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Diss Factsheets
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EC number: 482-120-7 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- 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: Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3050
- GLP compliance:
- yes
- Remarks:
- US EPA 40 CFR Part 792; OECD [C (97) 186/Final]
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): C-4000
- Physical state: liquid
- Analytical purity: 86.3 +/- 0.7%
- Purity test date: 2008-07-09
- Lot/batch No.: 51V034K7
- Expiration date of the lot/batch: 2008-10
- Storage condition of test material: refrigeratede
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 246 g to 275 g for males; 170 g to 203 g for females
- Fasting period before study:
- Housing: housed individually in clean, wire-mesh cages suspended above cage-board, which were changed at least three times weekly.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002; ad libitum
- Water (e.g. ad libitum): Reverse osmosis-treated (on-site) drinking water; ad libitum
- Acclimation period: All animals were housed for a 14-day acclimation/pretest period.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70.4°F to 70.6°F (21.3°C to 21.5°C)
- Humidity (%): 43.2% to 51.5%
- Air changes (per hr): Air handling units were set to provide a minimum of 10 fresh air changes per hour.
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark photoperiod
IN-LIFE DATES: From: 2008-08-05 To: 2008-09-02 and 03
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: PMI nutrition International, LLC Certified Rodent LabDiet® 5002
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substancewas added to PMI Nutrition International, LLC Certified Rodent 5002 on a weight/weight
basis and blended in a Hobart blender. The resulting premix was mixed thoroughly with additional PMI Nutrition International, LLC Certified Rodent 5002 in a V-Blender to obtain the appropriate dietary concentrations. Concentrations were prepared from lowest to highest. Test substance dietary admixtures will be corrected for test substance purity (correction factor of 1.159)
DIET PREPARATION
- Rate of preparation of diet (frequency): The control and test diets were prepared approximately weekly
- Mixing appropriate amounts with (Type of food): PMI nutrition International, LLC Certified Rodent LabDiet® 5002
- Storage temperature of food: placed in labeled storage bags and stored at room temperature.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Feed in dietary study
- Concentration in vehicle: ranged from 93.2% of nominal to 107% of nominal - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- In the present study, diet formulations prepared at target concentrations of 300, 1000 and 10,000 ppm C-4000 were evaluated for test substance concentration acceptability.
The analyzed formulations used for test substance administration met the WIL standard operating procedure requirements for concentration acceptability for diet admix formulations, i.e., the analyzed concentrations were 85% to 115% of the target concentrations. Chromatographic analysis of the basal diet administered to the Group 1 animals contained a chromatographic peak at approximately the same retention time as the test substance and at approximately the same level as that seen in analysis of the quality control (QC) blank samples. This peak was not present in acetonitrile
injections immediately prior to injections of the QC and Group 1 formulation samples, suggesting that the peak was due to an interfering matrix component and not test substance contamination of the control diet formulation. - Duration of treatment / exposure:
- 28 consecutive days
- Frequency of treatment:
- on a continuous basis for 28 consecutive days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
300, 1000 and 10000 ppm
Basis:
other: active ingredient; prepared using a correction factor for purity (1.159)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: doses determined based on the results of a 14-day range finding study
- Rationale for animal assignment (if not random): computerized randomization
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: at least weekly during the pretest period, throughout the test substance administration period and on the day prior to scheduled necropsy (non-fasted).
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; recorded weekly during the pretest period and throughout the test substance administration period. Food intake: Yes; g/animal/day for the corresponding body weight intervals
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: mean amounts of C-4000 consumed (mg/kg/day) by each sex per dose group were calculated from the mean food consumed (g/kg/day) and the appropriate target concentration of test substance in the diet (mg/kg)
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once during the pretest period (study week -1) and near the end of the treatment period (study week 3).
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Yes; overnight
- How many animals: all
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Yes; overnight
- How many animals: all
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during study week 3
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / other: physiological, home cage, handling, open field
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
The necropsies included, but were not limited to, examination of the external surface, all orifices, and the cranial, thoracic, abdominal and
pelvic cavities, including viscera.
Macroscopic Examination
A gross necropsy was conducted on all animals dying spontaneously, euthanized in extremis or at the scheduled necropsy. Animals euthanized in extremis or at the study termination were euthanized with C02 and exsanguinated. Necropsy included examination of the external surface, all orifices and the cranial, thoracic, abdominal and pelvic cavities, including viscera. At the time of necropsy the following tissues and organs were collected and placed in 10% neutral-buffered formalin (expect as noted).
Adrenals (2)
Lymph nodes
Aorta
Mesenteric
Bone with marrow
Sternum
Femur
Mandibular
Nasal cavity(d)
Ovaries (2) with oviducts(e)
Bone marrow smear (from femur[a])
Pancreas
Brain
Cerebrum Level 1
Cerebrum Level 2
Cerebellum with medulla/pons
Peripheral nerve (sciatic)
Peyer's patches
Pituitary
Prostate
Cervix
Salivary glands [mandibular (2)]
Epididymides (2)(b)
Seminal vesicles with coagulating gland (2)
Eyes with optic nerve (2)(c)
Gastrointestinal tract
Esophagus
Stomach
Duodenum
Jejunum
Ileum
Cecum
Colon
Rectum
Skeletal muscle (rectus femoris)
Skin with mammary gland(f)
Spinal cord
Cervical
Thoracic
Lumbar
Spleen
Testes (2)(b)
Thymus
Heart
Thyroid [with parathyroids, if present (2)(e)
Kidneys (2)
Liver (sections of two lobes)
Trachea
Lungs (including bronchi, fixed by inflation with fixative)
Urinary bladder
Uterus
Vagina
All gross lesions (when possible)
a - Not taken from animals found dead, not placed in formalin; not examined.
b - Testis and epididymis (right only) placed in Bouin’s solution.
c - Fixed in Davidson’s solution
d - Levels I and III according to method of Young (Young, 1981) examined
e - Parathyroids and oviducts examined microscopically if in plane of section or if gross lesion present.
f - For females; a corresponding section of skin was taken from the same anatomic area for males.
The following organs will be weighed fiom all animals at the scheduled necropsy:
Adrenals
Liver
Brain
Ovaries with oviducts
Epididymides (total and cauda)*
Spleen
Heart
Testes*
Kidneys
Thymus
*- These paired organs were weighed separately.
Paired organs were weighed together. Organ-to-body-weight ratios were calculated from animals euthanized at the scheduled necropsies.
Microscopic examination was performed on all tissues listed under macroscopic examination from all animals in the control and 10,000 ppm groups at the scheduled necropsy. The liver and thyroid were examined microscopically from all animals in the 300 and 1,000 ppm dose groups. - Other examinations:
- Estrous cycles, spermatogenic evaluations- motility and viablity assessment; morphology assessment; enumeration of epididymal and testicular sperm production rate
- Statistics:
- All statistical tests were performed using appropriate computing devices or programs.
Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance level 5%, comparing each test substance-treated group to the control group by sex. Each mean was presented with the standard deviation (S.D.), standard error (S.E.) and the number of animals (N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less. Due to the use of significant
figures and the different rounding conventions inherent in the types of software used, the means and standard deviations on the summary and individual tables may differ slightly.
Results and discussion
Results of examinations
- 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 specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY- unaffected
BODY WEIGHT AND WEIGHT GAIN- unaffected
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)- unaffected
OPHTHALMOSCOPIC EXAMINATION- unaffected
HAEMATOLOGY- unaffected
CLINICAL CHEMISTRY- higher total cholesterol in 10,000 ppm males
NEUROBEHAVIOUR- unaffected
ORGAN WEIGHTS- group mean absolute relative to body liver weights were slightly higher at 10,000 ppm; statistically significant only on a relative basis
GROSS PATHOLOGY- considered to be spontaneous and/or incidental in nature and unrelated to test substance administration
HISTOPATHOLOGY: limited to the liver and thyroid of the 10,000 ppm group males and females:
Microscopic examination of the liver revealed minimal enlargement of centrilobular hepatocytes due to cytoplasmic hypertrophy of a few 10,000 ppm group male and female rats. Minimal or mild hypertrophy and hyperplasia of the follicular epithelial cells of the thyroid was observed in animals of all groups, including the controls, with an increased incidence in the 10,000 ppm group males and females.
OTHER FINDINGS-It is relevant to the evaluations of selected reproductive organ parameters conducted in this study [estrous cycle evaluation in females, and epididymal sperm count, sperm production rate, motility and the percentage of morphologically normal sperm in males] that there were no test substance-related microscopic findings in reproductive organs of males or females in the 300, 1,000 or 10,000 ppm groups.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Effect level:
- 10 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The results of this study support the conclusion that a clear no-observed-effect level (NOEL) for oral administration of C-4000 to Crl:CD(SD) rats for 28 consecutive days was established at the dietary concentration of 1,000 ppm [approximately 77 mg/kg/day for males and 84 mg/kg/day for females]. In addition, the minimal level of response in the liver and thyroid of the rats in the 10,000 ppm group [approximately 723 mg/kg/day for males and 898 mg/kg/day for females] supports the conclusion that these liver and thyroid changes are an adaptive response, in contrast to toxicity. Therefore, oral administration of C-4000 at the dietary concentration of 10,000 ppm is the no-observed-adverse-effect level (NOAEL).
- Executive summary:
- The objective of the study was to evaluate the possible systemic toxic effects of C-4000 when administered orally in the diet to rats for 28 days, and to assess selected functional endpoints of the reproductive organs in males and females. The test substance, C-4000, was administered on a continuous basis in the diet for a minimum of 28 consecutive days to 3 groups (Groups 2-4) of Crl:CD(SD) rats. The dietary test substance concentrations were 300, 1,000 and 10,000 ppm active ingredient (a.i) for Groups 2-4, respectively. The diet formulations were prepared using a correction factor for purity (1.159). A concurrent control group (Group 1) received the basal diet on a comparable regimen. All groups (Groups 1-4) consisted of 10 animals/sex. Following 28 days of diet administration, all rats were euthanized by carbon dioxide anesthesia and exsanguinated. All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed daily, and detailed physical examinations were performed weekly. Individual body weights and food consumption were recorded weekly. Functional observational battery and locomotor activity data were recorded for all animals during the last week of administration (study week 3). Ophthalmic examinations were performed during study weeks -1 and 3. Clinical pathology evaluations (hematology, coagulation and serum chemistry) were performed for all animals at the scheduled necropsy (study week 4). Vaginal lavages to determine the stage of estrous were performed daily for all female animals beginning on study day 14 and continuing through the day prior to necropsy. Complete necropsies were conducted for all animals, and selected organs were weighed at the scheduled necropsy. Selected tissues were examined microscopically from all animals. Spermatogenic endpoints (motility/viability,morphology, enumeration of epididymal and testicular sperm and sperm production rates) were evaluated for all males at the scheduled necropsy. The analytical data indicate the rats in this study received the correct dosages of C-4000 in their feed; 300 ppm [approximately 22 mg/kg/day for males and 26 mg/kg/day for females]; 1,000 ppm [approximately 77 mg/kg/day for males and 84 mg/kg/day for females]; and 10,000 ppm [approximately 723 mg/kg/day for males and 898 mg/kg/day for females]. Control diets contained no C-4000. There were no test substance-related effects on survival, clinical observations, body weights, food consumption, functional observational battery, locomotor activity, ophthalmic examinations, hematology parameters or estrous or spermatogenic evaluations. The mean serum cholesterol for the 10,000 ppm group males was above the WIL Historical Reference Range Values (version 2.6) for 9 to 12 week old male rats and was considered a treatment-related effect. Male and female rats in the 10,000 ppm group had higher absolute and relative to body liver weights, but the differences were statistically significant only on a relative basis. These weight changes were consistent with microscopic findings of minimal centrilobular hepatocellular hypertrophy in the liver. The microscopic observations of the liver and thyroid were judged to be related to treatment with C-4000 only at the high dose, but at this dose the responses were below the threshold for toxicity. The types of responses observed, the minimal level of severity, and the incidence data were indicative of an adaptive response in this species, rather than a manifestation of overt toxicity. There was minimal enlargement of centrilobular hepatocytes due to cytoplasmic hypertrophy of a few 10,000 ppm group males and females. The liver cells were enlarged due to a minimal increased amount of dense eosinophilic cytoplasm, which resulted in a more prominent appearance of the central zones of the hepatic lobules. This minimal hepatocellular hypertrophy could correlate with the minimal, but statistically significant increase in liver weights when expressed as the liver to body weight ratio and was considered to be a test substance-related effect. Minimal or mild hypertrophy and hyperplasia of the follicular epithelial cells of the thyroid was observed in animals of all groups, including controls, with a higher incidence in the high dose group. Although this thyroid change occurred in animals of other groups without hepatocellular hypertrophy, the slight increased incidence of the thyroid follicular epithelial hyperplasia and hypertrophy, particularly in the 10,000 ppm group females, may be related to the hepatocellular hypertrophy in the animals of this group. The mean absolute and relative liver weights were within the range of WIL Historical Control values and were not considered adverse. Thus, the liver and thyroid changes are considered to be an adaptive response, in contrast to toxicity. It is relevant to the evaluations of selected reproductive organ parameters conducted in this study [estrous cycle evaluation in females, and epididymal sperm count, sperm production rate, motility and the percentage of morphologically normal sperm in males] that there were no test substance-related microscopic findings in reproductive organs of males or females in the 300, 1,000 or 10,000 ppm groups. The results of this study support the conclusion that a clear no-observed-effect level (NOEL) for oral administration of C-4000 to Crl:CD(SD) rats for 28 consecutive days was established at the dietary concentration of 1,000 ppm [approximately 77 mg/kg/day for males and 84 mg/kg/day for females]. In addition, the minimal level of response in the liver and thyroid of the rats in the 10,000 ppm group [approximately 723 mg/kg/day for males and 898 mg/kg/day for females] supports the conclusion that these liver and thyroid changes are an adaptive response, in contrast to toxicity. Therefore, oral administration of C-4000 at the dietary concentration of 10,000 ppm is the no-observed-adverse-effect level (NOAEL).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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