weeks on the study
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in Table No.2 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: After 11 weeks on the study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in Table No.3 were examined.
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: Faecal samples were obtained during week 9 and 12 for analysis. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see Table 4) - Other examinations:
- Tissues with a XX in Table 4 were weighed.
- Statistics:
- A Bartlett's test was used to test for homogeneity of the data. Depending on the results a Behrens-Fisher or Dunnett's test were performed. Fischer's exact test was used on microscopic and macroscopic findings. For normally distributed haematology data a Student's t-test with pooled error variance was used.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: No mortality occurred. Clinical signs observed in the 50,000 ppm group included oily and ungroomed coats, soft faeces, and brown staining. Hair loss occurred at a greater incidence in the treated animals when compared to controls. Oily coats continued through the first week of the recovery period, particularly in females receiving 50,000 ppm but following week one, they appeared ungroomed in addition to exhibiting hair loss. Soft faeces were also occasionally observed in the 7000-ppm females.
BODY WEIGHT AND WEIGHT GAIN: There were no treatment-related effects.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Although there was a slight increase in food consumption in the high-dose group compared to controls (8% in males and 10% in females) that continued through the recovery period, there was no effect observed on either body weight or food efficiency. Daily compound intake in the 1000; 7000; and 50,000 ppm groups were 78, 554, and 4159 mg/kg/day in males and 86, 612, and 4620 mg/kg/day in females, respectively.
FOOD EFFICIENCY: There were no treatment-related effects.
OPHTHALMOSCOPIC EXAMINATION: There were no treatment-related effects.
HAEMATOLOGY: There were slight (<5%), but significant increases in erythrocyte counts, haemoglobin, and packed cell volume in 7000- and 50,000-ppm males. The increase in haemoglobin was dose related. There was also a slight (6%), but significant, increase in platelet counts in high-dose males and females. None of these effects were observed at the end of the recovery period. There were also no treatment-related effects noted in the bone marrow smears.
CLINICAL CHEMISTRY: There were no treatment-related effects.
URINALYSIS: There were no treatment-related effects.
ORGAN WEIGHTS: Absolute and relative liver weights in treated males were slightly, but dose-related, decreased; however, at the end of the reversibility period the liver weights were comparable to controls.
GROSS PATHOLOGY: There were no treatment-related effects.
HISTOPATHOLOGY: There were no treatment-related effects. - Dose descriptor:
- NOAEL
- Effect level:
- 4 159.4 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: Overall effects
- Dose descriptor:
- NOAEL
- Effect level:
- 4 619.9 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: Overall effects
- Critical effects observed:
- not specified
- Conclusions:
- The subchronic oral NOAEL for dec-1-ene, homopolymer, hydrogenated is 50,000 ppm (4159.4 mg/kg/day in males and 4619.9 mg/kg/day in females).
- Executive summary:
In a 90-day oral toxicity study, dec-1 -ene, homopolymer, hydrogenated was administered to ten F-344 rats/sex/dose at dose levels of 0; 1000; 7000; or 50,000 ppm (equivalent to 77.5, 553.7, and 4159.4 mg/kg/day, respectively, in males and 85.5, 611.5, and 4619.9 mg/kg/day, respectively, in females ) in the diet for 13 weeks. An additional five rats per sex were administered control or 50,000 ppm for 13 weeks and were then left untreated for 4 weeks to examine recovery.
No animals died over the course of the study. Clinical signs observed in the 50,000 ppm group included oily and ungroomed coats, soft faeces, and brown staining. Hair loss occurred at a greater incidence in the treated animals when compared to controls. Oily coats continued through the first week of the recovery period, particularly in females receiving 50,000 ppm but following week one, they appeared ungroomed in addition to exhibiting hair loss. Soft faeces were also occasionally observed in the 7000-ppm females. Although there was a slight increase in food consumption in the high-dose group compared to controls (8% in males and 10% in females) that continued through the recovery period, there was no effect observed on either body weight or food efficiency. There were slight (<5%), but significant increases in erythrocyte counts, haemoglobin, and packed cell volume in 7000- and 50,000-ppm males. The increase in haemoglobin was dose related. There was also a slight (6%), but significant, increase in platelet counts in high-dose males and females. None of these effects were observed at the end of the recovery period. No treatment-related effects were noted in the bone marrow. Absolute and relative liver weights in treated males were slightly lower, however, at the end of the reversibility period the liver weights were comparable to controls. There were no treatment-related effects noted in clinical chemistry, urinalysis, gross pathology, or histopathology. A LOAEL was not identified in this study based on the lack of adverse effects. The NOAEL for this study is 50,000 ppm (4159.4 mg/kg/day in males and 4619.9 mg/kg/day in females).
This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was GLP compliant and was conducted according to OECD 408 guidelines. This study will influence the DNEL.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993-06-01 to 1993-11-30
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restrictions because it was compliant with GLPs. Additionally, methods used for the 91-day oral exposure part of the study appear to closely follow OECD 408.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- see princilpes of method if other than guideline
- Deviations:
- yes
- Remarks:
- see princilpes of method if other than guideline
- Principles of method if other than guideline:
- 1. On three days, the animal room temperature was outside the specified range of 68 to 76°F by -9 to +4°F, and on sixty-seven days, the relative humidity was outside the specified range of 40 to 70% by -24 to +10%.
2. On one occasion, the animal room temperature and relative humidity were not documented in the morning, prior to sanitization, as required by the protocol.
3. The males weighed 319 to 422 g at the initiation of dosing, instead of 200 to 275 g, as specified in the protocol. The females weighed 202 to 274 g at the initiation of dosing, instead of 200 to 250 g, as specified in the protocol.
4. Due to malalignment of the upper incisors on study day 1, F0 group 2 male no. 1304 was replaced with male no. 1307, an animal with the same body weight and no clinical signs.
5. On two occasions, the physical description of the dosing solutions was not addressed at the time of dose dispension.
6. During dosing on study day 10 and 32, an undetermined amount of apparent test material came out of the mouth of F0 group 3 male no.1305 and F0 group 2 male no. 1445, respectively.
7. F0 group 1 female no. 1548 struggled during dosing on study day 14.
8. On study days 18 and 21, dosing was not documented for F0 group 3 female no. 1590 and F0 group 1 female no. 1592, respectively.
9. Due to technical error during dosing on study day 28, the F0 control animals did not receive the vehicle control solution during the initial dosing procedure. Dosing was performed a second time and the correct volume was administered.
10. On one occasion prior to mating for the F0 animals (study day 21), the morning mortality check was not performed, however, all animals were found alive during the afternoon mortality check.
11. On one occasion during cohabitation, the food jar for F0 group 2 male no. 1401 and female no. 1528 was found empty. The empty food jar was replaced with a new jar.
12. On lactation day 7, the pups from group 4 female no. 1505 were dropped. All pups appeared normal except female pup no. 16, which died shortly thereafter.
13. Clinical observations were not performed for F0 group 2 female no. 1453 on lactation day 11. However, no clinical signs were noted on lactation days 10 or 12.
14. On lactation day 17, a replacement food jar was inadvertently placed on male pup no. 4 from group 3 female no. 1507. The pup was found dead approximately one hour later.
15. On lactation day 20 for F0 group 4 female no. 1502, post-dose observations were not performed within the specified range of one-half hour to two hours following dosing. However, there were no post-dose findings for this female at 3 hours and 2 minutes after dosing.
16. F0 group 1 females no. 1525 and 1583, F0 group 2 female no. 1510 and F0 group 3 female no. 1560 were found without food during lactation interval 14-21.
17. F1 group 2 female pup no. 1536-01 was not identified via toe clipping prior to submission to necropsy.
18. Observations were not recorded for F1 group 3 female pup no. 1545-17 at the time of scheduled necropsy on lactation day 2.
19. The observation for the lungs of F1 group 2 male pup no. 1527-01 found dead on lactation day 0 was not recorded at the time of necropsy.
20. On once occasion, observations for group 1 female no. 1592-09 were not recorded prior to or following dosing.
21. Due to ocular findings during the interim phase, F1 group 4 female no 1505-13 was replaced with female no. 1454-08, a female without ocular findings.
22. On day 1 of the interim phase, cage-side observations were not performed prior to dosing. However, all animals were found to be normal during post-dose observations.
23. The following animals were replaced at the start of the 91-day toxicity phase: group 1 male no. 1459-08 with male no. 1446-10, group 2 male no. 1506-04 with male no. 1543-04, group 2 male no. 1539-06 with male no. 1559-08, group 1 female no. 1459-12 with female no. 1446-14, group 2 female no. 1506-08 with female no. 1543-06, and group 2 female no. 1539-12 with female no. 1559-13. These animals were inadvertently not weighed on lactation day 21 and therefore did not receive consecutive control or test article treatment.
24. On one occasion each during dosing for the 91-day toxicity phase, an undetermined amount of apparent test material came out of the mouth and/or nose of four group 1 animals, three group 2 animals, two group 3 animals and one group 4 animal. On three occasions during dosing for the 91-day toxicity phase, an undetermined amount of apparent test material came out of the mouth of one group 1 animal.
25. During dose preparation on study day 26 for the 91-day toxicity phase, continuous stirring of the dosing mixtures during dosing was not documented.
26. On study days 53 and 69 during the 91-day toxicity phase, dosing was not documented for group 3 female no. 1537-11 and group 4 female no. 1579-10, respectively.
27. During dosing on study day 57, group 2 female no. 1543-06 in the 91-day toxicity phase struggled and bit the gavage needle and un undetermined amount of apparent test material came out of the mouth and reddish fluid came out of the nose.
28. During necropsy on study day 97 of the 91-day toxicity phase, the lung infusion procedure was not documented for group female no. 1508-14.
29. The method of euthanasia was not documented for the animals in the 91-day toxicity phase on study days 96 to 98.
30. Although no gross lesion was recorded, the mediastinal lymph nodes were retained during necropsy on study day 99 of the 91-day toxicity phase, for group 1 female no. 1568-17. - GLP compliance:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles river Laboratories, Raleigh, North Carolina
- Age at study initiation: 22 days old
- Weight at study initiation: Not reported
- Housing: Individually in suspended stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Not applicable because animals used in the subchronic study were the offspring from a reproduction study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 to 12 per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light
IN-LIFE DATES: From: 1993-06-01 To: 1993-11-30 - Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Specific amount of test compound was weighed into a beaker with the appropriate amount of vehicle. The mixture was stirred by hand then sufficient vehicle was added to achieve the desired concentration. Solutions were then stirred for 30 minutes using a stir bar.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: 0, 20, 100, or 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg of vehicle or solution was administered
- Lot/batch no. (if required): 920897 and 933384
- Purity: Not reported - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to study initiation, homogeneity and stability tests were performed. All test mixtures were analysed for verification of the test article concentration. Samples were found to be homogeneous and stable. All concentrations used were found to be within 20% of the nominal concentration.
- Duration of treatment / exposure:
- 91 days
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0, 100, 500, or 1000 mg/kg/day
Basis:
other: nominal in polyethylene glycol 400 - No. of animals per sex per dose:
- Twenty animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The same doses were used in the reproductive study
- Rationale for animal assignment (if not random): Twenty animals per sex were randomly selected from the oldest litters in each group from the reproduction study - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included mortality, morbidity, and overt signs of toxicity.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and at terminal sacrifice
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to study initiation and near study termination
- Dose groups that were examined: All groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in Table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in Table 2 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, a complete necropsy was performed
HISTOPATHOLOGY: Yes (see Table 3) - Other examinations:
- The liver, kidney, thyroid/parathyroid, adrenal glands, gonads, and brain were weighed.
- Statistics:
- Continuous data were analysed using a one way analysis of variance followed by a Dunnett's test (sometimes a modified Dunnett's test). Count data were analysed using a Chi-square or a Mann-Whitney U test.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: Three rats were found dead due to dosing errors. Clinical signs indicating gastrointestinal disturbances were noted in all groups including the control and were related to the vehicle used. There were no changes related to treatment.
BODY WEIGHT AND WEIGHT GAIN: There were no treatment-related effects.
FOOD CONSUMPTION: There were no treatment-related effects.
OPHTHALMOSCOPIC EXAMINATION: There were no treatment-related effects.
HAEMATOLOGY: There was a significant increase in prothrombin time in males at the 1000-mg/kg/day dose; however, there were no corresponding decreases in platelets or gross or histopathological changes observed; therefore, this is considered not related to treatment.
CLINICAL CHEMISTRY: There were no treatment-related effects.
ORGAN WEIGHTS: There were no treatment-related effects.
GROSS PATHOLOGY: There were no treatment-related effects.
HISTOPATHOLOGY: There were no treatment-related effects.
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Overall effects
- Critical effects observed:
- not specified
- Conclusions:
- The subchronic NOAEL for dec-1-ene, homopolymer, hydrogenated in rats is 1000 mg/kg/day.
- Executive summary:
In a 90-day oral toxicity, dec-1 -ene, homopolymer, hydrogenated was administered to 20 Sprague-Dawley Crl:CD®BR VAF/Plus® rats/sex/dose at dose levels 0, 100, 500, or 1000 mg/kg bw/day for 91 days. The toxicity of dec-1 -ene, homopolyer, hydrogenated was examined in F1 generation rats following a reproduction study where the test chemical was administered in an in utero phase (F0 generation).
F1 generation rats administered 0, 100, 500, or 1000 mg/kg/day exhibited minor gastrointestinal disturbances at all dose levels including the control. Transient changes in body weight, body weight gain, food consumption, haematology, and organ weights were observed, but were not considered treatment-related. There was a significant increase in prothrombin time in 1000-mg/kg/day males; however, there were no corresponding decreases in platelets, or macroscopic and microscopic changes observed. Therefore, this result was not considered biologically significant. There were no changes in clinical chemistry, mortality, or ophthalmology. No LOAEL is determined for this study, based on no adverse effects observed. The NOAEL is 1000 mg/kg/day.
This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was compliant with GLPs and methods used for the 91-day oral exposure part of the study appear to closely follow OECD 408.
This study will influence the DNEL.
- Endpoint:
- chronic toxicity: oral
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Referenceopen allclose all
Formulation Analysis:
Concentration analysis:
The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with target concentrations (i.e., mean sample concentration results were within or equal to 85% 115% of target concentration). A small response at the retention time of the test material was observed in the chromatograms of the Group 1 formulation prepared for use. It was considered not to derive from the formulation since a similar response was obtained in the analytical blanks.
Homogeneity Analysis:
The formulations of Groups 2 and 4 were homogeneous (i.e., coefficient of variation ≤ 10%).
Table 9. Results of Formulation Analysis |
|||||
Date of analysis |
Concentration (mg/mL) |
Recovery (%) |
|||
Target |
Nominal |
Analyzed |
Individual |
Mean |
|
2021-OCT-21 |
25.0 |
26.5 |
23.4 |
88 |
92 |
24.6 |
23.5 |
96 |
|||
22.2 |
20.8 |
94 |
|||
250 |
252 |
227 |
90 |
88 |
|
248 |
217 |
88 |
|||
250 |
218 |
87 |
|||
Table 10. Body Weights (grams) Result Summary |
|||||
|
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
|||||
Pre-mating |
|
||||
Day 1 Week 1 |
Mean |
311 |
308 |
317 |
312 |
SD |
11.1 |
15.4 |
16.4 |
25.3 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
336 |
331 |
341 |
334 |
SD |
13.6 |
19.0 |
17.8 |
29.8 |
|
N |
10 |
10 |
10 |
10 |
|
Mating Period |
|
||||
Day 1 Week 1 |
Mean |
352 |
345 |
357 |
352 |
SD |
16.8 |
21.9 |
21.3 |
30.5 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
360 |
358 |
368 |
361 |
SD |
19.4 |
22.4 |
22.6 |
31.3 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 15 Week 3 |
Mean |
374 |
372 |
378 |
376 |
SD |
21.3 |
21.3 |
23.1 |
34.3 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 22 Week 4 |
Mean |
|
|
398 |
|
SD |
|
|
--- |
|
|
N |
|
|
1 |
|
|
Females |
|||||
Pre-mating |
|
||||
Day 1 Week 1 |
Mean |
227 |
227 |
224 |
220 |
SD |
7.4 |
8.7 |
12.9 |
12.2 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
232 |
231 |
229 |
223 |
SD |
5.9 |
9.2 |
13.6 |
8.4 |
|
N |
10 |
10 |
10 |
10 |
|
Mating Period |
|
||||
Day 1 Week 1 |
Mean |
239 |
238 |
231 |
232 |
SD |
5.3 |
10.7 |
14.5 |
12.7 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
|
|
261 |
|
SD |
|
|
7.1 |
|
|
N |
|
|
2 x |
|
|
|
|||||
Day 15 Week 3 |
Mean |
|
|
262 |
|
SD |
|
|
--- |
|
|
N |
|
|
1 x |
|
|
Post Coitum |
|
||||
Day 0 |
Mean |
238 |
236 |
236 |
231 |
SD |
7.2 |
9.2 |
17.0 |
11.2 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 4 |
Mean |
253 |
247 |
246 |
243 |
SD |
7.2 |
11.8 |
16.0 |
12.0 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 7 |
Mean |
261 |
256 |
253 |
251 |
SD |
6.1 |
10.6 |
16.1 |
12.0 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 11 |
Mean |
277 |
271 |
267 |
266 |
SD |
7.4 |
13.4 |
14.9 |
13.4 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 14 |
Mean |
286 |
282 |
276 |
277 |
SD |
7.5 |
11.9 |
14.6 |
14.0 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 17 |
Mean |
312 |
304 |
300 |
301 |
SD |
8.5 |
9.9 |
14.0 |
17.0 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 20 |
Mean |
349 |
343 |
328 |
340 |
SD |
14.3 |
12.6 |
28.4 |
20.7 |
|
N |
10 |
9 |
8 |
10 |
|
Lactation |
|
||||
Day 1 |
Mean |
277 |
272 |
268 |
263 |
SD |
11.6 |
15.0 |
16.9 |
12.7 |
|
N |
9 |
8 |
10 |
10 |
|
|
|||||
Day 4 |
Mean |
289 |
286 |
275 |
271* |
SD |
7.3 |
13.6 |
16.5 |
12.5 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Day 7 |
Mean |
291 |
288 |
287 |
280 |
SD |
7.4 |
14.1 |
15.8 |
16.6 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Day 13 |
Mean |
303 |
301 |
292 |
292 |
SD |
6.9 |
13.2 |
15.3 |
12.9 |
|
N |
9 |
8 |
10 |
9 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
x Explanations for excluded data are listed in the tables of the individual values presented in the study report.
Table 11. Body Weight Gain (%) Result Summary |
|||||
|
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
|||||
Pre-mating |
|
||||
Day 1 Week 1 |
Mean |
0 |
0 |
0 |
0 |
SD |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
8 |
7 |
7 |
7 |
SD |
1.9 |
1.3 |
1.0 |
1.6 |
|
N |
10 |
10 |
10 |
10 |
|
Mating Period |
|
||||
Day 1 Week 1 |
Mean |
13 |
12 |
13 |
13 |
SD |
2.5 |
2.5 |
1.6 |
2.2 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
16 |
16 |
16 |
16 |
SD |
3.0 |
2.7 |
2.0 |
1.7 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 15 Week 3 |
Mean |
20 |
21 |
19 |
21 |
SD |
3.8 |
3.1 |
3.0 |
3.0 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 22 Week 4 |
Mean |
|
|
21 |
|
SD |
|
|
--- |
|
|
N |
|
|
1 |
|
|
Females |
|||||
Pre-mating |
|
||||
Day 1 Week 1 |
Mean |
0 |
0 |
0 |
0 |
SD |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
2 |
2 |
2 |
2 |
SD |
2.0 |
2.1 |
0.8 |
2.2 |
|
N |
10 |
10 |
10 |
10 |
|
Mating Period |
|
||||
Day 1 Week 1 |
Mean |
5 |
5 |
3 |
6 |
SD |
2.2 |
1.4 |
1.8 |
2.9 |
|
N |
10 |
10 |
10 |
10 |
|
|
|||||
Day 8 Week 2 |
Mean |
|
|
13 |
|
SD |
|
|
0.8 |
|
|
N |
|
|
2 x |
|
|
|
|||||
Day 15 Week 3 |
Mean |
|
|
16 |
|
SD |
|
|
--- |
|
|
N |
|
|
x |
|
|
|
|||||
Day 22 Week 4 |
Mean |
|
|
--- |
|
SD |
|
|
--- |
|
|
N |
|
|
0 x |
|
|
|
|||||
Day 29 Week 5 |
Mean |
|
|
--- |
|
SD |
|
|
--- |
|
|
N |
|
|
0 x |
|
|
|
|||||
Day 36 Week 6 |
Mean |
|
|
--- |
|
SD |
|
|
--- |
|
|
N |
|
|
0 x |
|
|
Post Coitum |
|
||||
Day 0 |
Mean |
0 |
0 |
0 |
0 |
SD |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 4 |
Mean |
6 |
5 |
4 |
5 |
SD |
1.9 |
2.6 |
1.4 |
1.9 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 7 |
Mean |
10 |
9 |
7 |
9 |
SD |
2.9 |
2.7 |
1.5 |
2.2 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 11 |
Mean |
16 |
15 |
13 |
15 |
SD |
3.6 |
3.7 |
3.3 |
3.1 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 14 |
Mean |
20 |
20 |
17 |
20 |
SD |
3.1 |
3.3 |
3.1 |
2.6 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 17 |
Mean |
31 |
29 |
27 |
30 |
SD |
4.6 |
3.2 |
5.9 |
3.6 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Day 20 |
Mean |
47 |
45 |
39 |
47 |
SD |
8.2 |
4.7 |
11.0 |
4.6 |
|
N |
10 |
9 |
8 |
10 |
|
Lactation |
|
||||
Day 1 |
Mean |
0 |
0 |
0 |
0 |
SD |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
9 |
8 |
10 |
10 |
|
|
|||||
Day 4 |
Mean |
4 |
5 |
3 |
4 |
SD |
2.9 |
3.1 |
3.7 |
1.8 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Day 7 |
Mean |
5 |
6 |
7 |
7 |
SD |
2.7 |
2.6 |
9.2 |
3.0 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Day 13 |
Mean |
9 |
11 |
9 |
12 |
SD |
4.1 |
4.5 |
6.0 |
3.6 |
|
N |
9 |
8 |
10 |
9 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
x Excluded data (Explanations listed in the tables of the individual values presented in the study report)
Table 12. Food Consumption (g/animal/day) Result Summary |
|||||
|
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
|||||
Pre-mating |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
22 |
22 |
23 |
22 |
SD |
1.7 |
1.4 |
1.7 |
1.3 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
21 |
21 |
22 |
22 |
SD |
1.8 |
1.2 |
1.1 |
0.8 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Pre-mating |
Mean |
22 |
21 |
23 |
22 |
Mating Period |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
22 |
21 |
24 |
23 |
SD |
1.2 |
0.4 |
2.8 |
1.9 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
20 |
19 |
21 |
21 |
SD |
1.4 |
0.8 |
1.6 |
0.9 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Mating Period |
Mean |
21 |
20 |
23 |
22 |
Females |
|||||
Pre-mating |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
15 |
15 |
15 |
15 |
SD |
0.1 |
0.5 |
1.0 |
0.5 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
15 |
15 |
15 |
15 |
SD |
0.3 |
0.8 |
0.8 |
0.9 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Pre-mating |
Mean |
15 |
15 |
15 |
15 |
Post-Coitum |
|
||||
Days 0-4 |
Mean |
19 |
19 |
18 |
19 |
SD |
1.0 |
2.5 |
1.7 |
1.2 |
|
N |
9 |
9 |
8 |
9 |
|
|
|||||
Days 4-7 |
Mean |
19 |
19 |
17 |
18 |
SD |
2.4 |
4.3 |
2.0 |
2.3 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Days 7-11 |
Mean |
19 |
18 |
18 |
19 |
SD |
2.2 |
1.8 |
2.1 |
1.4 |
|
N |
10 |
8 |
8 |
10 |
|
|
|||||
Days 11-14 |
Mean |
19 |
19 |
18 |
20 |
SD |
1.4 |
2.7 |
1.6 |
1.2 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Days 14-17 |
Mean |
21 |
20 |
20 |
21 |
SD |
1.0 |
2.5 |
1.5 |
1.5 |
|
N |
7 |
7 |
8 |
8 |
|
|
|||||
Days 17-20 |
Mean |
23 |
22 |
27 |
22 |
SD |
1.8 |
2.9 |
15.8 |
1.8 |
|
N |
10 |
9 |
8 |
10 |
|
Mean of means |
|
20 |
20 |
20 |
20 |
Lactation |
|
||||
Days 1-4 |
Mean |
30 |
32 |
29 |
29 |
SD |
7.1 |
4.5 |
6.2 |
3.0 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Days 4-7 |
Mean |
35 |
37 |
37 |
38 |
SD |
7.3 |
3.2 |
6.0 |
2.9 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Days 7-13 |
Mean |
46 |
48 |
46 |
49 |
SD |
10.7 |
3.5 |
7.8 |
2.4 |
|
N |
9 |
8 |
10 |
9 |
|
Mean of means |
|
37 |
39 |
37 |
39 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
x Excluded data (Explanations listed in the tables of the individual values presented in the study report)
Table 13. Relative Food Consumption (g/Kg body weight/day) Result Summary |
|||||
|
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
|||||
Pre-mating |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
66 |
65 |
67 |
67 |
SD |
4.4 |
1.7 |
1.5 |
1.4 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
64 |
63 |
66 |
66 |
SD |
4.6 |
1.2 |
0.1 |
2.9 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Pre-mating |
Mean |
65 |
64 |
66 |
67 |
Mating Period |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
61 |
59 |
66 |
65 |
SD |
2.8 |
1.7 |
4.3 |
0.8 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
54 |
52 |
56 |
56 |
SD |
2.3 |
0.3 |
1.6 |
2.3 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Mating Period |
Mean |
57 |
56 |
61 |
60 |
Females |
|||||
Pre-mating |
|
||||
Days 1-8 Weeks 1-2 |
Mean |
64 |
64 |
64 |
65 |
SD |
0.6 |
1.7 |
5.3 |
2.5 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
|
|||||
Days 8-15 Weeks 2-3 |
Mean |
65 |
67 |
66 |
67 |
SD |
1.6 |
3.1 |
4.6 |
4.4 |
|
N (Cage) |
2 |
2 |
2 |
2 |
|
Mean of means over Pre-mating |
Mean |
64 |
65 |
65 |
66 |
Post-Coitum |
|
||||
Days 0-4 |
Mean |
75 |
78 |
75 |
78 |
SD |
4.7 |
7.8 |
8.4 |
4.7 |
|
N |
9 |
9 |
8 |
9 |
|
|
|||||
Days 4-7 |
Mean |
73 |
74 |
69 |
71 |
SD |
8.5 |
14.3 |
6.9 |
7.9 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Days 7-11 |
Mean |
69 |
67 |
69 |
70 |
SD |
7.0 |
5.0 |
7.4 |
6.5 |
|
N |
10 |
8 |
8 |
10 |
|
|
|||||
Days 11-14 |
Mean |
66 |
67 |
67 |
71 |
SD |
4.6 |
7.5 |
6.1 |
4.8 |
|
N |
10 |
9 |
8 |
10 |
|
|
|||||
Days 14-17 |
Mean |
67 |
66 |
67 |
68 |
SD |
3.3 |
6.2 |
3.7 |
3.7 |
|
N |
7 |
7 |
8 |
8 |
|
|
|||||
Days 17-20 |
Mean |
65 |
65 |
87 |
64 |
SD |
5.2 |
7.3 |
64.2 |
6.2 |
|
N |
10 |
9 |
8 |
10 |
|
Mean of means |
|
69 |
69 |
72 |
70 |
Lactation |
|
||||
Days 1-4 |
Mean |
102 |
111 |
107 |
108 |
SD |
24.7 |
15.3 |
23.2 |
12.1 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Days 4-7 |
Mean |
122 |
130 |
127 |
136 |
SD |
25.7 |
12.5 |
19.1 |
4.8 |
|
N |
9 |
8 |
10 |
9 |
|
|
|||||
Days 7-13 |
Mean |
152 |
161 |
157 |
169 |
SD |
35.1 |
13.4 |
24.9 |
6.7 |
|
N |
9 |
8 |
10 |
9 |
|
Mean of means |
|
125 |
134 |
130 |
138 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
x Excluded data (Explanations listed in the tables of the individual values presented in the study report)
Table 14. Functional Observations Summary |
|||||
|
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
|||||
End of Treatment |
|
||||
Hearing Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Pupil L Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Pupil R Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Static R Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Grip Fore gram |
Mean |
948 |
893 |
761 |
823 |
SD |
140 |
94 |
200 |
90 |
|
N |
5 |
5 |
5 |
5 |
|
|
|||||
Grip Hind gram |
Mean |
625 |
493 |
599 |
556 |
SD |
79 |
50 |
96 |
89 |
|
N |
5 |
5 |
5 |
5 |
|
Females |
|||||
Hearing Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Pupil L Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Pupil R Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Static R Score 0/1 |
Median |
0 |
0 |
0 |
0 |
N |
5 |
5 |
5 |
5 |
|
|
|||||
Grip Fore gram |
Mean |
1335 |
1313 |
1200 |
1213 |
SD |
257 |
48 |
126 |
232 |
|
N |
5 |
5 |
5 |
5 |
|
|
|||||
Grip Hind gram |
Mean |
625 |
513 |
481 |
396* |
SD |
113 |
138 |
151 |
85 |
|
N |
5 |
5 |
5 |
5 |
|
+/++ Steel-test significant at 5% (+) or 1% (++) level
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Table 15. Summary of Select Hematology and Coagulation Values: F0 Generation |
|||
Day: 30 Relative to Start Date (Males) |
|
Reporting Hematology |
Reporting Coagulation |
LUC (10^9/L) |
PT (sec) |
||
Statistical Test |
[G] |
[G] |
|
Group 1 (Control – 0 mg/kg/day) |
Mean |
0.064 |
17.14 |
SD |
0.019 |
2.66 |
|
N |
5 |
5 |
|
|
|||
Group 2 (100 mg/kg/day) |
Mean |
0.042 |
16.04* |
SD |
0.008 |
0.46 |
|
N |
5 |
5 |
|
tCtrl |
0.66 |
0.94 |
|
|
|||
Group 3 (300 mg/kg/day) |
Mean |
0.036* |
16.42 |
SD |
0.005 |
0.41 |
|
N |
5 |
5 |
|
tCtrl |
0.56 |
0.96 |
|
|
|||
Group 4 (1000 mg/kg/day) |
Mean |
0.044 |
16.28 |
SD |
0.017 |
0.34 |
|
N |
5 |
4 |
|
tCtrl |
0.69 |
0.95 |
|
[G] - Anova & Dunnett: * = p ≤ 0.05
LUC: Large unstained cells
PT: Prothrombin Time
Table 16. Summary of Select Biochemistry Values: F0 Generation |
|||
Day: 51 Relative to Start Date (Females) |
|
Reporting Biochemistry |
|
TBIL (µmol/L) |
NA (mmol/L) |
||
Statistical Test |
[G1] |
[G1] |
|
Group 1 (Control – 0 mg/kg/day) |
Mean |
3.06 |
143.3 |
SD |
0.50 |
1.1 |
|
N |
5 |
5 |
|
|
|||
Group 2 (100 mg/kg/day) |
Mean |
2.10* |
143.0 |
SD |
0.63 |
1.2 |
|
N |
5 |
5 |
|
tCtrl |
0.69 |
1.00 |
|
|
|||
Group 3 (300 mg/kg/day) |
Mean |
2.18* |
145.6* |
SD |
0.35 |
0.9 |
|
N |
5 |
5 |
|
tCtrl |
0.71 |
1.02 |
|
|
|||
Group 4 (1000 mg/kg/day) |
Mean |
2.02* |
142.4 |
SD |
0.51 |
1.1 |
|
N |
5 |
5 |
|
tCtrl |
0.66 |
0.99 |
|
[G1] - Anova & Dunnett: * = p ≤ 0.05
TBIL: Total Bilirubin
NA: Sodium
Table 17. Summary of Macroscopic Findings (F0 Generation) |
||||
|
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
Males |
||||
End of Treatment |
|
|||
Animals examined |
10 |
10 |
10 |
10 |
Animals without findings |
9 |
8 |
7 |
7 |
Animals affected |
1 |
2 |
3 |
3 |
|
||||
Stomach |
|
|||
Focus/foci |
0 |
0 |
1 |
0 |
Liver |
|
|||
Right median lobe constricted |
0 |
1 |
0 |
0 |
Enlarged |
0 |
0 |
0 |
1 |
Kidneys |
|
|||
Pelvic Dilation |
0 |
0 |
0 |
1 |
Testes |
|
|||
Reduced in size |
0 |
1 |
0 |
0 |
Epididymides |
|
|||
Nodule(s) |
1 |
0 |
0 |
0 |
Reduced in size |
0 |
1 |
0 |
0 |
Seminal vesicles |
|
|||
Enlarged |
0 |
0 |
0 |
1 |
Thyroid gland |
|
|||
Enlarged |
0 |
0 |
1 |
1 |
Skin |
|
|||
Scab formation |
0 |
0 |
1 |
0 |
Females |
||||
Intercurrent Death |
|
|||
Animals examined |
1 |
1 |
|
1 |
Animals affected |
1 |
1 |
|
1 |
|
||||
General observations |
|
|||
Incomplete delivery, 2 dead pups, 1 alive pup |
1 |
0 |
|
0 |
Total litter loss |
0 |
1 |
|
1 |
Liver |
|
|||
Discolouration |
0 |
1 |
|
1 |
Uterus |
|
|||
Contents: |
1 |
0 |
|
0 |
|
|
|||
End of Treatment |
|
|||
Animals examined |
9 |
9 |
10 |
9 |
Animals without findings |
7 |
7 |
5 |
9 |
Animals affected |
2 |
2 |
5 |
0 |
|
||||
Brain |
|
|||
Discolouration |
0 |
0 |
1 |
0 |
Lungs |
|
|||
Focus/foci |
0 |
1 |
0 |
0 |
Ovaries |
|
|||
Cyst(s) |
0 |
1 |
0 |
0 |
Thyroid gland |
|
|||
Enlarged |
1 |
0 |
0 |
0 |
Reduced in size |
0 |
0 |
1 |
0 |
Thymus |
|
|||
Focus/foci |
1 |
0 |
1 |
0 |
Mandibular lymph node |
|
|||
Focus/foci |
0 |
0 |
1 |
0 |
Skin |
|
|||
Alopecia |
0 |
0 |
1 |
0 |
Eyes |
|
|||
Exophthalmus |
0 |
0 |
1 |
0 |
# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level
Table 18. Select Organ Weights (grams) Summary |
|||||
End of Treatment |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
|
Males |
|||||
Heart (Gram) |
Mean |
1.037 |
0.877** |
1.019 |
0.924* |
SD |
1.01 |
0.027 |
0.065 |
0.029 |
|
N |
5 |
5 |
5 |
5 |
|
|
|||||
Liver (Gram) |
Mean |
9.14 |
8.60 |
8.42 |
8.04** |
SD |
0.39 |
0.49 |
0.24 |
0.69 |
|
N |
5 |
5 |
5 |
5 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Table 19. Select Organ/Body Weight Ratios (%) Summary |
|||||
End of Treatment |
Group 1 (Control – 0 mg/kg/day) |
Group 2 (100 mg/kg/day) |
Group 3 (300 mg/kg/day) |
Group 4 (1000 mg/kg/day) |
|
Males |
|||||
Heart (%) |
Mean |
0.286 |
0.256* |
0.298 |
0.275 |
SD |
0.011 |
0.006 |
0.030 |
0.014 |
|
N |
5 |
5 |
5 |
5 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Although there were some statistically significant effects, none of the effects were considered toxicologically significant or treatment-related.
Although there was an apparent dose-related decrease in mandibular lymph node weight, the results only reached significance in high-dose females; therefore, this is not considered biologically significant and not likely adverse since there were no other findings.
No adverse effects observed.
Although there were some slight changes that may be related to treatment, the effects are minimal and are not supported by other data. The clinical signs are related to the oily nature of the test compound and are not considered adverse.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Five key short-term and three key read across sub-chronic toxicity studies available for assessment.
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
- Endpoint:
- sub-chronic toxicity: inhalation
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
- Endpoint:
- chronic toxicity: inhalation
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
- Endpoint:
- sub-chronic toxicity: dermal
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
- Endpoint:
- chronic toxicity: dermal
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Read-across studies within poly alpha olefins were also used to assess repeated dose toxicity through oral exposure. There were, however, no studies identified within category for repeated dose toxicity for either inhalation or dermal exposure.
Repeat Dose Oral Toxicity
A key OECD Guideline 422 combined 28-Day repeated dose toxicity study with the Reproduction / Developmental Toxicity Screening Test was conducted to evaluate the potential toxic effects of the test material (1-Dodecene, dimers; CAS# 62132-67-6) when given orally to Wistar Han rats (Charles River Laboratories Den Bosch BV, 2022).
The test material Wistar Han rats (10/sex/dose) were administered once daily via oral gavage in a corn oil vehicle at doses of 0, 100, 300, or 1000 mg/kg/day for a minimum of 28 days for males (including at least 2 weeks of treatment prior to mating and during the mating period up to and including the day before scheduled necropsy). Female rats were dosed 7 days a week for at least 14 days prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy.
Parameters were evaluated in this study included mortality/ moribundity, clinical signs, functional observations, body weight and food consumption, clinical pathology, measurement of thyroid hormones T3, T4 and TSH (F0 males and females), gross necropsy findings, organ weights and histopathologic examinations.
No treatment-related mortality was observed in the F0 animals. One control female (No. 43) was sacrificed in extremis on Day 23 post coitum. The female had a pale appearance and piloerection and at the point 3 pups were born of which 1 was alive and 2 were found dead. As no more pups were born and the condition of the animal deteriorated, the animal was sacrificed in extremis. At necropsy, the uterus of this female contained 3 alive and 5 dead fetuses. No other macroscopic or microscopic findings were observed. Based on this, the condition of this female was considered to be related to delivery difficulties.
One female in the 100 mg/kg/day (No. 60) dose group was sacrificed in extremis on Day 1 of lactation. The animal was found with a pale appearance and piloerection. Due to the deteriorating condition of this animal, it was sacrificedin extremis. Additionally, all 11 delivered pups were found to be dead. At necropsy, a pale liver was observed corresponding to microscopic moderate multifocal necrosis in the liver which likely contributed to the moribundity. Based on the single incidence of this event in the low dose group, the condition of this animal was not considered to be treatment-related.
No treatment-related clinical signs were observed either during daily detailed clinical or during the weekly arena observations. Incidental findings observed included scabs, wounds, and alopecia. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were not considered to be treatment-related.
Body weights and body weight gain were considered to be unaffected by treatment. Females at 1000 mg/kg/day displayed slightly lower (6% lower than control) absolute body weight on Day 4 of lactation was. As body weight gain was similar over this period and as this was only an incidental occurrence, this temporary lower body weight was not considered to be treatment-related. Food consumption before or after correction for body weight was not affected by treatment.
Hearing ability, pupillary reflex, static righting reflex and grip strength of the fore legs (males and females), and motor activity (females only) were considered unaffected by treatment at 100 and 300 mg/kg/day. Females at 1000 mg/kg/day displayed decreased grip strength of the hind legs (0.63x of control).In the absence of clinical signs and corroborative histopathological findings, this was not considered as adverse. An apparent upward trend in motor activity (total movements and ambulations) observed in male rats of all treatment groups was considered to have arisen as a result of slightly low control values and therefore not considered treatment-related. All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period.
Hematological parameters of rats were unaffected by treatment. A reduction of large unstained cell (LUC) counts was observed in male rats at 300 mg/kg/day. However, in the absence of a dose-related trend, this was considered to be unrelated to treatment. Coagulation parameters of rats were unaffected by treatment. A shorter prothrombin time (PT) observed in male rats at 100 mg/kg/day was considered to be unrelated to treatment in the absence of a dose-related trend.
Clinical chemistry parameters of male rats were unaffected by treatment. In female rats, a reduction in total bilirubin levels (TBIL) was observed at 100, 300, and 1000 mg/kg/day (0.69x, 0.71x and 0.66x of control, respectively). In the absence of corroborative histopathological findings, this was considered not adverse. Increased sodium levels were observed in female rats at 300 mg/kg/day but this considered to be minor and in the absence of a dose-related trend, unrelated to treatment.
Serum levels of thyroxine (T4) and thyroid-stimulating hormone (TSH) in male and female rats were unaffected by treatment. Serum total triiodothyronine (T3) levels in F0 males at 100 mg/kg/day were increased (Group mean values were 1.29x of control; however, an increase in the SD was also observed). Mean values were within the historical control data range and values at 300 mg/kg/day and 1000 mg/kg/day were comparable with the control group. Therefore, although treatment-related, this increase was not considered as adverse. Serum total T3 levels were increased in F0 females at 1000 mg/kg/day (1.26x of control). No historical control data for total T3 in lactating females was available at the Testing Facility. However, since only 1/10 individual females displayed a T3 value above the highest individual control value, the mean increase of T3 at 1000 mg/kg/day was considered unrelated to treatment.
Gross necropsy did not reveal any remarkable treatment-related findings and no treatment-related effects or alterations in organ weights were observed. Any differences, including those that reached statistical significance (males; heart at 100 mg/kg/day (absolute and relative to body weight) and 1000 mg/kg/day (absolute only); liver at 1000 mg/kg/day (absolute only)), were not considered to be treatment-related due to the direction of the change and/or a lack of dose-related trend.
Histopathology did not reveal any microscopic observations related to treatment with the test material. All of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no treatment-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Based on the lack of adverse treatment-related effects observed through the study period, the systemic toxicity No Observed Adverse Effect Level (NOAEL) for 1-Dodecene,dimers was determined to be≥1000 mg/kg/day in the rat.
Additionally, three 28-day and three 90-day repeated dose read across studies for oral exposure were also identified. For the 28-day repeated dose studies, studies were identified from 1-decene, homopolymer, hydrogenated; 1-dodecene dimer with 1-decene, hydrogenated, and 1 -dodecene trimer, hydrogenated, a structural analog. For 90-day exposures, studies were identified from 1-decene, homopolymer, hydrogenated and 1 -dodecene, trimer All studies were considered robust and of good quality.
Overall, the 28-day exposure studies produced no mortalities or significant clinical or systemic toxicity when the respective poly alpha olefins were administered orally.
For one of the 28-day repeated dose studies, 1-decene, homopolymer, hydrogenated, was administered to F-344 rats (5 sex/dose) in the diet for four weeks at nominal concentrations of 0, 8000; 20,000; or 50,000 ppm (equivalent overall mean daily intakes were 1039, 2538, or 6245 mg/kg/day for males and 995, 2481, or 6771 mg/kg/day for females) (Cooper, 1994). Dietary administration of 1 -decene, homopolymer, hydrogenated to male and female F-344 rats at levels up to 50,000 ppm for 4 weeks did not produce toxicologically significant effects. Therefore, the subacute oral NOAEL for 1 -decene, homopolymer, hydrogenated is 6245 mg/kg/day in males and 6771 mg/kg/day in females.
In the second 28-day repeated dose study conducted with 1-dodecene dimer with 1-decene, hydrogenated was administered to 6 Sprague-Dawley rats/sex/dose at dose levels 0, 200, 500, or 1000 mg/kg bw/day for 29 days (Cooper, 1989). A recovery group (6 rats), dosed with 0 or 1000 mg/kg/day of the test substance, was observed for two weeks post-dosing. No mortality, compound-related systemic toxicity or pathological changes were observed in the study or recovery groups at the limit dose of 1000 mg/kg 1 -dodecene, dimer with 1 -decene. Statistically significant changes occurred in food consumption, haematology, serum chemistry, and organ weights; however, none of the changes were considered to be of toxicological significance. No LOAEL could be determined due to lack of any affects. The NOAEL was reported as 1000 mg/kg/day.
Lastly, a short-term oral exposure study conducted with 1 -dodecene, trimer, a structural analogue for poly alpha olefins, found no compound-related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, or gross and histologic pathology when 1 -dodecene, trimer was administered to 5 Sprague-Dawley CD rats/sex/dose at dose levels 0 or 1000 mg/kg bw/day for 28 consecutive days (Coles, 1995). The NOAEL was reported as 1000 mg/kg/day.
In a 90-day study followed by a 4 week recovery with 1-dodecene, homopolymer, hydrogenated (Cooper, 1995), rats were dosed with 0, 1000, 7000, or 50,000 ppm (equivalent to 77.5, 553.7, or 4159.4 mg/kg, respectively, in males and 85.5, 611.5, and 4619.9 mg/kg, respectively, in females). No mortalities were observed in any treated group. Clinical signs observed in the 50,000 ppm group included oily and ungroomed coats as well as a slight increase in food consumption, including during the four week recovery period. Increased erythrocyte counts and hemoglobin concentrations (dose-response relationship) were reported for treated males. Marginally high packed cell volumes were reported for males treated at 7000 and 50,000 ppm. Platelet counts were slightly higher 50,000 ppm animals and slightly reduced liver weights were reported in males at end of treatment. All effects were not present at the end of the 4 week recovery period and therefore considered reversible.
In a 90-day one-generation reproduction study with subchronic toxicity with 1-dodecene, trimer, a structural analogue for poly alpha olefins (Knox et al., 2007, OECD 415/OECD 408), there were no signs of clinical toxicity, changes in body weight, haematological or clinical chemistry changes. The NOAEL was reported as 1000 mg/kg bw.
In a 91-day oral repeated dose study (Daniel, 1994), rats exposed to Ethylflo 166 in utero were treated with Ethylflo 166 at doses of 0, 250, 500, or 1000 mg/kg/day. Transient changes in body weight, body weight gain, food consumption, haematology, and organ weights were observed but were not considered treatment-related. The NOAEL was reported as 1000 mg/kg bw/day.
No significant or enduring toxicological effects were reported from these studies; therefore classification and labelling was not required for this endpoint.
Justification for Read Across
Several criteria justify the use of the read across approach to fill data gaps for poly alpha olefins using 1 -dodecene, trimer as an analogue. 1-dodecene, trimer, like other compounds in this category, is a poly alpha olefin, i. e., highly branched isoparaffinic chemicals produced by oligomerization of oct-1-ene, dec-1-ene, and/or dodec-1-ene. Therefore its physiochemical and toxicological properties are expected to be similar to those of other poly alpha olefins.
Justification for classification or non-classification
Using read-across information from studies performed with poly alpha olefins within category or from a structural analogue, it can be assumed that dec-1-ene, dimers, hydrogenated would not produce significant systemic toxicity following repeated exposure. Therefore, dec-1-ene, dimers, hydrogenated is not classified under CLP EU Regulation 1272/2008 for repeated dose toxicity.
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