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EC number: 214-686-6 | CAS number: 1185-57-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- reproductive toxicity, other
- Remarks:
- 13 weeks subchronic toxicity study
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data from peer reviewed journal
Data source
Reference
- Reference Type:
- publication
- Title:
- A 13-week subchronic toxicity study of test chemical in F344 rats
- Author:
- Takeshi Toyoda et. al.
- Year:
- 2 014
- Bibliographic source:
- Food and Chemical Toxicology,2014
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: As mentioned below
- Principles of method if other than guideline:
- 13 weeks subchronic toxicity study was performed to determine the toxic nature of test chemical on male and female Fischer 344/DuCrj rats
- GLP compliance:
- not specified
- Limit test:
- no
- Justification for study design:
- No data available
Test material
- Reference substance name:
- 2-hydroxypropane-1,2,3-tricarboxylate;iron(3+)
- Cas Number:
- 2338-05-8
- Molecular formula:
- C6H8O7xFe
- IUPAC Name:
- 2-hydroxypropane-1,2,3-tricarboxylate;iron(3+)
- Details on test material:
- - Name of test material: Ferric citrate
- Molecular formula: C6H8O7xFe
- Molecular weight: 244.9435 g/mol
- Substance type: Organic
- Physical state: Reddish brown color powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Details on species / strain selection:
- No data available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan (Yokohama, Japan)
- Age at study initiation: 5 weeks old when purchased and used after oneweek acclimatization.
- Weight at study initiation: No data
- Fasting period before study:no data
- Housing: The animals were housed 3–4 rats per polycarbonate cage with soft chip bedding. The cages and chip bedding were exchanged twice a week.
- Diet (e.g. ad libitum): Basal diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ± 5%
- Air changes (per hr): 18 times/hr
- Photoperiod (hrs dark / hrs light): 12 hr light dark cycle
IN-LIFE DATES: From: To: No data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: feed
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with diet at dose level of 0%, 0.25%, 1.0%, and 4.0% (w/w) (0, 125, 500 or 2000 mg/Kg bw/day)
DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data
VEHICLE
- Justification for use and choice of vehicle (if other than water): Basal diet
- Concentration in vehicle: 0%, 0.25%, 1.0%, and 4.0% (w/w) (0, 125, 500 or 2000 mg/Kg bw/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data - Details on mating procedure:
- No data available
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
- Details on study schedule:
- No data available
Doses / concentrations
- Remarks:
- 0%, 0.25%, 1.0%, and 4.0% (w/w) (Males: 0, 143.9, 595.9 or 2834.7 mg/Kg bw/day; Females: 0, 147.7, 601.4 or 2845.6 mg/Kg bw/day)
- No. of animals per sex per dose:
- Total: 40 males and 40 females
0 mg/Kg bw/day: 10 males and 10 females
143.9 mg/Kg bw/day for males and 147.7 mg/Kg bw for females: 10 males and 10 females
595.9 mg/Kg bw/day for males and 601.4 mg/Kg bw for females: 10 males and 10 females
2834.7 mg/Kg bw/day for males and 2845.6 mg/Kg bw/day: 10 males and 10 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a preliminary 4-week palatability study of test chemical with administration at the highest dose of 5.0% (w/w), significant decrease of body weight gain (>20% compared to the controls) was observed in males and females (data not shown). From these results, doses of test chemical were decided as 0%, 0.25%, 1.0%, and 4.0% (w/w) in both sexes for the present 13-week toxicity study, with diet replacement every week.
- Rationale for animal assignment (if not random): At the beginning of the experiment, the animals were randomly allocated to four groups of 10 male and 10 female rats each, based on their body weights measured just before starting the test chemical treatment.
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data - Positive control:
- No data available
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included. General condition and mortality
DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: body weights were measured once a week
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, The amounts of supplied and residual diet were weighed weekly in order to calculate the average daily food intake and test chemical intake through the entire treatment period.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY: No data
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data - Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes, Complete necropsy was performed for all animals, and the brain, thymus, lungs, heart, spleen, liver, adrenal glands, kidneys, and gonads were weighed.
HISTOPATHOLOGY: Yes, the brain, thymus, lungs, heart, spleen, liver, adrenal glands, kidneys, and gonads, skin, mammary gland, sternum with marrow, femur with marrow, mandibular and mesenteric lymph nodes, salivary glands, aorta, trachea, tongue, esophagus, stomach, small and large intestines, pancreas, urinary bladder, epididymides, seminal vesicles, prostate gland, bulbourethral glands, uterus, vagina, pituitary gland, thyroid glands, parathyroid glands, spinal cord with vertebrae, trigeminal nerve, sciatic nerve, harderian glands, femoral skeletal muscle, and nasal cavity were stained with hematoxylin and eosin for histopathological examination. The testes and eyes were fixed in Bouin’s fixative and Davidson’s solution, respectively. Bony tissues including the nasal cavity, vertebrae, sternum, and femur were decalcified with a mixture of 10% formic acid and 10% buffered formalin for up to 2 weeks. Histopathological assessment was first performed on all tissues of the control and highest dose groups. If a chemical treatment-related change appeared at the highest dose, the relevant tissues from the lower dose groups then also underwent examination. - Postmortem examinations (offspring):
- No data available
- Statistics:
- Variance in data for body and organ weights, as well as the results of hematology and serum biochemistry, was checked by Bartlett’s test for homogeneity. When the data were homogeneous, one-way analysis of variance (ANOVA) was conducted. In heterogeneous cases, the Kruskal–Wallis test was applied. When statistically significant differences were indicated, the Dunnett’s or non-parametric Dunnett’s multiple test were employed for comparisons between control and other groups. For incidences of histopathological findings, the Fisher’s exact probability test was applied. P values of < 0.05 were considered to be statistically significant.
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All animals were without any clinical signs
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No deaths were noted
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain of both sexes was significantly reduced with 4.0% (2834.7 mg/Kg bw/day for males and 2845.6 mg/Kg bw/day for females) test chemical treatment compared to the controls from the 1st week until the end of the experiment except in the 9th and 12th weeks in females. Comparing with the control groups, the average bodyweight gain during the experiment in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females were reduced by 13.4% and 5.9%, respectively.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Daily food intake of 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females was slightly higher than in the other groups. Since there was no avoidance of the experimental diet, average intakes of test chemical per body weight was dose-dependent
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant decreases of RBC and lymphocytes and increases of PLT and eosinophils were detected in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. In males, significant increases of MCV and MCH were observed in the 1.0% and 4.0% groups and with 4.0%, respectively
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- An increase of serum Fe levels and decreases of TP and transferrin were noted in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. Significant decrease of transferrin was also detected in 601.4 mg/Kg bw/day females. In males, increase of Na and decreases of AST and ALT were observed in the 2834.7 mg/Kg bw/day group. In females, significant increase of IP and decreases of Alb and Cl were found in the 2845.6 mg/Kg bw/day group. Increase of ALT in 595.9 mg/Kg bw/day males and decrease of K levels in 147.7 mg/Kg bw/day females were also detected, without any dose-dependence.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Treatment related pathological findings were noted in the colon, mesenteric lymph node, spleen and bone marrow. There was moderate to severe colitis in all 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. In the affected colons, numbers of eosinophils as well as neutrophils and macrophages had infiltrated into the lamina propria and submucosa. Absorptive epithelial cells of colonic mucosa were replaced by hyperplastic mucous cells with frequent mitotic figures. Eosinophilic infiltration was also observed occasionally in the submucosa of stomach, duodenum and cecum in 4.0% males and females with a lower incidence than in the colon. Mesenteric lymph nodes of all animals of 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females were macroscopically enlarged and histologically showed dilated sinuses featuring aggregation of plasmacytes and hemosiderin deposits. Infiltration of eosinophils was noted not only in the sinuses of mesenteric lymph nodes but also in the surrounding adipose tissue. In spleens of 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females, the degree of hemosiderin deposition was higher than in control groups. Hematopoietic cells in the bone marrow were increased in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. Although several lesions in other organs were sporadically detected, no significant treatment dependent alteration in their incidences was apparent.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 595.9 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- haematology
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- Remarks on result:
- other: no toxic effects on reproductive organ
- Dose descriptor:
- NOAEL
- Effect level:
- 601.4 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- haematology
- clinical biochemistry
- organ weights and organ / body weight ratios
- Remarks on result:
- other: No toxic effects on reproductive organ
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P1)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Anogenital distance (AGD):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Effect levels (F1)
- Dose descriptor:
- other: not specified
- Generation:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Remarks on result:
- not measured/tested
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Anogenital distance (AGD):
- not specified
- Nipple retention in male pups:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Any other information on results incl. tables
Table 1: Body weight and food intake data for F344 rats treated with test chemical for 13weeks
Group |
Body weight (g) |
Food intake (g/rat/day) |
Chemical intake (mg/Kg bw/day) |
|
Initial |
Final |
|||
Males |
|
|
|
|
0 |
106.0 ± 5.2 |
305.0 ± 10.7 |
13.9 |
0 |
0.25 |
105.8 ± 4.1 |
301.5 ± 12.8 |
13.4 |
143.9 |
1.0 |
105.9 ± 4.4 |
304.5 ± 18.7 |
13.9 |
595.9 |
4.0 |
105.7 ± 4.1 |
266.6 ± 10.1** |
14.5 |
2834.7 |
Females |
|
|
|
|
0 |
94.1 ± 3.0 |
174.8 ± 5.8 |
9.2 |
0 |
0.25 |
93.3 ± 3.5 |
173.2 ± 9.5 |
8.8 |
147.7 |
1.0 |
93.7 ± 3.4 |
174.7 ± 6.1 |
9.0 |
601.4 |
4.0 |
93.4 ± 2.8 |
166.1 ± 6.0* |
10.0 |
2845.6 |
Values are mean ± S.D. * and ** Significantly different from the controls at p < 0.05 and < 0.01, respectively
Table 2: Hematology data for F344 rats treated with test chemical for 13 weeks.
Dose Level (%) |
0 |
0.25 |
1.0 |
4.0 |
Males |
|
|
|
|
No. of animals examined |
10 |
10 |
10 |
10 |
WBC × 102/μl |
38.8 ± 11.6 |
33.9 ± 6.9 |
31.7 ± 4.4 |
45.0 ± 11.1 |
RBC × 104/µl |
908.0 ± 57.2 |
889.3 ± 70.0 |
849.1 ± 47.9 |
838.3 ± 48.5* |
HGB g/dl |
16.0 ± 1.0 |
15.6 ± 1.0 |
15.2 ± 0.8 |
16.1 ± 0.7 |
HCT % |
49.5 ± 2.7 |
49.1 ± 2.7 |
47.4 ± 2.3 |
49.3 ± 2.1 |
MCV fl |
54.6 ± 1.1 |
55.4 ± 1.4 |
55.9 ± 0.9* |
58.9 ± 1.3** |
MCH pg |
17.7 ± 0.3 |
17.6 ± 0.4 |
17.9 ± 0.2 |
19.2 ± 0.5** |
MCHC g/dl |
32.3 ± 0.7 |
31.8 ± 0.5 |
32.1 ± 0.5 |
32.6 ± 0.6 |
PLT × 104/μl |
68.2 ± 11.1 |
64.2 ± 11.5 |
65.5 ± 5.3 |
79.5 ± 4.7* |
Differential cell count |
|
|
|
|
Band % |
0.1 ± 0.2 |
0.3 ± 0.4 |
0.3 ± 0.3 |
0.3 ± 0.3 |
Seg % |
28.2 ± 4.4 |
30.9 ± 8.4 |
31.7 ± 5.8 |
34.9 ± 3.8 |
Eosin % |
1.3 ± 0.8 |
1.0 ± 0.5 |
1.3 ± 0.9 |
9.5 ± 7.0** |
Baso % |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Lymph % |
70.2 ± 4.6 |
67.6 ± 8.3 |
66.4 ± 5.8 |
55.1 ± 7.7** |
Mono % |
0.3 ± 0.4 |
0.3 ± 0.4 |
0.3 ± 0.4 |
0.3 ± 0.4 |
Ebl (per 200 WBC) |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.1 ± 0.3 |
Females |
|
|
|
|
No. of animals examined |
9a |
10 |
10 |
10 |
WBC × 102/μl |
21.1 ± 3.2 |
17.9 ± 5.7 |
17.2 ± 2.2 |
24.5 ± 6.2 |
RBC × 104/µl |
811.1 ± 33.9 |
770.5 ± 98.0 |
781.7 ± 48.2 |
749.9 ± 34.1* |
HGB g/dl |
15.3 ± 0.6 |
14.5 ± 1.9 |
15.0 ± 1.0 |
14.4 ± 0.7 |
HCT % |
46.8 ± 1.7 |
45.3 ± 5.3 |
46.2 ± 2.7 |
44.4 ± 1.6 |
MCV fl |
57.7 ± 0.9 |
58.9 ± 1.7 |
59.1 ± 1.1 |
59.2 ± 1.3 |
MCH pg |
18.8 ± 0.4 |
18.8 ± 0.7 |
19.2 ± 0.2 |
19.3 ± 0.3 |
MCHC g/dl |
32.7 ± 0.6 |
31.9 ± 0.8 |
32.4 ± 0.6 |
32.5 ± 0.9 |
PLT × 104/μl |
69.5 ± 8.3 |
69.7 ± 9.7 |
71.5 ± 7.1 |
80.6 ± 8.1* |
Differential cell count |
|
|
|
|
Band % |
0.2 ± 0.3 |
0.2 ± 0.2 |
0.1 ± 0.2 |
0.4 ± 0.5 |
Seg % |
29.1 ± 2.8 |
29.2 ± 5.4 |
27.1 ± 4.5 |
32.7 ± 6.3 |
Eosin % |
1.7 ± 0.8 |
0.9 ± 0.8 |
1.8 ± 2.1 |
10.2 ± 3.0* |
Baso % |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Lymph % |
68.2 ± 3.4 |
69.6 ± 5.6 |
70.8 ± 3.6 |
56.2 ± 8.4* |
Mono % |
0.8 ± 1.0 |
0.2 ± 0.3 |
0.3 ± 0.4 |
0.6 ± 0.5 |
Ebl (per 200 WBC) |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.2 ± 0.6 |
0.0 ± 0.0 |
Values are mean ± S.D. * and ** Significantly different from the controls at p < 0.05 and < 0.01, respectively.aThe number of effective animals was reduced to nine due to incidental nephroblastoma.
Table 3: Serum biochemistry data for F344 rats treated with test chemical for 13 weeks.
Dose Level (%) |
0 |
0.25 |
1.0 |
4.0 |
Males |
|
|
|
|
No. of animals examined |
10 |
10 |
10 |
10 |
TP (g/dl) |
6.3 ± 0.2 |
6.3 ± 0.2 |
6.4 ± 0.1 |
6.1 ± 0.2** |
Na (mEq/l) |
141.0 ± 0.5 |
141.8 ± 0.6 |
141.6 ± 2.0 |
142.4 ± 1.1** |
AST (IU/l) |
81.3 ± 5.6 |
78.2 ± 8.3 |
85.6 ± 9.8 |
72.0 ± 3.5* |
ALT (IU/l) |
53.4 ± 5.2 |
56.1 ± 7.2 |
60.6 ± 6.9* |
41.7 ± 4.8** |
Transferrin (mg/dl) |
148.0 ± 3.3 |
148.6 ± 5.1 |
150.5 ± 5.5 |
141.5 ± 4.7* |
Transferrin (mg/dl) |
148.0 ± 3.3 |
148.6 ± 5.1 |
150.5 ± 5.5 |
141.5 ± 4.7* |
Females |
|
|
|
|
No. of animals examined |
9a |
10 |
10 |
10 |
TP (g/dl) |
6.2 ± 0.1 |
6.3 ± 0.3 |
6.2 ± 0.3 |
5.6 ± 0.2** |
Alb (g/dl) |
4.2 ± 0.1 |
4.2 ± 0.2 |
4.1 ± 0.1 |
3.8 ± 0.1** |
Cl (mEq/l) |
103.1 ± 0.6 |
103.1 ± 1.2 |
103.1 ± 1.1 |
101.5 ± 1.1** |
IP (mg/dl) |
4.1 ± 0.3 |
4.3 ± 0.9 |
4.6 ± 1.0 |
6.6 ± 1.2** |
Transferrin (mg/dl) |
152.8 ± 5.6 |
149.7 ± 4.4 |
145.6 ± 4.9* |
137.9 ± 6.8** |
Fe (μg/dl) |
249.4 ± 36.9 |
288.8 ± 37.1 |
272.1 ± 33.4 |
308.4 ± 57.3* |
Values are mean ± S.D. * and ** Significantly different from the controls at p < 0.05 and < 0.01, respectively.aThe number of effective animals was reduced to nine due to incidental nephroblastoma.
Table 4: Organ weight data for F344 rats treated with test chemical for 13 weeks.
Dose Level (%) |
0 |
0.25 |
1.0 |
4.0 |
Males |
|
|
|
|
No. of animals examined |
10 |
10 |
10 |
10 |
Body weight (g) |
298.1 ± 11.4 |
293.7 ± 10.5 |
298.5 ± 17.8 |
265.2 ± 11.2** |
Absolute (g) |
|
|
|
|
Heart |
0.828 ± 0.043 |
0.837 ± 0.025 |
0.850 ± 0.049 |
0.760 ± 0.039** |
Relative (%) |
|
|
|
|
Brain |
0.641 ± 0.032 |
0.659 ± 0.020 |
0.639 ± 0.037 |
0.713 ± 0.030** |
Spleen |
0.202 ± 0.009 |
0.206 ± 0.008 |
0.201 ± 0.008 |
0.240 ± 0.009** |
Adrenals |
0.011 ± 0.002 |
0.012 ± 0.001 |
0.013 ± 0.001 |
0.013 ± 0.001** |
Kidneys |
0.586 ± 0.024 |
0.588 ± 0.020 |
0.586 ± 0.029 |
0.633 ± 0.029** |
Testes |
0.993 ± 0.065 |
1.010 ± 0.041 |
0.983 ± 0.061 |
1.102 ± 0.050** |
Females |
|
|
|
|
No. of animals examined |
9a |
10 |
10 |
10 |
Body weight (g) |
165.4 ± 5.4 |
167.5 ± 8.3 |
168.0 ± 5.6 |
161.7 ± 5.6 |
Absolute (g) |
|
|
|
|
Heart |
0.562 ± 0.036 |
0.563 ± 0.031 |
0.544 ± 0.026 |
0.508 ± 0.025** |
Spleen |
0.378 ± 0.035 |
0.402 ± 0.042 |
0.388 ± 0.024 |
0.438 ± 0.038** |
Relative (%) |
|
|
|
|
Heart |
0.340 ± 0.024 |
0.336 ± 0.011 |
0.324 ± 0.020 |
0.315 ± 0.013* |
Spleen |
0.229 ± 0.020 |
0.239 ± 0.018 |
0.231 ± 0.014 |
0.271 ± 0.025** |
Liver |
2.258 ± 0.092 |
2.339 ± 0.079 |
2.234 ± 0.112 |
2.399 ± 0.070** |
Values are mean ± S.D. * and ** Significantly different from the controls at p < 0.05 and < 0.01, respectively. a and b The number of effective animals was reduced to nine due to incidental nephroblastoma and failure of tissue sampling, respectively.
Table 5: Histopathological findings for F344 rats treated with test chemical for 13 weeks.
|
Dose level (%) |
Males |
Females |
||||||
0 |
0.25 |
1.0 |
4.0 |
0 |
0.25 |
1.0 |
4.0 |
||
Organs and findings |
No. of animals |
10 |
10 |
10 |
10 |
9a |
10 |
10 |
10 |
Spleen |
Increased hemosiderosis |
0 |
0 |
0 |
10** |
0 |
0 |
0 |
6* |
Colon |
Inflammation with eosinophilic infiltration |
0 |
0 |
0 |
10** |
0 |
0 |
0 |
10** |
|
Mucosal hyperplasia |
0 |
0 |
0 |
10** |
0 |
0 |
0 |
10** |
Mesentric lymphnode |
Inflitration of eosinophils |
0 |
0 |
0 |
10** |
0 |
0 |
0 |
10** |
|
Plasmacytosis |
0 |
0 |
0 |
7** |
0 |
0 |
0 |
7** |
|
Hemosiderosis |
0 |
0 |
0 |
10** |
0 |
0 |
0 |
9** |
Bone marrow Increased |
hematopoiesis |
0 |
0 |
0 |
8** |
0 |
0 |
0 |
9** |
** Significantly different from the controls at p < 0.05 and < 0.01, respectively. a The number of effective animals was reduced to nine due to incidental nephroblastoma.
Applicant's summary and conclusion
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) for reproductive toxicity is considered to be 1.0% (595.9 mg/kg bw/day for males and 601.4 mg/kg bw/day for females), When male and female Fischer 344/DuCrj rats were treated with test chemical orally in the 13 weeks.
- Executive summary:
The reproductive toxicity was considered on the basis of 13 weeks sub chronic toxicity study of test chemical .The study was performed using 40 male and 40 female Fischer 344/DuCrj rats. The test chemical was mixed with basal diet and used at dose level of 0%, 0.25%, 1.0%, and 4.0% (w/w) (Males: 0, 143.9, 595.9 or 2834.7 mg/Kg bw/day; Females: 0, 147.7, 601.4 or 2845.6 mg/Kg bw/day) for 13 weeks. During the study period, the animals were observed for general condition, mortality, changes in body weight and food intake, haemotology, clinical chemistry and were subjected to gross and histopathology. All animals were without any clinical signs and no deaths were reported. Reduction of body weight gain was noted in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. On hematology assessment, decreases of red blood cells and lymphocytes and increases of platelets and eosinophils were noted in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. Serum biochemistry demonstrated increased iron and decreased total protein and transferrin in both sexes treated with 2834.7 mg/Kg bw/day and 2845.6 mg/Kg bw/day test chemical respectively. In addition, an increase of serum inorganic phosphorus levels was noted in 2845.6 mg/kg bw females. Regarding organ weights, In males, absolute heart weights were decreased in the 4.0% group (2834.7 mg/Kg bw/day) compared to the controls. In addition, relative weights of brain, spleen, adrenals, kidneys, and testes were significantly increased in 2834.7 mg/Kg bw/day males. In females, decrease of absolute and relative heart weights, increase of absolute and relative spleen weights and increase of relative liver weights were observed in the 2845.6 mg/Kg bw/day group. Absolute weights of liver were also increased in 147.7 mg/Kg bw/day females without dose-dependence. On histopathological assessment, colitis with infiltration of eosinophils and hyperplasia of mucosal epithelium, eosinophilic infiltration in mesenteric lymph nodes, and increased hemosiderosis in spleen were observed as treatment-related toxicological changes in 2834.7 mg/Kg bw/day males and 2845.6 mg/Kg bw/day females. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for reproductive toxicity is considered to be 1.0% (595.9 mg/kg bw/day for males and 601.4 mg/kg bw/day for females), When male and female Fischer 344/DuCrj rats were treated with test chemical orally in the 13 weeks.
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