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EC number: 301-037-8 | CAS number: 93980-59-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
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- 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
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- Additional physico-chemical information
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- Endpoint summary
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- Environmental data
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- 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
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- Additional ecotoxological information
- Toxicological Summary
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- Acute Toxicity
- Irritation / corrosion
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- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
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- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Oral repeated dose toxicity, subacute (OECD 422, rat, m/f): NOAEL systemic = 1000 mg/kg bw/day
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:
- 05 Jan - 18 Aug 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted in 2016
- Deviations:
- yes
- Remarks:
- 5/10 animals/sex of the control and high dose group were selected for recovery whereas the guideline recommends to increase the number of animals to 5 additional rats/sex for each recovery group; no details on terminal procedures with pups provided
- GLP compliance:
- yes
- Limit test:
- no
- 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, Hino Breeding Center, Japan
- Age at study initiation: 9 weeks
- Weight at study initiation: 190 - 270 g (males) and 140 - 210 g (females)
- Housing: In groups of 2-3/sex/cage in hanging stainless steel cages with wire-mesh floor cages measuring 260 x 380 x 180 mm for quarantine and acclimatisation. After group allocation the animals were housed individually in hanging stainless steel cages with wire-mesh floor cages measuring 260 x 380 x 180 mm and 165 x 300 x 150 mm. Irradiated hemp mats with gamma ray were used for enrichment. During mating the females were housed in the males cages (1:1). After mating, females were housed in polycarbonat cages measuring 265 x 426 x 150 mm with wooden bedding and autoclaved gnawing wood enrichment.
- Diet: Pelleted diet, MF (Oriental Yeast), ad libitum
- Water: Chlorinated tap water from the municipal water supply (3-5 ppm level), administered via an automatic watering system for hanging cages and in polycarbonate bottles for polycarbonate cages, ad libitum
- Acclimation period: 14 days
DETAILS OF FOOD AND WATER QUALITY: Food and water quality were confirmed by analytical methods at regular intervals in the testing facility.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 05 Jan 2021 To: 05 May 2021 - Route of administration:
- oral: gavage
- Vehicle:
- other: 5% w/v gum arabic solution
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was weighed and gum arabic was added at final concentration of 5% w/v. Purified water was added to this mixture and kneaded to prepare 10.0% w/v formulation. A part of the 10.0% w/v formulation was taken with stirring by a magnetic stirrer and diluted with 5% w/v gum arabic solution to prepare the 1.00 and 3.00% w/v formulations.
The formulations and vehicle were subdivided into plastic containers and stored at the cold place (target range: 1 to 10 °C). On each dosing day formulations and vehicle were taken out from the storage place and dosed to the animals. The formulations were used within a stable period of 16 days after preparation
VEHICLE
- Justification for use and choice of vehicle: The test material did not dissolve in purified water or olive oil, but was found to be homogenate with 5% w/v gum arabic solution at a concentration of 10% w/v (non-GLP). The vehicle was used for a general toxicity and historical control data are available.
- Concentration in vehicle: 1, 3 and 10 % w/v
- Amount of vehicle: 20 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and stability of the test item formulations at 10.0 and 1.00 w/v% were confirmed with high performance liquid chromatography (HPLC) as part of a different study (CERI study no. X02-0328) from the bottom, middle and upper part of the formulations. The coefficient of variations of the concentrations of each layer were found to be in an acceptable range and all formulations were confirmed to be homogenious. Dose formulations were confirmed to be stable after 16 days of storage in a cold place.
Concentrations of the test item formulations were confirmed with HPLC in the first preparation (CERI study no. X02-0328). Actual concentrations of 10.0, 3.00 and 1.00% w/v formulations were 10.2, 3.06 and 1.03% w/v, respectively and considered to be acceptable. - Duration of treatment / exposure:
- Males were treated daily for 29 days, starting from 14 days prior to mating and including the mating period.
Females that delivered were treated daily for 14 days prior to mating, through mating and gestation until lactation Day 13.
Non-mating females of the satellite group were treated for 29 days. - Frequency of treatment:
- daily, 7 days/week
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Main group: 5 (control and high-dose group) and 10 (low- and mid-dose group)
Non-mating control: 10 (control and high-dose group only)
Recovery group: 10 (each 5 from the main group and 5 from the non-mating control; control and high-dose group only) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose levels were selected based on the results of a 14-day repeated dose oral toxicity study (CERI study no. C21-0051). Groups of 3 rats/sex were administered dose levels of 50, 200, 500 and 1000 mg/kg bw/day. No clinical signs of toxicity were noted and all animals gained weight as expected. Necropsy and organ weights of the liver, kidneys and spleen revealed no abnormal findings. The top dose for the main study was therefore set to 1000 mg/kg bw/day. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily for clinical signs and mortality during the treatment period and once daily during the recovery period. Females were observed for delivery and nursing conditions.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were made prior to dosing and once weekly thereafter.
- Examinations included: Animal reactions for external stimuli, handling observations and arena observations.
Animal reactions for external stimuli: Holding animals or bringing hand close to hold, easiness of removal and vocalisation
Handling observations: Muscle tone, subnormal temperature, hair appearance including piloerection, stained hair and unkempt hair, skin and mucous colour such as paleness, reddening and cyanosis, eyes including lacrimation, exophthalmos and pupillary size, salivation and secretion
Arena observations: Posture, motor activity level, respiration, gait characteristics, lid closure, tremor, twitch, convulsion, stereotypical behaviour and abnormal behaviour for one min or more (within five min), frequencies of defecation (number of faeces) and urination (number of pools)
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded for males and non-mating females on Days 1, 3, 7, 14, 21 and 28 and on Days 1, 7 and 14 of recovery and at necropsy. For females, individual body weights were recorded on Days 1, 3, 7 and 14, on gestation Days 0, 7, 14 and 20 and on postnatal days 0, 4, 8 and 13. For non-copulated females, body weight was recorded on Days 21, 28, 35, 42 and 49.
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
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected at terminal sacrifice from the abdominal aorta.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5/sex from the main group, 5 females from the non-mating group and males and females of the recovery group.
- Parameters examined: Red blood cell count (RBC), haemoglobin (Hb), haematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet count (Platelet), reticulocyte count ratio (Reticulo), white blood cell count (WBC), neutrophils (Neutro), lymphocytes (Lymph), eosinophils (Eosino), basophils (Baso) and monocytes (Mono), prothrombin time (PT) and activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected at terminal sacrifice from the abdominal aorta.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5/sex from the main group, 5 females from the non-mating group and males and females of the recovery group.
- Parameters examined: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (g-GTP), total cholesterol (T-Cho), triglycerides (TG), blood urea nitrogen (BUN), creatinine, total protein (T-Protein), albumin, A/G ratio, glucose, total bilirubin (T-Bil), total bile acids (TBA), inorganic phosphorus (IP), calcium (Ca), sodium (Na), potassium (K) and chloride (Cl)
PLASMA/SERUM HORMONES/LIPIDS: Yes
Blood was collected at terminal sacrifice from the abdominal aorta.
- Animals fasted: Yes
- How many animals: 5 males from the main group and 5 males from the recovery group.
- Parameters examined: Thyroid hormone (T4)
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected from each 5 animals/sex/group from the afternoon of the last observation day until the next morning, covering a period of 15-17 h.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: Urine volume, colour, turbidity, specific gravity, pH, protein, glucose, occult blood and urinary sediment
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: In each last dosing week.
- Dose groups that were examined: 5 animals/sex from each group (main group, non-mating group and recovery group).
- Battery of functions tested: Sensory activity / grip strength / motor activity
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
All parental animals were subjected to a detailed gross necropsy including external surface of the body, all orifices, subcutis, cranial, thoracic, abdominal and pelvic cavities, and their contents after bleeding from the ventral aorta under isoflurane anesthesia on the next day of last dosing and last recovery days. Non-copulated female, non-delivered females and dead female were subjected as with a survived animal on each found day. Vaginal smears were collected before gross necropsy in survived females, and stages of the oestrous cycle were determined with a light microscope after Giemsa staining. The number of implantation sites of the uterus after incision were counted for the mated females. Organs and tissues were collected from all animals of all groups. Trachea, lungs and urinary bladder were inflated with 10% neutralized buffered formalin before removal. Stomach and intestines were filled and fixed with 10% neutralized buffered formalin and the contents were washed away with water.
The following organ weights were recorded: Liver, heart, kidneys, testes, epididymides, prostate (with a part of the urethra), seminal vesicles (with coagulating gland), ovaries, uterus, brain, spleen, thymus, thyroid (with parathyroid) and adrenals.
HISTOPATHOLOGY: Yes
All organs/tissues were preserved in 10% neutralized buffered formalin. Testes and epididymides were fixed in modified Davidson’s fixative. Decalcification was done for the bone and bone marrow (femur) with 10% formic acid formalin before trimming.
The following organs and tissues were examined:
Respiratory system: Trachea, lungs
Digestive system: Submandibular glands, stomach, intestines (duodenum to rectum, including Peyer's patches), pancreas, liver
Cardiovascular system: Heart
Urinary system: Kidneys, urinary bladder
Reproductive system: Testes, epididymides, prostate (ventral and dorsolateral lobes), seminal vesicles (including coagulating gland), ovaries, uterus (horn and cervix), vagina
Nervous system: Brain (including cerebrum, cerebellum and pons), spinal cord (thoracic) and sciatic nerve
Hematopoetic system: Bone marrow (femur), axillar lymph nodes, mesenteric lymph nodes, spleen and thymus
Endocrine system: Pituitary gland, thyroid (including parathyroid) and adrenals
Sense organ: Eyeballs
Musculoskeletal system: Skeletal muscle (femoral region), bone (femur)
Skin and acessory organ: Mammary gland
Light microscopic examinations were performed after embedding in paraffin, sectioning and hematoxylin and eosin (HE) staining in each 5 animals of the control and high dose groups. Spleen in females of the recovery group was examined since treatment-related changes were suspected in organ weight. All macroscopic lesions were examined. - Statistics:
- Data on body weights of parental animals, food consumption, grip strength, locomotor activity count, haematology and blood chemistry, urine volume, urine specific gravity, organ weights, body weights on necropsy, mean oestrous cycle length, pairing days until copulation, gestation length, number of implantation sites, number of pups born, number of live pups, body weights of pups, AGD, number of nipples/areolae and T4 level of pups were analysed by Bartlett’s test for homogeneity of variance. If significant difference was not noted, the values of the control group and each test item group were analysed by Dunnet’s test. If significant difference was noted in the Bartlett test, the nonparametric Dunnet’s test was performed. The frequencies of defecation and urination were analysed by nonparametric Dunnett’s test. Body weights of pups were calculated on each sex as sample unit for each litter. Abnormal oestrous cyclicity, copulation index, conception index and delivery dam index were analysed by Fisher’s exact test between the control group and each test item group.
Indexes of delivery, birth, viability and sex ratio were examined by Bartlett’s test. If significant difference was not noted, the values of the control group and each test item group were analysed by Dunnet’s test. If significant difference was noted, the nonparametric Dunnet’s test was performed.
Data regarding body weights and food consumption during the recovery period, and parameters of haematology and blood chemistry, urine volume, urine specific gravity, organ weights and body weights at necropsy day for the recovery group were analysed by F-test for variance ratio. If there were no significant differences at a significance level of 5%, the Student t-test was performed. If there were significant differences at a significance level of 5% in the F-test, the Aspin-Welch test was performed. The frequencies of defecation and urination during the recovery period were analysed by Mann-Whitney U-test. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, 1/10 females showed staining around the nose and mouth on the day of delivery. At 300 mg/kg bw/day, 1/10 animals showed incomplete treatment of placenta and died during delivery. The effects were not related to treatment. There were no findings in males.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- There was no mortality at 1000 mg/kg bw/day. At 100 and 300 mg/kg bw/day, each 1/10 females died during delivery. The deaths were not related to treatment.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a statistically significant decrease in food consumption noted in males at 1000 mg/kg bw/day on Day 7 of the recovery period. As no findings were observed during the treatment-period and there were no related changes in body weight, the decrease was considered toxicologically not significant. For details, please refer to Table 1 under "Any other information on results incl. tables".
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In males at 100 mg/kg bw/day, MCHC was decreased (-2%). The finding was without any dose-response relationship and therefore not attributed to treatment.
There were no findings in mating females. In non-mating females, there was an increase in neutrophils (+60%) and a decrease in lymphocytes (-8%) at 1000 mg/kg bw/day. The findings were within the laboratory’s historical control range and, in the absence of any related changes, considered to be incidental.
After the recovery period, males of the 1000 mg/kg bw/day group showed an increase in reticulocytes (+20%), and females of the 1000 mg/kg bw/day group showed an elongated APTT (+1.5 s). The findings were not observed during the treatment period and/or within the laboratory’s historical control data and therefore not related to treatment.
For details, please refer to Table 2 under “Any other information on results incl. tables”. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a statistically significant increase in chloride concentration in non-mating females at 1000 mg/kg bw/day (+2%). The finding fell within the laboratory’s historical control range and there were no related findings, therefore the change was considered to be incidental. For details, please refer to Table 2 under “Any other information on results incl. tables”.
- Endocrine findings:
- not specified
- Description (incidence and severity):
- The following ED-related parameters were investigated in the study: T4 hormone levels, epididymides weight and histopathology, oestrus cyclicity, liver weight, mammary gland histopathology, ovary weight and histopathology, prostate weight and histopathology, seminal vesicles (with coagulating glands) weight and histopathology, testes weight and histopathology, thyroid weight and histopathology, uterus (with cervix) weight and histopathology, vagina histopathology, vaginal smears, adrenals weight and histopathology, brain weight and pituitary histopathology, fertility, foetal development, gestation length, litter size, litter viability, litter/pup weight, number of implantations and corpora lutea, number of live births, pre- and post-implantation losses, presence of anomalies, reproduction and sex ratio.
For details, please refer to the respective result fields and the endpoint summary. - Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, 1/10 males showed epithelial cells in the urine. In non-mating females, cloudy urine and white blood cells were observed at 0 and 1000 mg/kg bw/day without dose-relationship after treatment and after recovery. Epithelial cells were observed in the control group only. The findings were not related to treatment.
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, females showed decreased motor activity in the 50-60 min interval. The change was considered as single occurrence since no abnormal changes were observed in total (0-60 min interval) and there were no related changes in other parameters. There were no findings at 100 or 300 mg/kg bw/day. For details, please refer to Table 3 under "Any other information on results incl. tables".
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In males, absolute (+17%) and relative (+23%) adrenal weight were increased at 100 mg/kg bw/day. In addition, relative thymus weight was decreased (-19%) at 100 mg/kg bw/day. In mated females, absolute adrenal weight was increased (+15%) at 300 mg/kg bw/day. In the absence of a dose-response relationship the findings were considered to be incidental.
After the recovery period, absolute (-1%) and relative (-10%) spleen weight were statistically significantly decreased in females at 1000 mg/kg bw/day. As no findings were noted during the treatment period and in the absence of histopathological findings, the effects were considered toxicologically not significant. For details, please refer to Table 4 under "Any other information on results incl. tables". - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In females, macroscopic findings of spontaneous origin comprised blackish region and recessed region of the mucosa of the glandular stomach in all control and test item-treated groups. There was no dose-response relationship evident. For details, please refer to Table 5 under "Any other information on results incl. tables".
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related findings. Any observations occurred sporadically in control and test item-treated animals. The dead female at 100 mg/kg bw/day had staining of the lower abdomen, dark reddish change and oedematous change of the lungs, perforation in the forestomach and blackish region of the mucosa of the glandular stomach. The dead female at 300 mg/kg bw/day showed staining in the lower abdomen, dark reddish change and oedematous change of the lungs, bilateral discoloration if the kidneys, small thymus, bilateral enlargement of the adrenals and hydrothorax.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Thyroid hormone levels (T4) in males:
T4 levels were not affected by treatment at any dose level. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
- Key result
- Critical effects observed:
- no
- Conclusions:
- Based on the results of the study, the NOAEL for systemic toxicity was 1000 mg/kg bw/day in male and female rats.
Reference
Table 1: Summary of food consumption data in males (g/rat/day)
Males | ||||
Dose (mg/kg bw/day) | 0 | 100 | 300 | 1000 |
Group | Main + Recovery | Main | Main | Main + Recovery |
Day 3 | 26.23 ± 1.68 | 26.80 ± 1.59 | 27.19 ± 1.89 | 27.18 ± 0.68 |
Day 7 | 26.31 ± 1.58 | 27.40 ± 2.27 | 27.39 ± 1.65 | 26.96 ± 1.46 |
Day 14 | 25.95 ± 1.28 | 26.65 ± 1.88 | 27.03 ± 1.82 | 26.23 ± 1.06 |
Day 28 | 26.16 ± 1.22 | 27.51 ± 1.50 | 27.08 ± 1.87 | 26.21 ± 1.77 |
Recovery period Day 7 | 26.62 ± 1.29 | - | - | 24.94 ± 0.90* |
Recovery period Day 14 | 26.34 ± 2.16 | - | - | 26.20 ± 1.87 |
* significantly different from control at p < 0.05 |
Table 2: Summary of findings in haematology and clinical chemistry findings
Males | Females | |||||||||||||
Main group | Recovery group | Main group (Mating) | Non-mating | Recovery group (Mating) | ||||||||||
Dose (mg/kg bw/day) | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 1000 |
Number of animals | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
Haematology parameters | ||||||||||||||
MCHC (g/dL) | 36.44 ± 0.13 | 35.80 ± 0.51* | 35.90 ± 0.38 | 36.32 ± 0.41 | 36.86 ± 0.51 | 36.52 ± 0.81 | 36.58 ± 0.54 | 36.60 ± 0.43 | 35.68 ± 0.78 | 36.18 ± 0.53 | 36.30 ± 0.46 | 36.34 ± 0.68 | 36.16 ± 0.49 | 36.18 ± 0.73 |
Reticulo (%) | 4.034 ± 0.321 | 4.038 ± 0.533 | 3.888 ± 0.999 | 3.686 ± 0.375 | 3.302 ± 0.260 | 3.954 ± 0.354* | 4.056 ± 1.321 | 3.286 ± 0.741 | 4.750 ± 2.303 | 4.258 ± 0.707 | 3.696 ± 0.550 | 3.756 ± 0.741 | 3.572 ± 0.371 | 3.980 ± 0.375 |
HCD mean Range: mean ± 2 SD |
3.079 2.26 - 3.72 2.267 - 3.891 |
not reported | ||||||||||||
Neutro (%) | 19.34 ± 7.26 | 17.10 ± 4.87 | 22.32 ± 5.41 | 18.52 ± 1.35 | 16.98 ± 1.19 | 21.18 ± 5.56 | 44.70 ± 6.44 | 45.32 ± 4.56 | 39.42 ± 7.82 | 37.48 ± 8.71 | 11.78 ± 4.45 | 18.84 ± 2.49* | 18.48 ± 3.91 | 16.66 ± 6.48 |
HCD mean Range: mean ± 2 SD |
not reported | 20.49 11.4 - 36.2 3.95 - 37.03 |
||||||||||||
Lymph (%) | 74.72 ± 7.83 | 76.48 ± 5.26 | 71.70 ± 5.78 | 75.24 ± 1.20 | 75.60 ± 2.63 | 71.58 ± 6.79 | 48.84 ± 6.64 | 47.18 ± 4.83 | 53.92 ± 6.77 | 55.30 ± 7.25 | 83.22 ± 4.68 | 76.44 ± 2.77* | 75.66 ± 4.90 | 78.00 ± 6.60 |
HCD mean Range: mean ± 2 SD |
not reported | 74.31 58.2 - 84.2 57.25 - 91.37 |
||||||||||||
APTT (sec) | 24.80 ± 2.63 | 25.10 ± 1.59 | 25.20 ± 1.62 | 24.48 ± 2.22 | 25.02 ± 1.19 | 24.86 ± 3.82 | 17.90 ± 0.57 | 18.44 ± 2.32 | 17.66 ± 1.61 | 17.24 ± 1.66 | 19.68 ± 1.29 | 18.14 ± 2.11 | 15.38 ± 2.09 | 19.40 ± 1.08** |
HCD mean Range: mean ± 2 SD |
not reported | 16.63 9.4 - 18.9 12.37 - 20.89 |
||||||||||||
Clinical chemistry parameters | ||||||||||||||
Chloride (mEq/L) | 106.22 ± 1.08 | 105.56 ± 0.83 | 106.10 ± 0.88 | 105.42 ± 0.46 | 105.18 ± 1.18 | 104.74 ± 1.13 | 100.60 ± 3.12 | 101.18 ± 2.14 | 102.28 ± 2.49 | 101.00 ± 2.37 | 106.42 ± 1.36 | 108.96 ± 1.00** | 106.72 ± 1.25 | 105.84 ± 0.89 |
HCD mean Range: mean ± 2 SD |
not reported | 107.06 103.7 - 109.6 103.80 - 110.32 |
||||||||||||
significantly different from control at * p < 0.05 and ** p < 0.01; MCHC: mean corpuscular haemoglobin concentration; Reticulo: reticulocytes; Neutro: neutrophils; Lymph: lymphocytes; APTT: activated partial thromboplastine time; HCD: historical control data |
Table 3: Summary of findings on motor activity in males and non-mating females during Week 4 and in mating females during Week 7
Males | Females | |||||||||
Non-mating | Mating | |||||||||
Dose (mg/kg bw/day) | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 100 | 300 | 1000 |
Number of animals | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
0-10 | 45 ± 28 | 44 ± 36 | 30 ± 16 | 36 ± 6 | 74 ± 60 | 93 ± 21 | 48 ± 17 | 30 ± 21 | 30 ± 25 | 25 ± 31 |
10-20 | 19 ± 12 | 18 ± 11 | 16 ± 2 | 20 ± 10 | 29 ± 30 | 54 ± 30 | 36 ± 26 | 15 ± 13 | 9 ± 8 | 13 ± 15 |
20-30 | 8 ± 4 | 12 ± 14 | 18 ± 7 | 19 ± 10 | 25 ± 27 | 34 ± 24 | 13 ± 11 | 7 ± 11 | 20 ± 21 | 3 ± 4 |
30-40 | 7 ± 8 | 7 ± 6 | 5 ± 4 | 7 ± 10 | 8 ± 13 | 26 ± 21 | 22 ± 22 | 4 ± 5 | 7 ± 10 | 7 ± 11 |
40-50 | 9 ± 6 | 13 ± 13 | 6 ± 5 | 13 ± 14 | 3 ± 3 | 12 ± 18 | 3 ± 4 | 3 ± 5 | 5 ± 8 | 9 ± 18 |
50-60 | 2 ± 2 | 4 ± 6 | 7 ± 10 | 4 ± 3 | 7 ± 8 | 19 ± 15 | 32 ± 17 | 8 ± 11 | 13 ± 14 | 1 ± 1** |
Total | 91 ± 46 | 99 ± 63 | 83 ± 34 | 99 ± 36 | 145 ± 120 | 236 ± 67 | 153 ± 84 | 66 ± 23 | 84 ± 63 | 57 ± 53 |
**: significantly different from control at p < 0.01 |
Table 4: Organ weight findings
Males | Females | |||||||||||||
Main group | Recovery group | Main group (Mating) | Non-mating | Recovery group (Mating) | ||||||||||
Dose (mg/kg bw/day) | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 1000 |
Number of animals | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
Adrenals | ||||||||||||||
Absolute weight (mg) | 55.22 ± 3.53 | 69.81 ± 12.28* | 64.75 ± 6.24 | 67.50 ± 12.82 | 62.02 ± 8.26 | 64.62 ± 7.09 | 73.21 ± 12.29 | 79.71 ± 10.86 | 84.44 ± 8.45* | 74.57 ± 6.48 | 63.98 ± 13.00 | 70.92 ± 9.91 | 68.00 ± 7.07 | 68.68 ± 4.09 |
Relative weight (mg/100 g) | 12.14 ± 1.15 | 14.97 ± 2.54* | 13.87 ± 1.57 | 14.84 ± 2.36 | 12.58 ± 1.24 | 13.14 ± 1.75 | 24.59 ± 4.17 | 27.43 ± 3.17 | 28.27 ± 3.25 | 24.56 ± 2.07 | 24.78 ± 4.42 | 27.56 ± 3.33 | 24.32 ± 2.96 | 24.52 ± 2.84 |
Thymus | ||||||||||||||
Absolute weight (mg) | 504.76 ± 70.34 | 414.48 ± 75.77 | 450.27 ± 78.89 | 473.36 ± 41.05 | 387.86 ± 115.89 | 319.94 ± 82.94 | 198.35 ± 70.76 | 160.28 ± 36.57 | 182.62 ± 70.39 | 203.13 ± 39.22 | 411.42 ± 79.20 | 391.66 ± 98.01 | 348.94 ± 100.21 | 302.60 ± 78.16 |
Relative weight (mg/100 g) | 110.26 ± 13.35 | 89.19 ± 17.03* | 95.77 ± 12.61 | 104.34 ± 7.44 | 78.00 ± 18.93 | 65.00 ± 17.36 | 66.28 ± 21.98 | 55.40 ± 13.50 | 61.09 ± 23.42 | 67.06 ± 13.88 | 159.78 ± 28.74 | 151.66 ± 33.75 | 122.54 ± 24.70 | 106.24 ± 20.32 |
Spleen | ||||||||||||||
Absolute weight (g) | 0.690 ± 0.074 | 0.797 ± 0.106 | 0.812 ± 0.115 | 0.766 ± 0.186 | 0.762 ± 0.090 | 0.838 ± 0.124 | 0.498 ± 0.076 | 0.501 ± 0.049 | 0.531 ± 0.064 | 0.561 ± 0.083 | 0.516 ± 0.092 | 0.532 ± 0.071 | 0.612 ± 0.044 | 0.512 ± 0.081* |
Relative weight (g/100 g) | 0.152 ± 0.013 | 0.172 ± 0.022 | 0.172 ± 0.017 | 0.170 ± 0.042 | 0.156 ± 0.013 | 0.170 ± 0.030 | 0.166 ± 0.021 | 0.174 ± 0.018 | 0.179 ± 0.023 | 0.184 ± 0.026 | 0.200 ± 0.035 | 0.208 ± 0.033 | 0.220 ± 0.010 | 0.180 ± 0.025* |
* significantly different from control at p < 0.05 |
Table 5: Gross necropsy findings in the glandular stomach
Males | Females | |||||||||||||
Main group | Recovery group | Main group (Mating) | Non-mating | Recovery group (Mating) | ||||||||||
Dose (mg/kg bw/day) | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 100 | 300 | 1000 | 0 | 1000 | 0 | 1000 |
Number of animals examined | 5 | 5 | 5 | 5 | 5 | 5 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Glandular stomach | ||||||||||||||
Blackish region of mucosa | 0/5 | 0 | 0 | 0 | 0 | 0 | 5 | 4/0/1# | 4/0$ | 3/0§ | 1 | 0 | 0 | 0 |
Recessed region of mucosa | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0/0/0# | 0/0$ | 0/0§ | 0 | 0 | 0 | 0 |
#: scheduled sacrifice animal/ not copulated animal/ dead animal;$: scheduled sacrifice animal/ dead animal;§: scheduled sacrifice animal/ female animal did not deliver her pups |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises an adequate and reliable (Klimisch score 1) study performed with the registered substance, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, of Regulation (EC) No. 1907/2006.
Repeated dose toxicity: inhalation - systemic effects
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
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Oral repeated dose toxicity:
Sorbitan tridocosanoate was investigated in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD guideline 422 and in compliance with GLP (Riken Vitamin, 2021).The dose levels for the main study were selected based on the results of a preliminary 14-days dose range finding study.
Groups of 10 male and 10 female Crl:CD(SD) rats were exposed daily to the test item by oral gavage at doses of 100, 300 and 1000 mg/kg bw/day. Additional 10 rats/sex received the vehicle (5% gum arabicum solution) and served as control. A second control group of 10 non-mated animals/sex was included for the control and high dose group.
In the present study, male rats were treated daily for a total of 29 days, starting from 14 days prior to mating and including the mating period. Females that delivered were treated daily for 14 days prior to mating, throughout mating and gestation until lactation Day 13. Non-mating females of the satellite group were treated for 29 days.
Each 5 rats/sex of the control and high dose group from the main study and 5 rats/sex of the control and high dose group from the non-mated groups were observed for a 14-day recovery period.
Observations and examinations of the animals included mortality, clinical signs, detailed physical examination and arena observations, functional neurobehavioral observations (for 5 selected animals/sex/group), body weight, food consumption, oestrous cycle determination, haematology (for 5 selected animals/sex/group), clinical chemistry (for 5 selected animals/sex/group), measurement of thyroid hormones T4 in parental males, gross necropsy, organ weights and histopathology. For examinations on reproductive and developmental toxicity, please refer to IUCLID section 7.8.1.
Stability, homogeneity and achieved concentrations of the test item formulations in gum arabicum solution were confirmed by analytical methods.
There was no mortality that was considered to be related to treatment. Each one female of the 100 and 300 mg/kg bw/day groups died during delivery. Clinical signs of toxicity comprised staining around the nose on the day of delivery in 1/10 females at 1000 mg/kg bw/day and incomplete treatment of placenta in 1/10 females at 300 mg/kg bw/day which died during delivery. The effects were not related to treatment. There were no treatment-related findings with regard to physical examination and arena observation in males or females before pairing, in females during gestation or in females during lactation. At 1000 mg/kg bw/day, females showed decreased motor activity in the 50 - 60 min interval. The change was considered as single occurrence since no abnormal changes were observed in total (0 - 60 min interval) and there were no related changes in other parameters.
There were no adverse findings on body weight development or food consumption. Haematology findings comprised a slight decrease in MCHC in males of the 100 mg/kg bw/day group (-2%), an increase in neutrophils (+60%) as well as a decrease in lymphocytes (-8%) in non-mated females at 1000 mg/kg bw/day, an increase in reticulocytes (+20%) in males at 1000 mg/kg bw/day after recovery and an elongated APTT (+1.5 sec) in females at 1000 mg/kg bw/day after recovery. The findings were either not dose-related, within the laboratory’s historical control data and/or observed during the recovery period only and therefore not attributed to treatment.
Clinical chemistry showed a statistically significant increase in chloride in non-mating females at 1000 mg/kg bw/day (+2%), which fell within the laboratory’s historical control range and, in the absence of any related findings, was considered to be incidental.
Findings in urinalysis comprised epithelial cells in the urine of 1/10 males at 1000 mg/kg bw/day and cloudy urine as well as white blood cells in non-mating females at 0 and 1000 mg/kg bw/day after treatment and recovery. Without a dose-response relationship, all observations were considered unrelated to treatment.
Gross necropsy revealed no treatment-related macroscopical abnormalities. In females, macroscopic findings of spontaneous origin comprised blackish region and recessed region of the mucosa of the glandular stomach in all control and test item-treated groups. There was no dose-response relationship evident.
In males, absolute (+17%) and relative (+23%) adrenal weight were increased at 100 mg/kg bw/day. In addition, relative thymus weight was decreased (-19%) at 100 mg/kg bw/day. In mated females, absolute adrenal weight was increased (+15%) at 300 mg/kg bw/day. In the absence of a dose-response relationship, the findings were considered to be incidental. After the recovery period, absolute (-1%) and relative (-10%) spleen weight were statistically significantly decreased in females at 1000 mg/kg bw/day. As no findings were noted during the treatment period and in the absence of histopathological findings, the effects were considered toxicologically not significant.
Histopathological examination revealed no treatment-related findings in any organ. A number of observations occurred sporadically in control and test item-treated animals.
In conclusion, as no adverse effects of systemic toxicity were observed in the animals at any dose level tested, the No-Observed-Adverse-Effect-Level (NOAEL) for systemic toxicity was established at 1000 mg/kg bw/day in male and female rats.
Justification for classification or non-classification
The available data on repeated dose toxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.
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