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EC number: 265-477-1 | CAS number: 65122-06-7
- 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
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- 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 is from J-check
Data source
Reference
- Reference Type:
- other: Autharized database
- Title:
- Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422)
- Author:
- Ministry of Economy, Trade and Industry, Japan
- Year:
- 2 009
- Bibliographic source:
- Data sheet (in fiscal 2009): prepared by Hazard-Data Evaluation Committee of National Institute of Technology and Evaluation based on the GLP study report obtained by Japanese Ministry of Economy
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test of test material in Rats
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 1H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis-
- Cas Number:
- 13676-54-5
- Molecular formula:
- C21H14N2O4
- IUPAC Name:
- 1H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis-
- Details on test material:
- - Name of test material (as cited in study report):H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis
- Molecular formula :C21H14N2O4
- Molecular weight :358.35 g/mole
- Substance type: Organic
- Physical state: Pale yellow crystalline powder
- Impurities (identity and concentrations):2. 0%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age at study initiation of dosing: 9 weeks old
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- other: 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Test substance suspended in 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80 at 0, 40, 200 and 1000 mg/kg bw
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80
- Concentration in vehicle: 0, 40, 200 and 1000 mg/kg bw
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Male: 42 day
Female: 41 - 48 days (from 14 days before mating to day 4 of lactation) - Frequency of treatment:
- Daily
- Details on study schedule:
- not specified
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 40 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 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:
- Total: 106
0 mg/kg/day: 7 male, 12 female
40 mg/kg/day: 12 male, 12 female
200 mg/kg/day: 12 male, 12 female
1000 mg/kg/day: 7 male, 12 female
Recory group:
0 mg/kg/day: 5 male, 5 female
1000 mg/kg/day: 5 male, 5 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- not specified
- Positive control:
- not specified
Examinations
- Parental animals: Observations and examinations:
- Survival, clinical sign, body weigth, food consumption and urineanalysis and FOB were examiined.
- Oestrous cyclicity (parental animals):
- Estrous cyclicity, copulation and implantation were examined.
- Sperm parameters (parental animals):
- not specified
- Litter observations:
- Number of pups, number of live pups, sex ratio on days 0 and 4, clinical signs and body weight were examined.
- Postmortem examinations (parental animals):
- Hematology , clinical chemisrty , Oragn weight, gross pathology and histopathology were examined.
- Postmortem examinations (offspring):
- Gross pathology were examined.
- Statistics:
- not specified
- Reproductive indices:
- Fertility rat, gestation period, implantation index, live birth index, delivery index, parturition, or maternal behavior were examined.
- Offspring viability indices:
- Viability index on 0 and 4 day were examined.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs were observed in treated rats as compared to contorl.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No effect on survival of treated rats were observed at 40, 200 and 1000 mg/kg bw as compared to control.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No change in body weight were observed in treated rats as compared to control.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No change in food consumption were observed in treated rats as compared to control.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No changes in hematological parameters were observed in treated male and female rats as compared to control.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No changes in clinical chemisrty were observed in treated male and female rats as compared to control.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No effect was observed in male rats as compared to control.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No changes in behavior test were observed in treated male and female rats as compared to control.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw.
The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No effect on Estrous cyclicity, copulation and inplantation were observed.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No effect on Reproductive performance of treated male and female rats were observed as compared to control.
Effect levels (P0)
- 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:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- haematology
- clinical biochemistry
- urinalysis
- organ weights and organ / body weight ratios
- gross pathology
- neuropathology
- reproductive function (oestrous cycle)
- reproductive performance
- other: No effect observed
- Remarks on result:
- other: overall no developmental toxic effects observed
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No Clinical signs were observed in treated pups as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No effect on suvival of pups were observed as compared to control.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effect on body weight of pups were observed as compared to control.
- 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
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross pathological changes were observed in treated pups as compared to control.
- 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:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- gross pathology
- other: No effect observed
- Remarks on result:
- other: overall nodevelopmental toxic effects observed
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Relation to other toxic effects:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Absolute and relative organ weights in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test
Sex |
Dose level (mg/kg) |
Administration period |
Recovery period |
|||||||
0 |
40 |
200 |
1000 |
0 |
1000 |
|||||
Male |
||||||||||
Number of animals |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Final body weight(g) |
493.1 ± 35.9(7)a) |
480.7 ± 33.6(12) |
486.2 ± 27.2(12) |
466.6 ± 28.1(7) |
503.8 ± 12.5 |
510.0 ± 19.2 |
||||
Absolute organ weight |
|
|
|
|
|
|
||||
Brain(g) |
2.154 ± 0.079 |
2.122 ± 0.136 |
2.132 ± 0.061 |
2.064 ± 0.093 |
2.112 ± 0.030 |
2.168 ± 0.077 |
||||
Thymus(mg) |
359.2 ± 76.7 |
359.8 ± 105.9 |
334.0 ± 53.8 |
379.0 ± 39.2 |
368.2 ± 81.3 |
279.8 ± 52.8 |
||||
Heart(g) |
1.466 ± 0.171 |
1.528 ± 0.147 |
1.572 ± 0.156 |
1.648 ± 0.210 |
1.636 ± 0.145 |
1.636 ± 0.193 |
||||
Liver(g) |
12.088 ± 1.724 |
11.506 ± 0.575 |
12.304 ± 0.993 |
11.750 ± 0.792 |
13.082 ± 0.587 |
12.634 ± 0.882 |
||||
Spleen(g) |
0.826 ± 0.112 |
0.802 ± 0.087 |
0.756 ± 0.078 |
0.798 ± 0.099 |
0.782 ± 0.070 |
0.794 ± 0.145 |
||||
Kidneys(g) |
3.268 ± 0.364 |
3.172 ± 0.288 |
3.206 ± 0.320 |
3.002 ± 0.119 |
3.218 ± 0.133 |
3.376 ± 0.285 |
||||
Adrenals(mg) |
72.00 ± 15.34 |
65.94 ± 7.89 |
66.40 ± 7.42 |
66.04 ± 8.25 |
66.96 ± 7.48 |
64.50 ± 9.45 |
||||
Testes(g) |
3.339 ± 0.294(7) |
3.440 ± 0.291(12) |
3.472 ± 0.277(12) |
3.554 ± 0.236(7) |
3.284 ± 0.252 |
3.232 ± 0.631 |
||||
Epididymides(g) |
1.350 ± 0.085(7) |
1.388 ± 0.083(12) |
1.376 ± 0.082(12) |
1.406 ± 0.089(7) |
1.438 ± 0.121 |
1.340 ± 0.241 |
||||
Relative organ weight |
||||||||||
Brain(g%) |
0.442 ± 0.035 |
0.452 ± 0.018 |
0.450 ± 0.032 |
0.444 ± 0.036 |
0.418 ± 0.013 |
0.426 ± 0.009 |
||||
Thymus(mg%) |
72.96 ± 11.71 |
76.58 ± 21.76 |
70.04 ± 7.72 |
81.10 ± 5.48 |
73.20 ± 16.87 |
54.90 ± 10.64 |
||||
Heart(g%) |
0.298 ± 0.026 |
0.328 ± 0.038 |
0.330 ± 0.016 |
0.354 ± 0.037 |
0.324 ± 0.034 |
0.320 ± 0.027 |
||||
Liver(g%) |
2.460 ± 0.166 |
2.458 ± 0.149 |
2.590 ± 0.155 |
2.520 ± 0.124 |
2.598 ± 0.134 |
2.476 ± 0.118 |
||||
Spleen(g%) |
0.170 ± 0.012 |
0.170 ± 0.019 |
0.160 ± 0.020 |
0.172 ± 0.030 |
0.156 ± 0.011 |
0.156 ± 0.025 |
||||
Kidneys(g%) |
0.666 ± 0.026 |
0.676 ± 0.048 |
0.678 ± 0.080 |
0.646 ± 0.060 |
0.638 ± 0.043 |
0.660 ± 0.042 |
||||
Adrenals(mg%) |
14.62 ± 2.23 |
14.12 ± 1.84 |
14.08 ± 2.48 |
14.18 ± 2.11 |
13.26 ± 1.28 |
12.60 ± 1.36 |
||||
Testes(g%) |
0.676 ± 0.030(7) |
0.718 ± 0.079(12) |
0.717 ± 0.075(12) |
0.764 ± 0.077(7) |
0.654 ± 0.039 |
0.634 ± 0.118 |
||||
Epididymides(g%) |
0.276 ± 0.022(7) |
0.291 ± 0.025(12) |
0.284 ± 0.019(12) |
0.301 ± 0.032(7) |
0.284 ± 0.024 |
0.262 ± 0.041 |
||||
Female |
||||||||||
Number of animals |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Final body weight(g) |
305.2 ± 26.7 |
314.4 ± 13.2 |
318.0 ± 22.2 |
314.2 ± 20.1 |
294.2 ± 31.1 |
299.0 ± 17.1 |
||||
Absolute organ weight |
||||||||||
Brain(g) |
1.958 ± 0.044 |
1.940 ± 0.059 |
1.972 ± 0.052 |
2.008 ± 0.052 |
1.952 ± 0.048 |
1.990 ± 0.066 |
||||
Thymus(mg) |
223.2 ± 71.3 |
323.4 ± 54.4 |
303.6 ± 74.3 |
356.6 ± 46.3* |
377.0 ± 111.5 |
335.2 ± 99.4 |
||||
Heart(g) |
1.028 ± 0.082 |
1.030 ± 0.037 |
1.078 ± 0.073 |
1.094 ± 0.070 |
0.912 ± 0.053 |
0.962 ± 0.040 |
||||
Liver(g) |
11.058 ± 0.861 |
10.332 ± 0.882 |
10.618 ± 0.689 |
10.824 ± 0.585 |
7.354 ± 0.986 |
7.922 ± 0.804 |
||||
Spleen(g) |
0.768 ± 0.094 |
0.624 ± 0.041 |
0.794 ± 0.063 |
0.902 ± 0.141 |
0.594 ± 0.065 |
0.522 ± 0.078 |
||||
Kidneys(g) |
2.212 ± 0.196 |
2.118 ± 0.151 |
2.386 ± 0.240 |
2.186 ± 0.222 |
1.986 ± 0.123 |
1.938 ± 0.075 |
||||
Adrenals(mg) |
81.30 ± 9.55 |
82.64 ± 4.70 |
79.46 ± 12.12 |
75.76 ± 16.53 |
77.86 ± 19.32 |
73.22 ± 10.90 |
||||
Relative organ weight |
||||||||||
Brain(g%) |
0.646 ± 0.059 |
0.618 ± 0.026 |
0.618 ± 0.036 |
0.642 ± 0.039 |
0.668 ± 0.070 |
0.670 ± 0.056 |
||||
Thymus(mg%) |
72.96 ± 22.82 |
102.52 ± 13.98* |
94.82 ± 18.35 |
113.64 ± 14.99** |
127.10 ± 26.70 |
113.00 ± 35.65 |
||||
Heart(g%) |
0.336 ± 0.034 |
0.328 ± 0.011 |
0.338 ± 0.008 |
0.346 ± 0.009 |
0.314 ± 0.026 |
0.322 ± 0.008 |
||||
Liver(g%) |
3.632 ± 0.195 |
3.286 ± 0.249* |
3.344 ± 0.180 |
3.444 ± 0.075 |
2.494 ± 0.086 |
2.646 ± 0.166 |
||||
Spleen(g%) |
0.254 ± 0.038 |
0.200 ± 0.014* |
0.250 ± 0.020 |
0.286 ± 0.043 |
0.202 ± 0.008 |
0.176 ± 0.025 |
||||
Kidneys(g%) |
0.728 ± 0.033 |
0.672 ± 0.036 |
0.750 ± 0.043 |
0.694 ± 0.040 |
0.680 ± 0.060 |
0.650 ± 0.039 |
||||
Adrenals(mg%) |
26.70 ± 2.88 |
26.30 ± 1.17 |
25.08 ± 4.44 |
23.94 ± 3.94 |
26.52 ± 6.48 |
24.50 ± 3.87 |
||||
a) Number of animals examied.
Values are expressed as Mean ± S.D.
Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01
Histopathological findings in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test
Sex Organ Finding |
Dose level (mg/kg) Number of animals |
Administration period |
Recovery period |
||||
0 |
40 |
200 |
1000 |
0 |
1000 |
||
7 |
12 |
12 |
7 |
5 |
5 |
||
Male (Grade) |
|||||||
Urinary bladder |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Testis |
<5> |
<0> |
<0> |
<5> |
<0> |
<1> |
|
Degeneration, seminiferous tubular epithelium, focal |
1+ |
1 |
|
|
0 |
|
0 |
Degeneration, seminiferous tubular epithelium, diffuse |
1+ |
0 |
|
|
0 |
|
1 |
Epididymis |
<5> |
<0> |
<0> |
<5> |
<0> |
<1> |
|
Decrease, sperm |
|
0 |
|
|
0 |
|
1 |
Seminal vesicle |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Prostate |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Cell infiltration, lymphocyte, interstitium |
1+ |
1 |
|
|
2 |
|
|
Coagulating gland |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Pituitary |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Cyst, anterior lobe |
1+ |
1 |
|
|
0 |
|
|
Cyst-like lesion, anterior lobe |
1+ |
0 |
|
|
1 |
|
|
Thyroid |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Ectopic thymic tissue |
1+ |
0 |
|
|
1 |
|
|
Ultimobrancheal remnant |
1+ |
1 |
|
|
1 |
|
|
Parathyroid |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Adrenal |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Brain |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Spinal cord |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
Sciatic nerve |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
< > : Number of animals examined.
Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,
Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01
Sex Organ Finding |
Dose level (mg/kg) Number of animals |
Administration period |
Recovery period |
Non-pregnant |
||||
0 |
40 |
200 |
1000 |
0 |
1000 |
1000 |
||
12 |
11 |
12 |
11 |
5 |
5 |
1 |
||
Female (Grade) |
||||||||
Heart |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Lymph node, mandibular |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Lymph node, mesenteric |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Thymus |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Cyst |
1+ |
3 |
|
|
1 |
|
|
|
Spleen |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Prostate |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
|
|
Extramedullary hematopoiesis, erythrocytic |
1+ |
2 |
|
|
2 |
|
|
|
Bone marrow, femur |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Trachea |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Lung (and bronchus) |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Accumulation, foam cell, alveolus |
1+ |
1 |
|
|
1 |
|
|
|
Mineralization, arterial wall, focal |
1+ |
1 |
|
|
1 |
|
|
|
Stomach |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Cyst, mucosa, glandular stomach |
1+ |
0 |
1 |
0 |
0 |
0 |
0 |
|
Hyperplasia, foveola, glandular stomach |
1+ |
0 |
0 |
1 |
3 |
0 |
0 |
|
Necrosis, mucosa, glandular stomach, focal |
1+ |
0 |
0 |
1 |
3 |
0 |
0 |
|
Small intestine, duodenum |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Small intestine, jejunum |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Small intestine, ileum |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Large intestine, cecum |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Large intestine, colon |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Large intestine, rectum |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Liver |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Proliferation, bile duct |
1+ |
1 |
|
|
0 |
|
|
|
Kidney |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Basophilic tubule |
1+ |
0 |
|
|
1 |
|
|
|
Cell infiltration, inflammatory, pelvis, focal |
1+ |
0 |
|
|
1 |
|
|
|
Cell infiltration, lymphocyte, interstitium, focal |
1+ |
1 |
|
|
0 |
|
|
|
Fibrosis, focal |
1+ |
1 |
|
|
0 |
|
|
|
Urinary bladder |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Ovary |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<1> |
|
Uterus |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Vagina |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Pituitary |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Cyst, Rathke's pouch |
1+ |
0 |
|
|
1 |
|
|
|
Thyroid |
<5> |
<0> |
<0> |
<5> |
<0> |
<0> |
<0> |
|
Ultimobrancheal remnant |
1+ |
3 |
|
|
2 |
|
|
|
< > : Number of animals examined.
Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,
Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01
Fertility and pregnancy data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test
Dose level(mg/kg) |
Administration period |
|||
0 |
40 |
200 |
1000 |
|
Number of pairs examined |
12 |
12 |
12 |
12 |
Estrous cycle |
4.18 ± 0.34 |
4.03 ± 0.09 |
4.00 ± 0.00 |
4.08 ± 0.29 |
Irregular estrous cycle |
1/12 |
1/12 |
1/12 |
1/12 |
Number of pairs with successful mating |
12 |
12 |
12 |
12 |
Mating index (%)a) |
100.0 |
100.0 |
100.0 |
100.0 |
Number of pregnant females |
12 |
12 |
12 |
12 |
Fertility index (%)b) |
100.0 |
100.0 |
100.0 |
91.7 |
Pairing days until mating |
3.0 ± 1.3 |
3.4 ± 1.8 |
2.8 ± 1.1 |
2.8 ± 1.1 |
Number of estrous stages without mating |
0.0 ± 0.0 |
0.3 ± 0.5* |
0.0 ± 0.0 |
0.0 ± 0.0 |
a) Mating index (%) = (Number of pairs with successful mating/number of pairs examined)×100
b) Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating)×100
Values are expressed as Mean ± S.D.
Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01
Delivery and litter data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test
Dose level(mg/kg) |
Administration period |
|||
0 |
40 |
200 |
1000 |
|
Number of females examined |
12 |
11 |
12 |
11 |
Number of females with live pups |
12 |
11 |
12 |
11 |
Gestation index (%)a) |
100.0 |
100.0 |
100.0 |
100.0 |
Gestation length (days) |
22.4 ± 0.5 |
22.4 ± 0.5 |
22.3 ± 0.5 |
22.3 ± 0.5 |
Number of corpora lutea |
16.3 ± 1.4 |
16.5 ± 1.8 |
17.3 ± 1.2 |
15.8 ± 1.9 |
Number of implantation sites |
15.2 ± 1.4 |
15.2 ± 1.5 |
15.9 ± 1.0 |
14.8 ± 1.9 |
Implantation index (%)b) |
92.94 ± 4.90 |
92.47 ± 5.65 |
91.98 ± 5.40 |
93.83 ± 6.46 |
Delivery index (%)c) |
97.25 ± 3.41 |
94.67 ± 7.56 |
91.88 ± 10.99 |
92.85 ± 7.84 |
Number of pups delivered |
14.8 ± 1.5 |
14.4 ± 1.7 |
14.6 ± 1.7 |
13.8 ± 2.6 |
Number of live pups on day 0 |
14.6 ± 1.6 |
14.4 ± 1.7 |
14.6 ± 1.7 |
13.6 ± 2.7 |
Number of live pups on day 4 |
14.5 ± 1.7 |
13.1 ± 3.1 |
14.5 ± 1.8 |
13.2 ± 2.6 |
Live birth index (%)d) |
98.84 ± 2.72 |
100.00 ± 0.00 |
100.00 ± 0.00 |
98.55 ± 3.24 |
Viability index on day 4 (%)e) |
99.31 ± 2.40 |
91.58 ± 19.79 |
99.36 ± 2.22 |
96.68 ± 4.03 |
Sex ratio of total number of offspring at birth (M/Total) |
0.46(81/177) |
0.50(79/158) |
0.49(85/175) |
0.45(68/152) |
Sex ratio of total number of live offspring at birth (M/Total) |
0.46(80/175) |
0.50(79/158) |
0.49(85/175) |
0.44(66/150) |
Sex ratio of total number of live offspring on day 4 (M/Total) |
0.46(80/174) |
0.51(73/144) |
0.48(84/174) |
0.44(64/145) |
Sex ratio of total number of offspring at birth (M/Total, litter) |
0.457 ± 0.112 |
0.505 ± 0.141 |
0.505 ± 0.141 |
0.453 ± 0.153 |
Sex ratio of total number of liveoffspring at birth (M/Total, litter) |
0.456 ± 0.120 |
0.505 ± 0.141 |
0.484 ± 0.093 |
0.444 ± 0.157 |
Sex ratio of total number of live offspring on day 4 (M/Total, litter ) |
0.458 ± 0.117 |
0.506 ± 0.142 |
0.481 ± 0.094 |
0.444 ± 0.146 |
Body weight of pups (g) on day 0 male female
on day 4 male female |
6.9 ± 0.6 6.4 ± 0.5
10.7 ± 1.4 10.2 ± 1.3 |
6.6 ± 0.7 6.3 ± 0.8
10.4 ± 1.6 9.9 ± 1.5 |
6.8 ± 0.5 6.5 ± 0.6
10.2 ± 1.1 9.8 ± 1.1 |
6.8 ± 0.5 6.4 ± 0.5
10.7 ± 1.4 10.3 ± 1.4 |
a) Gestation index (%) = (Number of females with live pups/number of pregnant females)×100
b) Implantation index (%) = (Number of implantation sites/number of corpora lutea)×100
c) Delivery index (%) = (Number of pups delivered/number of implantation sites)×100
d) Live birth index (%) = (Number of live pups on day 0/number of pups delivered)×100
e) Viability index (%) = (Number of live pups on day 4/number of live pups on day 0)×100
Values are expressed as Mean±S.D.
Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01
Applicant's summary and conclusion
- Conclusions:
- NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Crl:CD (SD) male and female rats treated with test material orally by gavage.
- Executive summary:
In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD) male and female rats treated with test material in the concentration of0, 40, 200 and 1000 mg/kg/day orally by gavage in0.1 w/v% Tween 80 added 0.5 w/v% CMC-Na solution. No efect on survival, clinical signs, body weight, food consumption, behavior test, hematology, blood chemistry, urinalysis, organ weight and gross pathology were observed in treated male and female rats as compared to control. Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. Focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, clinical signs, body weights, development and growth of pups and gross pathological changes were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.
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