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EC number: 915-671-3 | CAS number: -
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-09-04 to 2014-03-07
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 03 Oct 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- adopted 30 May 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 2001/59/EC
- Version / remarks:
- adopted 06 Aug 2001
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of 1,1'-(2,2,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione and 1,1'-(2,4,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione
- EC Number:
- 915-671-3
- Molecular formula:
- C17H22N2O4
- IUPAC Name:
- Reaction mass of 1,1'-(2,2,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione and 1,1'-(2,4,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 – 8 weeks (males) and 8 – 9 weeks (females)
- Weight at study initiation: 200 - 257 g (mean 215.13 g) males and 141 - 166 g (mean 151.75 g) females
- Housing: individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 030713)
- Diet: Altromin 1324 maintenance diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days under laboratory conditions
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was ground to a fine powder with the help of a mortar and the ground test item was weighed into a tared glass bottle on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item. The formulation was mixed thoroughly using a homogenizer. The test item formulation was prepared once a week and stored at ambient temperature.
VEHICLE
- Concentration in vehicle: 4, 10, 20 and 25* mg/mL (*treatment with 25 mg/mL for the first three days, afterwards treatment with 20 mg/mL)
- Amount of vehicle: 5 mL/kg bw
- Lot/batch no.: 1101401034 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- For determination of the concentration of test item in dosing formulations, samples of 5 mL were retained from low and mid dose group in study weeks 2 and 3 and from the high dose group in study weeks 1 and 4. Stability of the test item in the vehicle was assessed from one of the dose preparations after 8 days of storage.
Concentration analysis revealed a mean achieved concentration of 100.0%, 103.5% and 100.1% in the low, middle and high dose group, respectively. Homogeneity was determined for the low and high dose group only and revealed a mean recovery between 103.5 to 109.2% at the low dose group and between 102.4 and 106.1% at the high dose group, respectively. The stability of the control and high dose group after 7 days of storage was between 97.7 and 95.7%. - Duration of treatment / exposure:
- 28 days with 14 day recovery period
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- 5 animals were treated for the first three days with 125 mg/kg bw/day and afterwards with 100 mg/kg bw/day for the remaining treatment period and 2 animals were treated with 100 mg/kg bw/day for the whole treatment period.
- Dose / conc.:
- 125 mg/kg bw/day (actual dose received)
- Remarks:
- Animals were treated for the first three days with 125 mg/ kg bw/day and afterwards with 100 mg/kg bw/day for the remaining treatment period.
- No. of animals per sex per dose:
- 20 and 50 mg/kg bw/day: 5 (main group)
100 mg/kg bw/day: 6 (main group) and 6 (recovery group); each 5/6 males and 5/6 females were treated at 125 mg/kg bw/day for the first 3 days of treatment and. Due to mortality observed at 125 mg/kg bw/day, the high dose level was reduced to 100 mg/kg bw/day from Day 4 onward. To compensate for the animals that died in the period that the high-dose group was administered 125 mg/kg bw/day, 1 male and 1 female rat per group were added to the high-dose group and administered 100 mg/kg bw/day for the whole treatment period of 28 days. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dosing was based on a range finding study
- Rationale for animal assignment: before the first administration all animals used for the study were weighed and assigned to the experimental groups with achieving a most homogenous variation in body weight throughout the groups of males and females
- Post-exposure recovery period in satellite groups: 14 days
The highest dose level was chosen with the aim of inducing toxic effects without deaths or severe suffering. Animals from high dose group were treated with 125 mg/kg bw/day from Day 1 - 3 . After 2 spontaneous deaths, from Day 4 the dose was reduced to 100 mg/kg bw and 4 reserve animals were added to the high dose group. - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGES SIDE OBSERVATIONS: Yes
- Time schedule for examinations: The animals were checked once daily for clinical signs and twice daily for morbidity and mortality, except for weekends and public holidays when observations were made once daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first administration and at least once a weak thereafter.
- Detailed clinical examinations included: spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size.
BODY WEIGHT: Yes
- Time schedule for examinations: On the first day of administration and weekly during the treatment and recovery period.
FOOD CONSUMPTION: Yes
- Time schedule for food consumption: Food consumption was measured weekly during the treatment and recovery period in the recovery animals.
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before the first administration and in the last week of the treatment period, as well as at the end of the recovery period in the recovery animals.
- Dose groups that were examined: All animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery period prior to or as part of the sacrifice of the animals.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked: Haematocrit, haemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, reticulocytes, platelet count, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils and large unstained cells. Coagulation parameters examined included prothrombin time and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery period prior to or as part of the sacrifice of the animals.
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked: Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, total protein, albumin, urea, total bilirubin, total bile acids, total cholesterol, glucose, sodium and potassium.
URINALYSIS: Yes
- Time schedule for collection of urine: Urinalysis was performed with samples collected prior to or as part of the sacrifice of the animals.
- Metabolism cages used for collection of urine: The samples were drawn from the bladdder during necropsy.
- Animals fasted: Yes
- Parameters checked: Specific gravity, nitrite, pH value, protein, glucose, ketones, urobilinogen, bilirubin, blood and leukocytes.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Before the first exposure and once during the four weeks of exposure, as well as in the last week of the recovery period multiple detailed behavioural observations were made using a functional observational battery of tests.
- Dose groups that were examined: All animals in all groups
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. One day after the last administration (study Day 29) all surviving animals of the main group and 2 weeks after the last administration all surviving animals of the recovery group (study Day 43) were sacrificed using anesthesia and were subjected to a detailed gross necropsy which includes careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents.
- The following organ weights were determined for all animals: Liver, kidneys, adrenals, testes, epididymides, prostate, seminal vesicles and coagulating glands, ovaries, uterus with cervix, thymus, thyroid/parathyroid glands, spleen, brain, pituitary gland and heart.
HISTOPATHOLOGY: Yes. Samples of the following tissues from each animal were preserved and examined microscopically: Brain (cerebrum, cerebellum and pons), spinal cord, eye, liver, kidney, adrenal glands, stomach, small and large intestines (including Peyer's patches), thymus, thyroid glands, spleen, lung and trachea, mammary glands, skin, heart, ovaries, uterus with cervix, vagina, testes, epididymides, prostate and seminal vesicles with coagulating glands, urinary bladder, lymph nodes (mesenteric and axillary), peripheral nerve (e.g. sciatic nerve) with skeletal muscle, sternum with bone marrow, pituitary gland, oesophagus and head with nasal cavity. - Statistics:
- Parameters like body weight gain and food consumption were calculated for each animal as the difference in weight measured from one week to the next. The relative organ weights were calculated in relation to the brain weight and in relation to the body weight (measured at necropsy).
The toxicological and pathological data were evaluated via the validated computerized system E-Workbook. A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights were performed for each gender by comparing values of test item-treated with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Statistical comparisons of data acquired during the recovery period were performed with a Student’s t-Test. The statistics were performed with E-Workbook software (p<0.05 is considered as statistically significant).
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Moderate to severe salivation, moving the bedding and piloerection were noted in all treatment-groups and considered to be treatment-related. Slight indications of diarrhea, piloerection, slight salivation and moving the bedding were also noted among control animals, but the clinical signs were more prominent and consistently observed in test item-treated animals. Moving the bedding, salivation and piloerection were only seen immediately after dose administration, therefore the findings were considered to be transient and non-adverse.
In addition, high dose group males showed transient occurences of respiratory sounds, eyes half closed, eschar and bloated belly. In females of the high dose group, nasal discharge, alopecia and bloated belly was noted in the main and recovery group. Transient appearances of respiratory sounds (slight to severe) were observed in females of all dose groups, but more frequently seen in animals of the high dose group. The findings were considered to be treatment-related and toxicologically relevant. For details please refer to tables 1 and 2 under “Any other information on results incl. tables”. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 50 mg/kg bw/day: 1/5 females died (study Day 22), treatment-related
100/125 mg/kg bw/day: After two spontaneous deaths at 125 mg/kg bw/day the dose level was adjusted to 100 mg/kg bw/day from study Day 4 onward. Within the whole study period, 3/6 males (study Days 4, 9 and 17) and 1/6 females (study Day 17) of the main group and 2/6 males (study Days 3 and 4) and 1/6 females (study Day 3) of the recovery group died or were killed for humane reasons during the treatment preriod, treatment-related. All deaths/unscheduled sacrifices were attributed to local lesions in the forestomach, treatment-related. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 20 mg/kg bw/day: reduced body weight gain in both sexes during the first week of treatment, not treatment-related
50 mg/kg bw/day: slightly decreased body weight gain in females at the beginning of treatment, not treatment-related
100/125 mg/kg bw/day: considerably attenuated body weight increase in males during the first and second week of treatment (approx. 15 and 70% of controls, respectively, statistically not significant), during this time mortality occured in 4/10 males in this group, treatment-related findings consistent with changes in food intake; increased body weight gain in females during the first 2 weeks (118 and 112% of control) followed by a slight decrease in the third week (approx. 3 g), both increase and decrease statistically not significant, findings in females were attributed to the marked decrease in body weight of a single animal and accompanied by mortality of a second female in this group; consistent with changes in food intake - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 100/125 mg/kg bw/day: Decreased in males between Days 1-28 due to lower food consumption in week 1 and 2 (-39.4% and -16.9%, statistically not significant), attributed to two isolated males which were found dead or prematurely killed for ethical reasons. A slight decrease within the first two study weeks (-15% and -18.9%) was also observed in the male recovery group, which were attributed to individual animals with poor health condition. In females there was a considerable decrease in food consumption in first study week in animals of the main group (-41.6%, statistically not significant) and a slight decrease (-14.8%) in animals of the recovery group. All findings in males and females were considered to be secondary due to histopathological changes in the forestomach and attributed to treatment. All observations were found to be fully reversible in recovery animals after two weeks of recovery.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- 20 mg/kg bw/day: A statistically significant decrease in haemoglobin was observed in males, the data were within the historical control range and considered to be not treatment-related.
50 mg/kg bw/day: A statistically significant decrease in haemoglobin and in red blood cell count was observed in males at the end of the treatment period. The data were within the historical control range and fully reversible after 2 weeks of recovery and therefore considered to be not treatment-related. A statistically significant increase in mean corpuscular volume (MCV) and a statistically non-significant increase in reticulocytes (Ret) was noted in females at the end of treatment, as well as a statistically significant increase in basophils. The increases in MCV and Ret were without dose relation and all findings were within the historical control range and fully reversible after 2 weeks recovery and therefore considered to be not treatment-related.
100/125 mg/kg bw/day: A statistically significant decrease in haematocrit and haemoglobin was noted in males. The changes remained within the historical control range and were fully reversible after two weeks of recovery and therefore considered to be not treatment-related. Males of the recovery group showed a statistically significant decrease in mean Ret and a statistically significant decrease in white blood cells. The findings were not consistent with animals of the main group and therefore not attributed to treatment. In females, there was a statistically significant increase in MCV and Ret at the end of treatment. The effects were fully reversible after 2 weeks of recovery in recovery animals and remained within the historical control range. Therefore all findings were not related to treatment. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 20 and 50 mg/kg bw/day: A statistically non-significant increase in alanine aminotransferase and aspartate aminotransferase and a statistically non-significant increase in cholesterol was noted in both sexes at the end of treatment. The findings occurred without dose-relation and were within the historical control range and thus considered to be without treatment-relation.
100/125 mg/kg bw/day: A statistically significant increase in total bile acids was noted in males at the end of treatment, which was fully reversible after two weeks of recovery. In addition, a statistically significant decrease in total protein was observed in male recovery animals at the end of recovery. The observations remained within the historical control range and were without histopathological abnormalities, therefore the findings were considered to be not treatment-related. In both sexes, there was a statistically non-significant increase in alanine and aspartate aminotransferase as well as cholesterol. Without a clear dose-relation the findings were considered to be not treatment-related. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- High levels of erythrocytes were found in 2/6 males and 2/6 females at the end of the recovery period and a high level of glucose was found in 1/6 females at the end of treatment. In addition, an increased urine protein concentration was observed in 1/6 female at the end of the recovery period. All observations were slight, in the normal range of normal variation and without dose relation and therefore considered to be not treatment-related.
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 20 mg/kg bw/day: increased relative liver weight in males, not dose-related, reversible, in the absence of histopathological findings the changes were considered to be related to metabolic adaption but not treatment-related
50 mg/kg bw/day: decreased absolute weight of epididymides, not dose-related, considered to be incidental; increased relative liver weight in males, not dose-related, reversible, in the absence of histopathological findings the changes were considered to be related to metabolic adaption but not treatment-related; increased mean absolute + relative spleen weight and increased relative thyroid weight in males at the end of treatment, sex specific, without histopathological findings, considered to be possibly related to compensation of local irritative effects in the forestomach; increased absolute liver weight in females, no dose relation, considered to be a change of metabolic adaption.
100/125 mg/kg bw/day: increased relative liver weight in males, not dose-related, reversible, in the absence of histopathological findings the changes were considered to be related to metabolic adaption but not treatment-related; increased mean absolute + relative spleen weight and increased relative thyroid weight in males at the end of treatment, sex specific, without histopathological findings, considered by the study author to be possibly related to compensation of local irritative effects in the forestomach; the cause of the effects is unclear. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Macroscopic findings being indicative of necrotizing inflammation in the forestomach were observed in all test item groups of both sexes at 20, 50 and 100/125 mg/kg bw/day. Findings at 100/125 mg/kg bw were found to be non-reversible after two weeks of recovery. Thickened and/or dark red mucosa and several foci were observed at macroscopical examination and the findings were accompanied by forestomach epithelial (squamous) hyperplasia and hyperkeratosis, parakeratosis and/or dyskratosis at histopathological examination. The incidence and group mean severity of the lesions was higher at 50 and 100/125 mg/kg bw/day. The findings were considered to be treatment-related but explained to be a result of local irritating effects and thus not attributed to systemic toxicity. The necrotic and inflammatory lesions showed a tendency to recover after 14 days of recovery. For details please refer to table no. 3 under "any other information on results incl. tables". In addition, gross necropsy findings in the lungs, spleen and seminal vesicles were observed in single cases in individual animals, but the observations were explained by accidental aspiration or the poor condition of the animals and due to treatment. For details please refer to table no. 4 under "Any other information on results incl. tables".
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Necrotizing inflammation in the forestomach was observed in all test item groups of both sexes at 20, 50 and 100/125 mg/kg bw/day, which was accompanied by forestomach epithelial (squamous) hyperplasia and hyperkeratosis, parakeratosis and/or dyskratosis. The incidence and group mean severity of the lesions was higher at 50 and 100/125 mg/kg bw/day. The findings were considered treatment-related but to be a result of local irritating effects and thus not attributed to systemic toxicity. After 14 days of recovery, the necrotic and inflammatory lesions were still present but to a lesser extent and not all animals were affected. For details please refer to table no. 5 under "any other information on results incl. tables".
In addition, several necrotic/inflammatory lesions and/or reactive alterations to the local injuries were recorded in the trachea, lung and/or oesophagus of decedent animals (please refer to table no. 6 under "any other information on results incl. tables"). The findings were attributed to the animal’s morbidity. Lymphoid atrophy of spleen and/or atrophy of thymus were recorded in some decedents and considered to be secondary responses to peracute stressful condition. 3/6 males of the high dose group showed reduced/low secretion of seminal vesicles and coagulating glands, but as histomorphological alterations were lacking the findings were considered to be secondary events due to poor conditions. In addition, 1/6 females of the high dose group had focal decidual-like alterations of the uterus and vaginal mucification. The causes of the alterations were unclear, but as no other histomorphological alterations were noted the findings were considered to be unrelated to treatment. - Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- There was necrotizing inflammation in the forestomach in all test item-treated groups of both sexes with a dose dependently increasing incidence, which was accompanied with forestomach epithelial (squamous) hyperplasia and hyperkeratosis, parakeratosis and/or dyskeratosis as reactive changes to the forestomach injuries.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment-related adverse effect observed
- Dose descriptor:
- NOAEL
- Remarks:
- local
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
- Dose descriptor:
- LOAEL
- Remarks:
- local
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Primary or secondary results of local irritative effects in the forestomach. As the forestomach is not a human tissue, there is no relevance for human exposure.
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1: Clinical findings in males
Clinical sign | Occurence / Total number of animals | Recovery animals | ||||
0 mg/kg bw/day | 20 mg/kg bw/day | 50 mg/kg bw/day | 100/125 mg/kg bw/day | 0 mg/kg bw/day | 100/125 mg/kg bw/day | |
Diarrhea, slight | 3/5 | 3/5 | 2/5 | 4/6 | 1/5 | 2/6 |
Piloerection, slight | 4/5 | 4/5 | 5/5 | 6/6 | / | 5/6 |
Salivation, slight | 1/5 | 5/5 | 5/5 | 4/6 | 2/5 | 4/6 |
Moving the bedding | 3/5 | 5/5 | 5/5 | 6/6 | 1/5 | 6/6 |
Salivation, moderate | 1/5 | 5/5 | 5/5 | 4/6 | / | 5/6 |
Salivation, severe | / | 5/5 | 5/5 | 6/6 | / | 5/6 |
Piloerection, moderate | / | 1/5 | 1/5 | 5/6 | / | 4/6 |
Piloerection, severe | / | / | 4/5 | 2/6 | / | 5/6 |
Respiratory sounds, moderate | / | / | / | 2/6 | / | / |
Eyes half closed | / | / | / | 2/6 | / | / |
Respiratory sounds, strong | / | / | / | 2/6 | / | 2/6 |
Nasal discharge, slight | / | / | / | 2/6 | / | / |
Diarrhea, severe | / | / | / | 4/6 | / | 3/6 |
Diarrhea, moderate | / | / | / | 1/6 | / | 1/6 |
Eschar | / | / | / | / | / | 1/6 |
Respiratory sounds, slight | / | / | / | 1/6 | / | / |
Bloated belly | / | / | / | / | / | 1/6 |
Table 2: Clinical findings in females
Clinical sign | Occurence / Total number of animals | Recovery animals | ||||
0 mg/kg bw/day | 20 mg/kg bw/day | 50 mg/kg bw/day | 100/125 mg/kg bw/day | 0 mg/kg bw/day | 100/125 mg/kg bw/day | |
Diarrhea, slight | / | / | / | 6/6 | 3/5 | 2/6 |
Piloerection, slight | / | 5/5 | 5/5 | 6/6 | / | 6/6 |
Salivation, slight | 5/5 | 4/5 | 6/6 | 1/5 | 5/6 | |
Moving the bedding | / | 5/5 | 5/5 | 6/6 | / | 6/6 |
Salivation, moderate | 5/5 | 5/5 | 6/6 | / | 5/6 | |
Salivation, severe | / | 5/5 | 5/5 | 6/6 | / | 5/6 |
Piloerection, moderate | / | 1/5 | 1/5 | 6/6 | / | 5/6 |
Piloerection, severe | / | / | / | 6/6 | / | 5/6 |
Respiratory sounds, moderate | / | / | 1/5 | 3/6 | / | 1/6 |
Eyes half closed | / | / | / | / | / | 1/6 |
Respiratory sounds, strong | / | / | / | 2/6 | / | 1/6 |
Nasal discharge,red | / | / | / | 1/6 | / | 2/6 |
Nasal discharge, slight | / | / | / | 1/6 | / | 2/6 |
Diarrhea, severe | / | / | / | 1/6 | / | 2/6 |
Diarrhea, moderate | / | / | 2/6 | / | 2/6 | |
Respiratory sounds, slight | / | 1/5 | 2/5 | / | / | 3/6 |
Nasal discharge, moderate | / | / | / | 1/6 | 1/5 | / |
Alopecia, flanks | / | / | / | 1/6 | / | / |
Bloated belly | / | / | / | 1/6 | / | / |
Alopecia | / | / | / | 1/6 | / | / |
Table No. 3: Macroscopical findings in the stomach observed at gross necropsy
Sex | Macroscopic finding | Necropsy finding occurence/total no. of animals at dose [mg/kg bw/day] | |||||
At the end of treatment | After recovery | ||||||
0 | 20 | 50 | 100/125 | 0 | 100/125 | ||
Male | Thickened mucosa | 1/5 | / | 1/5 | 2/6 | / | / |
Focus depressed | / | / | 1/5 | 1/6 | / | / | |
Abnormal content, foam | / | / | / | 1/6 | / | / | |
Gaseous distention, slimy fluid | / | / | / | 1/6 | / | / | |
Focus(es) (dark), mucosa fundus, foci, dark red 5x1 mm | / | / | 1/5 | / | / | 1/6 | |
Focus(es) (dark), several, black 2 mm | / | / | 1/5 | 1/6 | / | / | |
Focus(es) (dark), mucosa fundus, foci, dark red 4x1 mm | / | / | / | 1/6 | / | / | |
Focus(es) (dark), several, black 4x1 mm | / | / | / | / | / | 1/6 | |
Discoloured (dark), mucosa fundus, discoloration red | / | / | / | / | / | 1/6 | |
Gaseous distention, red | / | / | / | / | / | 1/6 | |
Discloured (dark), granular mucosa | / | / | / | / | / | 1/6 | |
Female | Gaseous distention | / | / | 1/5 | 1/6 | / | / |
Abnormal content, slimy | / | / | / | 1/6 | / | / | |
Discoloured (dark), mucosa red | / | / | / | / | / | 1/6 |
Table No. 4: Macroscopic findings at gross necropsy without treatment relation
Sex | Macroscopic finding | Necropsy finding occurence/total no. of animals at dose [mg/kg bw/day] | |||||
At the end of treatment | After recovery | ||||||
0 | 20 | 50 | 100/125 | 0 | 100/125 | ||
Male | Seminal vesicles, small in size | / | / | / | 2/6 | / | 1/6 |
Seminal vesicles, small in size, both vesicles | / | / | 1/5 | / | / | / | |
Duodenum, gaseous distention | / | / | / | 3/6 | / | 1/6 | |
Jejunum, discoloured (dark) | / | / | / | / | / | 1/6 | |
Jejunum, gaseous distention | / | / | / | 3/6 | / | 2/6 | |
Ileum with Peyer's patches, gaseous distention | / | / | / | 2/6 | / | 1/6 | |
Caecum, gaseous distention | / | / | 1/5 | 3/6 | / | / | |
Colon/rectum/anus, gaseous distention | / | / | / | 3/6 | / | / | |
Kidneys, discoloured (pale) | / | / | / | 1/6 | / | / | |
Kidneys, dilated pelvis, right | / | 1/5 | 1/5 | / | 1/5 | / | |
Kidneys, dilated pelvis, left | / | / | / | / | / | 1/6 | |
Kidneys, dilated pelvis | / | 1/5 | / | / | / | / | |
Kidneys, discoloured (pale), right, both, beige | / | 1/5 | / | / | / | / | |
Kidneys, discoloured (pale), both, light brown | / | 1/5 | / | / | / | / | |
Kidneys, large in size | / | / | / | / | / | 1/6 | |
Thymus, discoloured (dark) | / | / | / | 1/6 | / | 1/6 | |
Brain, cut | / | / | / | 1/6 | / | / | |
Caecum, fluid content | / | / | / | / | / | 1/6 | |
Spleen, cut in two pieces | / | / | / | / | / | 1/6 | |
Lungs, not collapsed | / | / | / | / | / | 1/6 | |
Female | Axillary lymph nodes, discoloured, dark | / | / | 1/5 | / | / | / |
Mesenteric lymph nodes, discoloured, dark | / | / | 1/5 | / | / | / | |
Ovaries, discoloured, both | / | 1/5 | / | / | / | / | |
Ovaries, discoloured, both, dark red | / | / | / | 1/6 | / | / | |
Ovaries, discoloured (dark), left, dark red | / | / | / | / | 1/5 | ||
Ovaries, discoloured (dark), right, red | / | / | / | / | / | 1/6 | |
Uterus/cervix, fluid distension | / | 1/5 | 1/5 | / | / | 1/6 | |
Uterus/cervix, nodules | / | / | / | 1/6 | / | / | |
Pancreas, discoloured (dark) reddish | 1/5 | / | / | / | 1/5 | 2/6 | |
Duodenum, gaseous distention | / | / | 1/5 | 1/6 | / | 1/6 | |
Jejunum, gaseous distention | / | / | 1/5 | 1/6 | / | 1/6 | |
Ileum with Peyer's patches, gaseous distention | / | / | / | 1/6 | / | 1/6 | |
Ileum with Peyer's patches, discoloured, dark | / | / | 1/5 | / | / | / | |
Caecum, gaseous distention | / | / | 1/5 | 1/6 | / | / | |
Caecum, fluid content | / | / | / | / | / | 1/6 | |
Colon/rectum/anus, gaseous distention | / | / | 1/5 | 1/6 | / | / | |
Spleen, small in size | / | / | / | 1/6 | / | / | |
Kidneys, dilated pelvis, both | / | 1/5 | / | / | 1/5 | / | |
Thyroid, cut in two pieces | / | / | / | / | / | 1/6 | |
Lungs, discoloured (dark), red | / | / | / | / | / | 1/6 | |
Thymus, discoloured (dark), red | / | / | / | / | / | 1/6 |
Table No. 5: Histopathological findings in the forestomach of surviving animals
Histopathological finding incidence/severity |
At the end of treatment | After recovery | ||||||||||
0 mg/kg bw/day | 20 mg/kg bw/day | 50 mg/kg bw/day | 100/125 mg/kg bw/day | 0 mg/kg bw/day | 100/125 mg/kg bw/day | |||||||
5 males | 5 females | 5 males | 5 females | 5 males | 4 females | 3 males | 5 females | 5 males | 5 females | 4 males | 5 females | |
Inflammation, necrotizing | 0 | 0 | 3/1.3 | 2/1.0 | 5/1.4 | 4/1.8 | 3/2.0 | 5/1.2 | 0 | 0 | 0 | 0 |
Epithelial hyperplasia, reactive | 0 | 0 | 3/1.3 | 2/1.0 | 5/2.0 | 4/1.8 | 3/2.3 | 5/2.0 | 0 | 0 | 0 | 0 |
Dyskeratosis | 0 | 0 | 2/1.5 | 2/1.0 | 3/1.3 | 2/2.5 | 3/1.7 | 4/1.0 | 0 | 0 | 0 | 0 |
Hyperkeratosis and parakeratosis | 0 | 0 | 3/1.3 | 2/1.0 | 5/1.8 | 4/1.8 | 3/2.0 | 5/1.8 | 0 | 0 | 4/1.0 | 4/1.0 |
Granulation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2/1.0 | 3/1.3 |
Table No. 6: Histopathological findings in decedent animals
Histopathological finding incidence/severity |
At the end of treatment | After recovery | ||||
50 mg/kg bw/day | 100/125 mg/kg bw/day | 100/125 mg/kg bw/day | ||||
Trachea | ||||||
Inflammation, necrotising | 0 | 1/1.0 | 1/1.0 | 0 | 1/4.0 | 0 |
Hypertrophy, mucosal epithelium | 0 | 0 | 0 | 1/1.0 | 0 | 0 |
Flocculent content in the lumen | 0 | 0 | 0 | 0 | 1/2.0 | 0 |
Lung | ||||||
Aspiration, pneumonia | 0 | 0 | 1/1.0 | 1/1.0 | 0 | 0 |
Bronchial mucous content, with celluluar debris and foreign material | 0 | 0 | 1/1.0 | 0 | 0 | 0 |
Increased macrophages, at bronchiolar alveolar duct area, with flocculent material | 0 | 0 | 0 | 0 | 0 | 1/1.0 |
Haemorrhage, at bronchiolar alveolar duct area, with flocculent material | 0 | 0 | 0 | 0 | 1/1.0 | 0 |
Oesophagus | ||||||
Inflammation, necrotising (recorded as grade 3) focal, submucosal (recorded as grade 1) |
0 | 0 | 2/1.0 | 1/3.0 | 0 | 0 |
Epithelial hyperplasia, reactive | 0 | 0 | 2/1.0 | 1/2.0 | 0 | 0 |
Dyskeratosis | 0 | 0 | 0 | 1/1.0 | 0 | 0 |
Hyperkeratosis and parakeratosis | 0 | 0 | 1/2.0 | 0 | 0 | 0 |
Forestomach | ||||||
Inflammation, necrotizing | 0 | 1/1.0 | 3/2.7 | 1/2.0 | 2/3.5 | 1/4.0 |
Epithelial hyperplasia, reactive | 0 | 0 | 3/2.0 | 1/2.0 | 2/1.5 | 1/1.0 |
Dyskeratosis | 0 | 0 | 2/1.5 | 1/2.0 | 2/1.0 | 1/1.0 |
Hyperkeratosis and parakeratosis | 0 | 1/1.0 | 3/2.0 | 1/2.0 | 2/2.0 | 1/1.0 |
Spleen | ||||||
Lymphoid atrophy | 0 | 1/2.0 | 0 | 1/4.0 | 2/1.0 | 1/1.0 |
Thymus | ||||||
Atrophy | 0 | 1/1.0 | 2/1.0 | 1/3.0 | 2/1.5 | 1/1.0 |
Applicant's summary and conclusion
- Conclusions:
- Necrotic inflammation in the forestomach was observed in all test item treated groups of both sexes, showing a dose-dependent increase in the severity and in the number of animals affected. Based on the data changes recorded in the study were not considered to be due to the systemic exposure to the test item, and were rather considered to be the primary or secondary results of local irritative effects of the test item in the forestomach, caused by the corrosive nature of the test item. As the forestomach is not a human tissue there is no relevance for human exposure. Based on the results of this study, the NOAEL for systemic toxicity was 100 mg/kg bw/day in male and female rats, which was the highest doses tested. The NOAEL for local toxicity was 50 mg/kg bw/day in male and female rats. As the forestomach is not a human tissue, the exposure is not relevant for humans.
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