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EC number: 283-042-4 | CAS number: 84539-54-8
- 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
Endpoint summary
Administrative data
Description of key information
In a 28-day oral (gavage) key repeated dose toxicity study in rats conducted with the nearest analogue Fe(3K)EDDHSA, the NOEL was established at 1000 mg/kg bw/day, the highest dose level tested. No treatment- related effects were observed in animals in any parameter tested. In a key subacute 28-day dermal toxicity study conducted with another closely related substance Fe(Na)EDDHA, the NOEL was established at 100 mg/kg bw/day based on slight effects on the liver and skin and due to increased adrenal weight noted at the high dose level of 1000 mg/kg bw/day. No data on repeated inhalation exposure are required. Exposure by the inhalation route is considered to be negligible. The target substance Fe(3Na)EDDHSA does not need to be classified for systemic organ toxicity after repeated exposures.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2000-08-29 to 2000-10-06
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EEC, directive No. 96/54, B7, 30th September 1996
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 424 (Neurotoxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA, guideline 799, 9620-62-128, 15th August 1997
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
44 Sprague-Dawley rats (22 males and 22 females) were received at test facility.
- Source: Iffa Credo, L'Arbresle, France
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: 196 g (range: 182 g to 209 g) for the males and 156 g (range: 137 g to 175 g) for the females
- Fasting period before study: no
- Housing: individually in suspended wire-mesh cages (43.0 cm x 21.5 cm x 18.0 cm). A metal tray containing autoclaved sawdust (SICSA, Alfortville, France) was placed under each cage.
- Diet (e.g. ad libitum): free access to A04 C pelleted maintenance diet, batch No. 00331 (UAR, Villemoisson, Epinay-sur-Orge, France. Prior blood sampling the animals were fasted overnight.
- Water (e.g. ad libitum): filtered tape water
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2,
- Humidity (%): 50 ± 20
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- purified water, obtained by reverse osmosis
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was dissolved in the required quantity of vehicle in order to achieve the concentrations of 30, 90 and 200 mg/mL and then homogenized using a magnetic stirrer.
The test substance dosage forms were made up to 4 days from days 1 to 3 and up to 9 days, from day 4 of treatment, and were stored at +4°C prior to use. The dosage forms were delivered each day to the animal room.
VEHICLE
- Concentration in vehicle: 30, 90 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Chemical analysis of the dosage forms
Before the start of treatment, the suitability of the proposed dosage form preparation procedure was determined by the analysis of stability of dosage forms which were prepared using this procedure. During the treatment period, the concentration of the test material was checked in dosage forms prepared for use in the study.
Stability
Two dosage forms were prepared to evaluate the stability:
- a dosage form at low concentration (2 mg/mL),
- a dosage form at high concentration (200 mg/mL). Each dosage form was analysed immediately after preparation and was then stored at 4°C (protected from light) and sampled after 4 and 9 days storage. Samples taken on days 4 and 9 were analyzed as soon as possible after sampling.
Concentration
The concentration of samples taken from each dosage form (including the control) prepared for use in weeks 1 and 4 was determined. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 150, 450 and 1000 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The dose-levels were selected on the basis of the results of a 7-day range-finding toxicity study by oral route performed in the same species (CIT/Study No. 20508 TSR) in which no clinical signs or macroscopic findings were noted in any treated groups. Consequently the same dose-levels were selected. - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice a day for mortality or signs of morbidity and at least once a day for clinical signs
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before the first day of treatment and then at the end of weeks 1, 2, 3 and 4 (at least 12 hours after the last treatment. All animals of each group were observed in the cage, in the hand and in the standard arena, by observers unaware of the animal's treatment. Detailed clinical observation in week 4 was performed before blood sampling.
The following parameters were assessed:
- in the hand: fur appearance, salivation, lachrymation, piloerection, exophthalmia, reactivity to handling, pupil size (presence of myosis or mydriasis),
- in the standard arena (2-minute recording): grooming, palpebral closure, defecation and urination counts, tremors, twitches, convulsions, gait, arousal (hypo- and hyper- activity), posture, stereotypic behaviour and breathing, ataxia, hypotonia.
BODY WEIGHT: Yes
- Time schedule for examinations: once before allocation of the animals into groups, on the first day of treatment, and then once a week until the end of the study.
FOOD CONSUMPTION (gavage study):
The quantity of food consumed by the animals of each cage was recorded once a week, over a 7-day period, until the end of the study (calculated as mean values in g/animal/day)
OPHTHALMOSCOPIC EXAMINATION: No (pupil reflex was examined: see Neurobehavioural Examination)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of week 4
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes, prior to blood sampling, the animals were deprived of food for an overnight period of at least 14 hours
- How many animals: all animals
- Parameters were examined:
Erythrocytes (RBC)
Hemoglobin (HB)
Mean Cell Volume (MCV)
Packed Cell Volume (PCV)
Mean Cell Hemoglobin Concentration (MCHC)
Mean Cell Hemoglobin (MCH)
Thrombocytes (PLAT)
Leucocytes (WBC)
Differential White Cell count with cell morphology: neutrophils (N), eosinophils (E), basophils (B), lymphocytes (L), monocytes (M)
Prothrombin Time
Activated Partial Thromboplastin Time
Fibrinogen
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of week 4
- Animals fasted: Yes, prior to blood sampling, the animals were deprived of food for an overnight period of at least 14 hours
- How many animals: all animals
- Parameters were examined:
Sodium (Na+), Potassium (K+), Chloride (C1-), Calcium (Ca++)
Inorganic phosphorus (I.PHOS) Glucose (GLUC)
Urea (UREA)
Creatinine (CREAT)
Total Bilirubin (TOT.BIL)
Total Proteins (PROT)
Albumin (ALB)
Albumin/globulin ratio (A/G)
Cholesterol (CHOL)
Triglycerides (TRIG)
Alkaline phosphatase (ALP)
Aspartate aminotransferase (ASAT)
Alanine aminotransferase (ALAT)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: All animals were evaluated before the first day of treatment, and then at the end of week 4, at least 12 hours after the last treatment. The observer performing the evaluation was not aware of the treatment group of the animal.
Reactivity to manipulation or to different stimuli in week 4 was performed before blood sampling.
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity / grip strength / motor activity (was measured by automated infra-red sensor equipment recording individual animal activity over 30-min period, before the first day of treatment and then in week 4)/ other: pupil reflex, visual stimulus, auditory startle reflex, tail pinch response, righting reflex, landing foot splay, at the end of observation: rectal temperature
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
A complete macroscopic post-mortem examination was performed on all study animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.
HISTOPATHOLOGY: Yes
A microscopic examination was performed on:
- all tissues listed in the tissue procedures table (please refer to table in "Any other information on materials and methods incl. tables" for animals of the control and high-dose groups (groups 1 and 4) killed at the end of the treatment period,
all macroscopic lesions of all the animals of the low- and intermediate- dose groups (groups 2 and 3) killed on completion of the treatment period. - Other examinations:
- ORGAN WEIGHTS
The organs specified in the Tissue Procedures Table ((please refer to table in "Any other information on materials and methods incl. tables") were weighed wet as soon as possible after dissection. The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated. - Statistics:
- Scheme of statistical analysis is attached (see below)
- 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:
- not examined
- 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:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortalities and no treatment-related clinical signs were noted.
BODY WEIGHT AND WEIGHT GAIN
The mean body weight gain of males and females given the test substance at 150, 450 and 1000 mg/kg/day was similar to that of respective control groups throughout the treatment period (males: +158 g, +139 g and +145 g vs. +146 g in controls; females: +66 g, +74 g and + 76 g vs. +70 g in controls
FOOD CONSUMPTION
The mean food consumption of males and females given the test substance was similar to that of respective control groups throughout the treatment period.
HAEMATOLOGY
No toxicologically significant changes were noted
CLINICAL CHEMISTRY
No treatment-related differences from controls were noted in the treated animals for all the parameters examined.
NEUROBEHAVIOUR
No specific signs of a neurotoxic action of the test substance were noted.
ORGAN WEIGHTS
No treatment-related effects were noted in the organ weights.
GROSS PATHOLOGY
The following necropsy findings were noted in the digestive tract:
blackish contents were noted in several parts of the digestive tract of treated animals as follows:
- stomach, in 1/5 males given 1000 mg/kg/day,
- ileum in 1/5 females given 450 mg/kg/day and in 1/5 males given 1000 mg/kg/day,
- cecum, in 1/5 females given 150 mg/kg/day, in 4/5 males and all the females given 450 mg/kg/day and in 4/5 males and all the females given 1000 mg/kg/day,
- colon, in 1/5 females given 150 mg/kg/day, in 3/5 males and 4/5 females given 450 mg/kg/day and in 3/5 males and 1/5 females given 1000 mg/kg/day,
- rectum, in 1/5 males given 450 mg/kg/day and in 1/5 males given 1000 mg/kg/day.
Microscopic examination revealed no changes that related to this blackish material which was consequently considered to be a remnant of the test substance and therefore of no toxicological importance.
HISTOPATHOLOGY: NON-NEOPLASTIC
No changes were seen that were related to treatment.
OTHER FINDINGS
No other findings - Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects were noted in any parameter tested
- Critical effects observed:
- not specified
- Conclusions:
- The daily administration of the test substance, EDDHAS Fe 3K (batch No. CED 0701), at the dose-levels of 150, 450 and 1000 mg/kg/day, by oral route (gavage) to rats for 28 days did not produce any signs of toxicity.
Consequently, under our experimental conditions, the No Observable Effect Level (NOEL) was established at 1000 mg/kg/day. - Executive summary:
The objective of this study was to evaluate the potential toxicity of the test substance, EDDHAS Fe 3K, following daily oral administration (gavage) to Spague-Dawley rats for 28 days.
Methods
Groups of five males and five females Sprague-Dawley rats received the test substance, EDDHAS Fe 3K, daily by gavage at the dose-levels of 150, 450 or 1000 mg/kg/day for 28 days. An additional group of five males and five females received the vehicle alone (purified water) under the same experimental conditions, and acted as a control group. The animals were checked daily for mortality and clinical signs. A functional observation battery was performed on all animals of each group, once in predose and then in week 4; in addition, a detailed clinical observation was performed on all animals of each group, once a week until the end of the treatment period. Motor activity was recorded on all animals once in predose and in week 4. Body weight and food consumption were recorded once a week. Hematological and blood biochemical investigations were performed for all animals at the end of the treatment period. On completion of the treatment period, all animals were killed and submitted to a complete macroscopic post-mortem examination. Designated organs were weighed and selected tissues were preserved. A microscopic examination was performed on designated tissues of the animals of the control and high dose-level group.
Results
Mortality
No unscheduled deaths occurred during the study.
Clinical signs
No clinical signs of toxicological significance were observed in any treated animals.
Functional observation battery and motor activity
No specific signs of a neurotoxic action of the test substance were noted.
Body weight and food consumption
Overall body weight gains were similar in control and treated groups and food consumption was considered to be unaffected by treatment.
Hematology and blood biochemistry
No changes of toxicological significance were noted in any parameters.
Organ weights
No notable differences in organ weights were noted between control and treated groups.
Macroscopic and microscopic examinations
No changes of toxicological importance were observed.
Conclusion
The daily administration of the test substance, EDDHAS Fe 3K, at the dose-levels of 150, 450 and 1000 mg/kg/day, by oral route (gavage) to rats for 28 days did not produce any signs of toxicity. Consequently, under our experimental conditions, the No Observable Effect Level (NOEL) was established at 1000 mg/kg/day.
Reference
Chemical Analyses of the Dosage Forms
Stability
The results of the analyses demonstrated a satisfactory stability of the two dosage forms over a 9-day period at +4°C (protected from light).
Concentration
Throughout the study, a satisfactory agreement was observed between the nominal and actual concentrations of the test material in the dosage forms administered since the deviations from nominal concentration were in the requested range of +10%.
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:
- There is no deficiencies in the available data set. The data on structurally related substances is reliable and consisitent.
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: inhalation
- Data waiving:
- exposure considerations
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: inhalation
- Data waiving:
- exposure considerations
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
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
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1996-01-26 to 1995-03-03
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Sprague-Dawley derived; Tif:RAIf (SPF); hybrids of RII/1 x RII/2
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Laboratory Animal Breeding, Pharmaceutical Division, CIBA-GEIGY Limited, 4332 Stein, Switzerland
- Age at study initiation: young adult, based on body weight ranges
- Weight range at acclimation period: 213.9-228.1 g (males), 211.8-235.7 g (females)
- Housing: individually, in macrolon cages type 3 with wire mesh tops and granulated soft wood bedding
- Diet: pelleted, certified standard diet Nafag No. 890 (NAFAG AG, Gossau, SG, Switzerland), provided ad libitum (exception: food was withheld overnight prior to blood removal performed at the end of the treatment period)
- Water: tap water, ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 55 ± 15 %
- Air changes: approximately 15 air changes/hour
- Photoperiod: 12 hours dark / 12 hours light - Type of coverage:
- occlusive
- Vehicle:
- water
- Details on exposure:
- TEST SITE
- Area of exposure: dorsal area of the trunk
- Coverage: at least 10 % of the body surface area
- Type of wrap: gauze patches, aluminium foil and adhesive but non-irritating tape
- Time intervals for shavings or clipplings: once weekly
REMOVAL OF TEST SUBSTANCE
- Washing: with lukewarm water
- Time after start of exposure: 6 hours (on each day of treatment)
TEST MATERIAL/VEHICLE
- Amount applied: 4 mL/kg bw
- Concentrations: 2.5, 25 and 250 mg/mL
- Constant volume used: yes, adjusted weekly to individual animal body weight
USE OF RESTRAINERS FOR PREVENTING INGESTION: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Control analyses of the test item concentration in the vehicle was carried out at all dose levels on samples collected on experimental days 1, 7, 14 and 21. Samples were analysed by RCC Umweltchemie AG, 4452 Itingen, Switzerland (Project No. 329207). The test article concentrations in the vehicle were found to be in the range from 82.5 % to 105.3 % of the nominal concentrations.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 6 hours per day, on 5 days per week
- Remarks:
- Doses / Concentrations:
0, 10, 100 and 1000 mg/kg bw/day
Basis:
nominal per unit body weight - No. of animals per sex per dose:
- 5 animals
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: no rationale is given in the report.
- Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule: twice daily on working days and once daily on weekend days for mortality, and once daily for general observations.
- Skin irritation: Following each application, approximately 17 hours after patch removal, local skin reactions at the application site were assessed according to Draize et al. (1944).
BODY WEIGHT:
- Time schedule: on study days -7, 1, 8,15, 22 and 28
FOOD CONSUMPTION:
- Food consumption for each animal was determined weekly and mean daily diet consumption calculated as g food/kg bw/day.
HAEMATOLOGY:
- Time schedule for collection of blood: once, at the end of the treatment period
- Anaesthetic used for blood collection: ether
- Animals fasted: food was withheld overnight prior to blood sampling
- How many animals: all animals
- Parameters examined: erythrocyte count, haematocrit, mean corpuscular volume, red cell volume distribution width, haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, haemoglobin concentration distribution width, prothrombin time and leukocyte, neutrophil, eosinophil, basophil, lymphocyte, monocyte, large unstained cells and thrombocyte counts
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: once, at the end of the treatment period
- Animals fasted: food was withheld overnight prior to blood sampling
- How many animals: all animals
- Parameters examined: glucose, urea, creatinine, total bilirubin, total protein, albumin, globulin, cholesterol, triglycerides, sodium, potassium, calcium, chloride and inorganic phosphorus concentration, and A/G ratio and aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY:
The following organs or tissues were examined microscopically:
skin application site, skin remote site, liver, spleen, kidneys, thymus, thyroid with parathyroid gland, prostate, seminal vesicle, testis, epididymis, ovary - Other examinations:
- ORGAN WEIGHT
The weights of the following organs were determined at necropsy:
brain, heart, liver, kidneys, adrenals, thymus, ovaries or testes, and spleen - Statistics:
- Each treated group was compared to the control group by Wilcoxon's two-sample test (non-parametric) and tested for increasing or decreasing trends from control up to the respective dose group by Jonckheere's test for ordered alternatives (parametric).
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- 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:
- 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:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No treatment related clinical signs and changes in behavior were noted and all animals survived.
BODY WEIGHT AND WEIGHT GAIN
A slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. Otherwise the body weight was comparable in all groups: "During week 1 of treatment, female group 4 (1000 mg/kg) did not gain body weight. Afterwards, mean body weight gain was essentially comparable to that of the control group. At end of treatment the mean body weight was 4% lower than that of the control group".
FOOD CONSUMPTION
Food consumption was not influenced by treatment.
HAEMATOLOGY AND CLINICAL CHEMISTRY
No effects on haematology and clinical chemistry parameters were noted.
ORGAN WEIGHTS
There was an increased adrenal weight in males at 1000 mg/kg bw/day: "Mean absolute and relative adrenal weights of males in group 4 (1000 mg/kg) were 23 % and 22 % higher than those of the control group, respectively".
GROSS PATHOLOGY
No treatment related macroscopical findings were noted.
HISTOPATHOLOGY
The skin application site of females treated at 1000 mg/kg bw revealed epidermal hyperkeratosis and an increased severity of acanthosis. In one female, an additional epidermal parakeratosis and a chronic dermal inflammation were observed. In 2/5 males at 1000 mg/kg bw, centrilobular hypertrophy of hepatocytes was noted. - Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on slight effects on the liver and skin and due to increased adrenal weight noted at 1000 mg/kg bw/day.
- Critical effects observed:
- not specified
- Conclusions:
- Under the conditions of this test, dermal treatment of rats with FeNaEDDHA resulted in depressed body weight gain of females during week 1 of treatment at 1000 mg/kg body weight with consequent marginal body weight reduction at study end as compared to controls. All animals survived to scheduled sacrifice, and no clinical signs of overt toxicity were noted.
Histopathological examination revealed local intolerance at the skin application site for the high dose females (1000 mg/kg body weight). In addition, hypertrophy of liver hepatocytes in individual males of the high dose group was found, most likely indicative of adaptive changes.
For both sexes the NOEL (No observable effect level) was 100 mg/kg body weight. - Executive summary:
In a repeat-dose dermal toxicity study (CIBA-GEIGY Limited, 1996b), FeNaEDDHA in distilled water was administered to the skin (clipped fur) of 5 Sprague-Dawley derived rats/sex/dose level at dose levels of 10, 100 or 1000 mg/kg bw/day for a period of 28 days (5 days per week basis). Male and female animals of the concurrent control group were treated with the vehicle only. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. Based on the slight effects on the liver and skin and due to the increased adrenal weight noted at 1000 mg/kg bw/day under the conditions of this study, the NOEL was established at 100 mg/kg bw/day.
This dermal toxicity study in the rat is acceptable and satisfies the requirement for test guideline OECD 410.
Reference
SIGNS OF LOCAL IRRITATION
The skin application site of all animals of the high dose group (1000 mg/kg) was discolored after treatment start, due to staining properties of the test article. Therefore, evaluation of erythema was impeded in the high dose group. From treatment day 19 onwards, one female presented with slight crust formation at the site of application. No further local skin reactions were noted in this and all other groups.
CHEMICAL ANALYSIS OF DOSE FORMULATIONS
The calculated overall mean contents of the test item in the dose formulations used for the low, mid and high dose groups were 102, 103 and 89.7 % of the nominal concentrations, respectively (RCC Project No. 392207). The test item was proved to be stable in the vehicle under actual conditions of administration over the period of dosing.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The dermal study available meets required adequacy criteria and herewith demonstrating a good quality of data base
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1996-01-26 to 1995-03-03
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Sprague-Dawley derived; Tif:RAIf (SPF); hybrids of RII/1 x RII/2
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Laboratory Animal Breeding, Pharmaceutical Division, CIBA-GEIGY Limited, 4332 Stein, Switzerland
- Age at study initiation: young adult, based on body weight ranges
- Weight range at acclimation period: 213.9-228.1 g (males), 211.8-235.7 g (females)
- Housing: individually, in macrolon cages type 3 with wire mesh tops and granulated soft wood bedding
- Diet: pelleted, certified standard diet Nafag No. 890 (NAFAG AG, Gossau, SG, Switzerland), provided ad libitum (exception: food was withheld overnight prior to blood removal performed at the end of the treatment period)
- Water: tap water, ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 55 ± 15 %
- Air changes: approximately 15 air changes/hour
- Photoperiod: 12 hours dark / 12 hours light - Type of coverage:
- occlusive
- Vehicle:
- water
- Details on exposure:
- TEST SITE
- Area of exposure: dorsal area of the trunk
- Coverage: at least 10 % of the body surface area
- Type of wrap: gauze patches, aluminium foil and adhesive but non-irritating tape
- Time intervals for shavings or clipplings: once weekly
REMOVAL OF TEST SUBSTANCE
- Washing: with lukewarm water
- Time after start of exposure: 6 hours (on each day of treatment)
TEST MATERIAL/VEHICLE
- Amount applied: 4 mL/kg bw
- Concentrations: 2.5, 25 and 250 mg/mL
- Constant volume used: yes, adjusted weekly to individual animal body weight
USE OF RESTRAINERS FOR PREVENTING INGESTION: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Control analyses of the test item concentration in the vehicle was carried out at all dose levels on samples collected on experimental days 1, 7, 14 and 21. Samples were analysed by RCC Umweltchemie AG, 4452 Itingen, Switzerland (Project No. 329207). The test article concentrations in the vehicle were found to be in the range from 82.5 % to 105.3 % of the nominal concentrations.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 6 hours per day, on 5 days per week
- Remarks:
- Doses / Concentrations:
0, 10, 100 and 1000 mg/kg bw/day
Basis:
nominal per unit body weight - No. of animals per sex per dose:
- 5 animals
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: no rationale is given in the report.
- Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule: twice daily on working days and once daily on weekend days for mortality, and once daily for general observations.
- Skin irritation: Following each application, approximately 17 hours after patch removal, local skin reactions at the application site were assessed according to Draize et al. (1944).
BODY WEIGHT:
- Time schedule: on study days -7, 1, 8,15, 22 and 28
FOOD CONSUMPTION:
- Food consumption for each animal was determined weekly and mean daily diet consumption calculated as g food/kg bw/day.
HAEMATOLOGY:
- Time schedule for collection of blood: once, at the end of the treatment period
- Anaesthetic used for blood collection: ether
- Animals fasted: food was withheld overnight prior to blood sampling
- How many animals: all animals
- Parameters examined: erythrocyte count, haematocrit, mean corpuscular volume, red cell volume distribution width, haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, haemoglobin concentration distribution width, prothrombin time and leukocyte, neutrophil, eosinophil, basophil, lymphocyte, monocyte, large unstained cells and thrombocyte counts
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: once, at the end of the treatment period
- Animals fasted: food was withheld overnight prior to blood sampling
- How many animals: all animals
- Parameters examined: glucose, urea, creatinine, total bilirubin, total protein, albumin, globulin, cholesterol, triglycerides, sodium, potassium, calcium, chloride and inorganic phosphorus concentration, and A/G ratio and aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY:
The following organs or tissues were examined microscopically:
skin application site, skin remote site, liver, spleen, kidneys, thymus, thyroid with parathyroid gland, prostate, seminal vesicle, testis, epididymis, ovary - Other examinations:
- ORGAN WEIGHT
The weights of the following organs were determined at necropsy:
brain, heart, liver, kidneys, adrenals, thymus, ovaries or testes, and spleen - Statistics:
- Each treated group was compared to the control group by Wilcoxon's two-sample test (non-parametric) and tested for increasing or decreasing trends from control up to the respective dose group by Jonckheere's test for ordered alternatives (parametric).
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- 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:
- 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:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No treatment related clinical signs and changes in behavior were noted and all animals survived.
BODY WEIGHT AND WEIGHT GAIN
A slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. Otherwise the body weight was comparable in all groups: "During week 1 of treatment, female group 4 (1000 mg/kg) did not gain body weight. Afterwards, mean body weight gain was essentially comparable to that of the control group. At end of treatment the mean body weight was 4% lower than that of the control group".
FOOD CONSUMPTION
Food consumption was not influenced by treatment.
HAEMATOLOGY AND CLINICAL CHEMISTRY
No effects on haematology and clinical chemistry parameters were noted.
ORGAN WEIGHTS
There was an increased adrenal weight in males at 1000 mg/kg bw/day: "Mean absolute and relative adrenal weights of males in group 4 (1000 mg/kg) were 23 % and 22 % higher than those of the control group, respectively".
GROSS PATHOLOGY
No treatment related macroscopical findings were noted.
HISTOPATHOLOGY
The skin application site of females treated at 1000 mg/kg bw revealed epidermal hyperkeratosis and an increased severity of acanthosis. In one female, an additional epidermal parakeratosis and a chronic dermal inflammation were observed. In 2/5 males at 1000 mg/kg bw, centrilobular hypertrophy of hepatocytes was noted. - Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on slight effects on the liver and skin and due to increased adrenal weight noted at 1000 mg/kg bw/day.
- Critical effects observed:
- not specified
- Conclusions:
- Under the conditions of this test, dermal treatment of rats with FeNaEDDHA resulted in depressed body weight gain of females during week 1 of treatment at 1000 mg/kg body weight with consequent marginal body weight reduction at study end as compared to controls. All animals survived to scheduled sacrifice, and no clinical signs of overt toxicity were noted.
Histopathological examination revealed local intolerance at the skin application site for the high dose females (1000 mg/kg body weight). In addition, hypertrophy of liver hepatocytes in individual males of the high dose group was found, most likely indicative of adaptive changes.
For both sexes the NOEL (No observable effect level) was 100 mg/kg body weight. - Executive summary:
In a repeat-dose dermal toxicity study (CIBA-GEIGY Limited, 1996b), FeNaEDDHA in distilled water was administered to the skin (clipped fur) of 5 Sprague-Dawley derived rats/sex/dose level at dose levels of 10, 100 or 1000 mg/kg bw/day for a period of 28 days (5 days per week basis). Male and female animals of the concurrent control group were treated with the vehicle only. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. Based on the slight effects on the liver and skin and due to the increased adrenal weight noted at 1000 mg/kg bw/day under the conditions of this study, the NOEL was established at 100 mg/kg bw/day.
This dermal toxicity study in the rat is acceptable and satisfies the requirement for test guideline OECD 410.
Reference
SIGNS OF LOCAL IRRITATION
The skin application site of all animals of the high dose group (1000 mg/kg) was discolored after treatment start, due to staining properties of the test article. Therefore, evaluation of erythema was impeded in the high dose group. From treatment day 19 onwards, one female presented with slight crust formation at the site of application. No further local skin reactions were noted in this and all other groups.
CHEMICAL ANALYSIS OF DOSE FORMULATIONS
The calculated overall mean contents of the test item in the dose formulations used for the low, mid and high dose groups were 102, 103 and 89.7 % of the nominal concentrations, respectively (RCC Project No. 392207). The test item was proved to be stable in the vehicle under actual conditions of administration over the period of dosing.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The dermal study available meets required adequacy criteria and herewith demonstrating a good quality of data base
Additional information
No repeated dose toxicity studies are available for the target substance Fe(3Na)EDDHSA. The data on other structurally related substances have been used to assess toxicity potential of Fe(3Na)EDDHSA at repeated exposures.
Oral route
Fe(3K)EDDHSA
(EC 462- 490 -6) was tested in a 28-day oral gavage study in Sprague
Dawley rats (Centre International de
Toxicologie,
2001, OECD Guideline 407). Groups of five males and five females
received the test substance daily at the dose-levels of 150, 450 or 1000
mg/kg/day for 28 days. An additional group of five males and five
females received the vehicle alone (purified water) under the same
experimental conditions, and acted as a control group.
The animals were checked daily for mortality and clinical signs. A
functional observation battery was performed on all animals of each
group, once in pre-dose and then in week 4; in addition, a detailed
clinical observation was performed on all animals of each group, once a
week until the end of the treatment period. Motor activity was recorded
on all animals once in pre-dose and in week 4. Body weight and food
consumption were recorded once a week. Haematological and blood
biochemical investigations were performed for all animals at the end of
the treatment period. On completion of the treatment period, all animals
were killed and submitted to a complete macroscopic post-mortem
examination. Designated organs were weighed and selected tissues were
preserved. A microscopic examination was performed on designated tissues
of the animals of the control and high dose-level group.
No mortalities and no clinical signs of toxicological significance were observed in any treated animals. No specific signs of a neurotoxic action of the test substance were noted. Overall body weight gains were similar in control and treated groups and food consumption was considered to be unaffected by treatment. Haematology and biochemistry parameters were without of toxicological significance. No notable differences in organ weights were noted between control and treated groups. Macroscopic and microscopic examinations revealed no changes of toxicological importance. The No Observable Effect Level (NOEL) was established at 1000 mg/kg bw.
The subchronic toxicity of Fe(Na)EDDHA (CAS 84539 -55 -9) by oral route was investigated in rats (Novartis Crop Protection AG, 1998). The test item was administered to 10 Sprague-Dawley derived rats/sex/dose level by oral gavage at 5, 50 or 200 mg/kg bw/day for 90 days. A concurrent control group was treated with the vehicle only. Additional 10 animals/sex of the high dose and control group were kept on control diet for a 4 -week recovery period before sacrifice. Treatment with the test item resulted in lower food intake and impaired body weight development at 200 mg/kg bw/day. Reversible effects on red blood cell (normochromic anaemia) and white blood cell parameters, and higher values of platelets and prothrombin activity were noted at 50 and/or 200 mg/kg bw/day. In addition, changes of blood chemistry and urine parameters concerning the liver and kidneys were noted. The body weight relative heart weight was increased in males at 200 mg/kg bw/day. Under the conditions of this study, the NOAEL for Fe(Na)EDDHA when administered daily by oral gavage for three months was 10 mg/kg bw/day (estimated from the LOAEL).
Estimation of NOAEL:
A more realistic NOAEL was estimated from the LOAEL of 50 mg/kg bw/day applying an assessment factor of 5. This method is applicable and scientifically justified for this test, as only slight adverse effects were observed at 50 mg/kg bw/day (haematology parameters - anaemia). To take the relatively large concentration gap between 5 (clear NOEL) and 50 mg/kg bw/day into account, 5 mg/kg bw/day was not taken as NOAEL, but extrapolated from the LOAEL. The guidance on information requirements and CSA, R.8 (ECHA, 2008 -2010) recommends a factor between 3 and 10 for extrapolation from LOAEL to NOAEL. An assessment factor of 5 seems to be appropriate and conservative enough for the current study as only slight effects were observed at the LOAEL of 50 mg/kg bw/day. Consequently a NOAEL of 10 mg/kg bw/day is calculated for this study.
In a dose range-finding subacute oral toxicity study (CIBA-GEIGY Limited, 1996a), Fe(Na)EDDHA was administered to 5 Sprague-Dawley derived rats/sex/dose level by oral gavage at 50, 200 or 1000 mg/kg bw/day for 28 days. A concurrent control group was treated with the vehicle only. Treatment with the test item resulted in impaired body weight development at 200 and 1000 mg/kg bw/day and correspondend lower food intake. Anaemia without erythropoietic response was noted at 200 and 1000 mg/kg bw/day. At the same dose levels, the kidney was revealed as target organ by microscopical examination, by blood chemistry data evaluation and by organ weight evaluation. In addition, body weight relative organ weight changes were noted in the heart, adrenals and spleen. However, the relevance of these findings was considered as equivocal. This study was used as scientific basis for dose level selection for the above-mentioned 90 -day repeated dose oral toxicity study in the rat.
It seems that the toxicity of Fe(Na)EDDHA is higher that that of Fe(3K)EDDHSA.
Dermal route
In a repeated dose dermal toxicity study (CIBA-GEIGY Limited, 1996b), Fe(Na)EDDHA was administered to the skin of 5 Sprague-Dawley derived rats/sex/dose level at 10, 100 or 1000 mg/kg bw/day for 28 days (5 days/week). A concurrent control group was treated with the vehicle only. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, and no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. Based on the slight effects on the liver and skin and due to the increased adrenal weight noted at 1000 mg/kg bw/day, the NOEL was established at 100 mg/kg bw/day.
Inhalation route
In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after inhalation (required in section 8.6) does not need to be conducted as repeated dose toxicity studies for oral and dermal application are available. Inhalation exposure is regarded negligible as the particle size distribution for particles below 100 µm were found to be 2.7 % and no particles were found less than 10 µm. In addition, the substance showed only very low toxicity after acute inhalation exposure with an LD50 of greater than 4200 mg/m³ in rats.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study conducted with the nearest analogue Fe(3K)EDDHSA (EC 462-490-6)
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Inhalation is not relevant route of exposure
Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Inhalation is not relevant route of exposure
Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Key study conducted with the related substance Fe(Na)EDDHA (CAS 8453955-9)
Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Key study conducted with the related substance Fe(Na)EDDHA (CAS 8453955-9)
Justification for classification or non-classification
Based on the results of the key repeated dose toxicity study conducted with the nearest analogue Fe(3K)EDDHSA and considering the NOEL of 1000 mg/kg bw/day established for the oral route, Fe(3Na)EDDHSA is not subject to classification and labelling according to the Regulation No 1272/2008 (CLP) since no treatment-related effects were noted in any parameter tested.
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