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EC number: 221-112-8 | CAS number: 3006-93-7
- 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
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Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral, other
- Remarks:
- Repeated Dose and Reproduction/Developmental Toxicity Screening Test
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 15-10-2010 to 31-03-2011
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
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)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1,1'-(1,3-phenylene)bis-1H-pyrrole-2,5-dione
- EC Number:
- 221-112-8
- EC Name:
- 1,1'-(1,3-phenylene)bis-1H-pyrrole-2,5-dione
- Cas Number:
- 3006-93-7
- Molecular formula:
- C14H8N2O4
- IUPAC Name:
- 1,1'-(1,3-phenylene)bis-1H-pyrrole-2,5-dione
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- - Purity: 99.3%
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Co., Ltd
- Age at study initiation: 9 weeks
- Weight at study initiation: 476.7± 33.3g (males) and 286.0± 20.2 (female) at Day 0 of test item adminstration
- Fasting period before study: 16 hrs
- Housing: Individual in aluminum front and floor stainless steel mesh breeding cage
- Diet: Radiation sterilized solid feed (CRF-1, Lot No. 100203, 100302, Oriental Yeast Co.) ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.8 to 23.2 ° C
- Humidity (%): 53.8 to 64.8%
- Air changes (per hr): 12 times per hr
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% methyl cellulose aqueous solution (suspended)
- Details on oral exposure:
- VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- Males: 42 days
Females; 42-52 days (from 14 days before mating to day 4 of lactation) - Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Dose / conc.:
- 240 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- Males: 7 rats/group (control and high dose groups of main study)
+5 rats/group (control and high dose groups of recovery).
12 rats/group (low and middle dose groups of main study).
Females: 12 rats/group (all groups of main study)
+ 5 rats/group (control and high dose groups of recovery). - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
In the 14-day range finding study with 6 males and 6 females at doses of 0, 20, 60, 200, 600 mg/kg bw/day, following findings were reported.
600 mg/kg bw/day: Death (M6/6, F6/6), diarrhea, mucous stool, soiled fur, ptosis (MF), body weight↓(MF), food consumption↓(MF), enlarged lumen of the stomach, red or black
patches in the stomach, enlarged lumen of the small intestine, liquid content in the stomach and the large intestine, reddish content in the small and large
intestine, atrophy of the thymus, blackish discoloration of the large intestine, brownish discoloration of the lymph node, red patch / edema of the thymus,
enlarged adrenal, emaciation (MF)
200 mg/kg bw/day: Diarrhea, suppressed body weight gain, enlarged lumen of the stomach / small intestine / large intestine, atrophy of the spleen and the thymus (F1/6), Hct↓,
Hgb↓, RBC↓(M), TP↓, Alb↓, BUN↓ (M), monocyte↑(F), red or brown patches in the mesenteric lymph node (MF)
60 mg/kg bw/day: Hct↓, Hgb↓, RBC↓ (M), TP↓, Alb↓, BUN↓(M)
20 mg/kg bw/day: No effect
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes (males only)
Behaviour: Yes (Functional Observational Battery:detailed observation, sensory reactivities, grasping power, motor activity). - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes and organ weights
HISTOPATHOLOGY: Yes
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Death occurred in 4 females and 2 males at 240 mg/kg bw/day. These animals showed loose stools, diarrhea, abnormal respiration noise, irregular respiration, etc. before death.
In animlas that survived, salivation was observed in males in the 60 mg/kg group and in animals of both sexes in the 240 mg/kg group. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Death occurred in 2 males and 2 females in the 240 mg/kg group of the main study group and 2 females in the 240 mg/kg group of the satellite group.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Inorganic phosphorus and blood potassium concentration were decreased in females in the 240 mg/kg group of the satellite group; these changes were considered to be related to the dysfunction of the digestive tract by the test substance.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Total excretion volume of potassium and urinary potassium concentration were decreased, urinary pH was lowered and urinary protein was slightly increased in the 240 mg/kg group, total protein, albumin and α1 globulin were decreased and an α2 globulin ratio was increased in males in the 240 mg/kg group of the main study group, inorganic phosphorus was decreased in females in the 60 and 240 mg/kg groups of the main study group; these changes were considered to be related to the dysfunction of the digestive tract by the test substance.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Death occured in 4 females and 2 males at 240 mg/kg bw/day. At necropsy, dilatation of the gastric lumen with gas and/or liquid contents was observed in all of the above animals, and brownish mesenteric lymph nodes, red patches in the stomach, dilatation of the lumen of the small intestine with gas and/or liquid red contents and dilatation of the lumen of the large intestine (cecum) with gas contents in some of them.
In the pathological examination of animals that survived, brownish mesenteric lymph nodes, black patches in the glandular stomach, dilatation of the intestinal lumen (duodenum, jejunum and cecum) with gas contents and gas contents in the large intestine (colon) were observed, and these were considered to reflect gastric injury and dysfunction of the digestive tract by the test substance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathologically, blood absorption by the mesenteric lymph nodes was observed in all of the animals which were found dead, and brown pigments in the mesenteric lymph nodes, hemorrhage from the forestomach, edema, polymorphonuclear cell infiltration and inflammation in the glandular stomach in some of them. From these pathological findings, the cause of death was considered to be gastric injury and dysfunction of the digestive tract by the test substance.
The following histopathological findings also confirmed the presence of the gastric injury by the test substance in animals that survived: blood absorption by the mesenteric lymph nodes, brown pigments in the mesenteric lymph nodes and hemorrhage from the forestomach in males or females in the 60 or 240 mg/kg group. - Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathologically, squamous cell hyperplasia in the forestomach was noted in 4/4 dead females at 240 mg/kg bw/day.
Squamous cell hyperplasia and an increase in apoptosis in the forestomach, proliferation of surface mucous cell in the glandular stomach in males or females in the 60 or 240 mg/kg group. An increase in mitosis in the glandular stomach was observed in animals of both sexes given 15 mg/kg or more. The latter finding was considered to be an effect of the test substance but was concluded to be toxicologically meaningless because there were no other findings suggestive of gastric injury in those groups. - Other effects:
- not examined
- Details on results:
- Please refer to Figures 1-6, Tables 1- 16 and Appendices 1 - 18 for all relevant data.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- < 15 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 15 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
Target system / organ toxicity
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 15 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 60 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- mesenteric lymph node
- stomach
- Treatment related:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 240 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- intestine
- mesenteric lymph node
- stomach
- Treatment related:
- yes
Applicant's summary and conclusion
- Conclusions:
- In a repeated dose and reproduction/developmental toxicity screening test with 1,1'-(1,3-phenylene)bis-1H-pyrrole-2,5-dione in Crl:CD (SD) rats, the NOAEL for both sexes was 15 mg/kg bw/day and the NOEL was <15 mg/kg bw/day.
- Executive summary:
In a repeated dose and reproduction/developmental toxicity screening test (C545 (314 -026)), 1,1'-(1,3-phenylene)bis-1H-pyrrole-2,5-dione (99.3%) was administered to four groups of Crl:CD (SD) rats (12 animals/sex/group) by gavage in 0.5% methyl cellulose at dose levels of 0, 15, 60 and 240 mg/kg bw/day 7 days per week for 42 days (males) and 42-52 days (females).
Death occurred in 4 females and 2 males at 240 mg/kg bw/day. These animals showed loose stools, diarrhea, abnormal respiration noise, irregular respiration, etc. before death. In animals that survived, salivation was observed in males in the 60 mg/kg group and in animals of both sexes in the 240 mg/kg group. Total excretion volume of potassium and urinary potassium concentration were decreased, urinary pH was lowered and urinary protein was slightly increased in the 240 mg/kg group, total protein, albumin and α1 globulin were decreased and an α2 globulin ratio was increased in males in the 240 mg/kg group of the main study group and inorganic phosphorus was decreased in females in the 60 and 240 mg/kg groups of the main study group. Inorganic phosphorus and blood potassium concentration were decreased in females in the 240 mg/kg group of the satellite group; these changes were considered to be related to the dysfunction of the digestive tract by the test substance. There were no effects on body weight, food consumption, hematologic parameters, blood coagulation or organ weight.
At necropsy, dilatation of the gastric lumen with gas and/or liquid contents was observed in all animals that died, and brownish mesenteric lymph nodes, red patches in the stomach, dilatation of the lumen of the small intestine with gas and/or liquid red contents and dilatation of the lumen of the large intestine (cecum) with gas contents in some of them. In the pathological examination of animals that survived, brownish mesenteric lymph nodes, black patches in the glandular stomach, dilatation of the intestinal lumen (duodenum, jejunum and cecum) with gas contents and gas contents in the large intestine (colon) were observed, and these were considered to reflect gastric injury and dysfunction of the digestive tract by the test substance.
Histopathologically, blood absorption by the mesenteric lymph nodes was observed in all of the animals which were found dead, and brown pigments in the mesenteric lymph nodes, hemorrhage from the forestomach, edema, polymorphonuclear cell infiltration and inflammation in the glandular stomach in some of them. From these pathological findings, the cause of death was considered to be gastric injury and dysfunction of the digestive tract by the test substance. Squamous cell hyperplasia in the forestomach was noted in 4/4 dead females at 240 mg/kg bw/day. The following histopathological findings also confirmed the presence of the gastric injury by the test substance in animals that survived: blood absorption by the mesenteric lymph nodes, brown pigments in the mesenteric lymph nodes, squamous cell hyperplasia and an increase in apoptosis in the forestomach, hemorrhage from the forestomach, proliferation of surface mucous cell in the glandular stomach in males or females in the 60 or 240 mg/kg group. An increase in mitosis in the glandular stomach was observed in animals of both sexes given 15 mg/kg or more. This finding was considered to be an effect of the test substance but was concluded to be toxicologically meaningless because there were no other findings suggestive of gastric injury in those groups.
The NOAEL for both sexes was 15 mg/kg bw/day and the NOEL was <15 mg/kg bw/day.
This repeated dose and reproduction/developmental toxicity screening study in the rat is acceptable and satisfies the guideline requirement for this oral study (OECD 422) in rats.
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