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EC number: 604-721-7 | CAS number: 150114-71-9
- 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: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 5 March 2002 to 23 December 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Remarks:
- Study conducted to GLP in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries. Testing Guidelines for Toxicology Studies, 1985 (Subchronic Dermal Toxicity Study (Repeated dose dermal toxicity: 21-days study)).
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4-amino-3,6-dichloropyridine-2-carboxylic acid
- EC Number:
- 604-721-7
- Cas Number:
- 150114-71-9
- Molecular formula:
- C6H4Cl2N2O2
- IUPAC Name:
- 4-amino-3,6-dichloropyridine-2-carboxylic acid
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Appearance: tan powder
Constituent 1
- Specific details on test material used for the study:
- Purity: 94.5%
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: ca. 8 weeks
- Weight at study initiation (group mean): 190.5 - 192.4 g (males); 129.0 - 130.7 g (females)
- Housing: Individually housed in stainless steel cages with wire-mesh floors which were suspended above absorbent cage paper. Cages contained feed containers and pressure activated nipple-type watering systems.
- Diet: ad libitum
- Water: municipal water, ad libitum
- Acclimation period: at least 16 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20.9 - 22.2 °C
- Humidity: 45.9 - 54.9 % (relative)
- Air changes: 12 - 15 air changes per hour
- Photoperiod: 12 hours of darkness / 12 hours of light (06:00 to 18:00)
Administration / exposure
- Type of coverage:
- semiocclusive
- Vehicle:
- methylcellulose
- Details on exposure:
- DERMAL EXPOSURE
Dermal exposure was accomplished by applying the test material to an area that was not less than 10 % of the total body surface. The area on the back of each rat was clipped free of hair at least 24 hours prior to initiation of dosing and on an as needed basis during the dose regime (approximately weekly). An area starting at the scapulae (shoulders) to the wing of the ilium (hipbone) and half way down the flank on each side of the animal was shaved. Animals were acclimated to the semi-occlusion bandages during the three days prior to dosing. The test material or vehicle (0.5 % aqueous MC, dissolved in distilled water) was applied as an aqueous suspension directly to the skin for approximately six hours/day, seven days/week such that a dose volume of 4 mL/kg body weight yielded the appropriate dose. The test material was uniformly applied as a suspension rather than paste due to logistical difficulties with the preparation and accurate application of a paste. Dose amounts were calculated for each animal based on weekly body weights. The vehicle (0.5 % MC) was applied to the backs of control animals at a dose volume of 4 mL/kg. The exposure site was semi-occluded with gauze dressing, non-absorbent cotton, and wrapped in an elastic bandage to hold the test material, gauze dressing and cotton in place. Approximately six hours after application, bandage, gauze and cotton were removed and the exposure site wiped with a water-dampened towel to remove any residual test material. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Homogeneity
Homogeneity analyses of dose suspensions targeted to contain 100 or 1000 mg/kg were determined prior to the start of the study. Samples stored at room temperature were analysed by HPLC with ultraviolet detection and external standard quantification.
The 100 mg/kg/day and 1000 mg/kg/day suspensions were shown to be homogeneously mixed at the study start, with percent relative standard deviations (% RSD) of 0.439 and 1.68 %, respectively.
- Stability
The stability of test material in 0.5% methylcellulose and stored in clear glass containers stored at room temperature was determined prior to the study start by reanalysing concentrations of 100 and 1000 mg/kg 34 days after initial concentration verification. The method used for analysing the test material was a solvent extraction method, followed by analysis using HPLC with ultraviolet detection and external standards.
The test material in the vehicle stored in clear glass vials at room temperature was shown to be stable for at least 34 days. The percent of initial concentration after 34 days was 99.6 %for the 100 mg/kg/day group and 102 % for the 1000 mg/kg/day group.
- Concentration Verification
Analyses of all dose levels, plus control, were conducted prior to the study start. The method used for analysing the test material was a solvent extraction method, followed by analysis using HPLC with ultraviolet detection and external standards.
Results indicated an acceptable agreement between actual and targeted levels with actual values ranging from 105 to 108 % of the targeted concentrations. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Animals were dosed six hours/day, seven days per week.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- corresponds to 0 mg/mL
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- corresponds to 25 mg/mL (male) and 26.2 mg/mL (females)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- corresponds to 125 mg/mL (males) and 134.0 mg/mL (females)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- corresponds to 250 mg/mL (males) and 269.0 mg/mL (females)
- No. of animals per sex per dose:
- 10 males and 10 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The high-dose of 1000 mg/kg/day was chosen based on consideration of the findings from existing toxicity studies. This dose also represented the limit test dose level set by several regulatory agencies for dermal toxicity studies. The remaining dose levels were expected to provide dose-response data for any treatment-related effect(s) observed in the high-dose group and to ensure definition of a no-observed-effect level (NOEL).
- Rationale for animal assignment: Animals were stratified by pre-exposure body weight and then randomly assigned to treatment groups using a computer program.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day
- Cage side observations: This examination was performed with the animals in their cages and was designed to: 1) detect significant clinical abnormalities that are clearly visible upon a limited examination and 2) to monitor the general health of the animals. Significant clinical abnormalities that may have been observed included, but were not limited to: changes in activity, repetitive behaviour, vocalisation, incoordination/lameness, injury, neuromuscular function (convulsion, fasciculation, tremor, twitches), altered respiration, blue/pale skin and mucous membranes, severe eye injury (rupture), faecal consistency, and faecal/urinary quantity. At least twice daily all animals were observed for morbidity and mortality, and the availability of feed/water.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: pre-exposure and weekly throughout the study.
- Detailed clinical observations: The examination included cage-side, hand-held, and open-field observations that were recorded categorically or using explicitly defined scales.
DERMAL IRRITATION: Yes
- Time schedule for examinations: The dermal test site was subjectively evaluated weekly, using the testing laboratory's modification of the acute dermal irritation scoring system recommended by the Organisation for Economic Co-Operation and Development (see Table 1). In addition, necrosis, scabs and/or scars would have been noted if present. However they would not have been graded.
BODY WEIGHT: Yes
- Time schedule for examinations: All rats were weighed during the pre-exposure period and weekly throughout the study. Body weight gains were calculated.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Feed consumption data were collected weekly throughout the study. Feeders were weighed at the start and end of a measurement cycle and consumption was calculated using the following equation:
Feed consumption (g/day) = (initial weight of feeder - final weight of feeder) / (number of days in measurement cycle x number of animals in cage)
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-exposure and prior to termination using indirect ophthalmoscopy
- Dose groups that were examined: All animals
- Ophthalmoscopic examination: One drop of 0.5% tropicamide ophthalmic solution was instilled in each eye to produce mydriasis prior to the indirect ophthalmic examinations. Eyes were also examined by a prosector during necropsy through a moistened glass slide pressed to the cornea.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Collected from the orbital sinus at scheduled necropsy
- Anaesthetic used for blood collection: Yes (CO₂)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked included: Haematocrit (Hct), Haemoglobin (Hgb) concentration, Red blood cell (RBC) count, Total white blood cell (WBC) count, Platelet (PLAT) count, Differential WBC count, RBC indices (MCH, MCV and MCHC), Prothrombin time (PT).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Collected from the orbital sinus at scheduled necropsy
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked included: Alkaline phosphatase (AP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Albumin (ALB), Cholesterol (CHOL), Creatinine (CREAT), Electrolytes (Na, K, PO₄, Cl and Ca), Glucose (GLU), Total bilirubin (TBILI), Total protein (TP), Urea nitrogen (UN).
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected from all non-fasted animals during the week prior to necropsy
- Metabolism cages used for collection of urine: Yes (for a 16 hour period)
- Animals fasted: No
- Parameters checked included: Colour, Appearance, Specific gravity, pH, Bilirubin, Glucose, Proteins, Ketones, Blood, Urobilinogen
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- ANIMAL SACRIFICE
Fasted animals submitted alive for necropsy were anaesthetised by the inhalation of CO₂, weighed, and blood samples were obtained from the orbital sinus. Their tracheas were exposed and clamped, and the animals were euthanised by decapitation.
GROSS PATHOLOGY: Yes
A complete necropsy was conducted on all animals. The necropsy included an examination of the external tissues and all orifices. The head was removed, the cranial cavity opened and the brain, pituitary and adjacent cervical tissues were examined. The eyes were examined in situ by application of a moistened glass slide to each cornea. The skin was reflected from the carcass, the thoracic and abdominal cavities were opened and the viscera examined. All visceral tissues were dissected from the carcass, re-examined and selected tissues were incised. The nasal cavity was flushed via the nasopharyngeal duct and the lungs were distended to an approximately normal inspiratory volume with neutral, phosphate buffered 10 % formalin using a hand-held syringe and blunt needle.
The brain, liver, kidneys, heart, adrenals, testes, epididymides, uterus, ovaries, thymus, cecum (full and empty), and spleen were trimmed and weighed immediately. The ratios of organ weight to terminal body weight were calculated.
HISTOPATHOLOGY: Yes
Sections from the following tissues, which were preserved in neutral, phosphate-buffered 10 % formalin were processed by standard histologic procedures from control- and high-dose group animals.
Tissues included: adrenals, aorta, auditory sebaceous glands, bone (including joint), bone marrow, brain (cerebrum, brainstem, cerebellum), cecum, cervix, coagulating glands, colon, cranial nerve - optic, duodenum, epididymides, eyes, gross lesions, heart, ileum, jejunum, kidneys, lacrimal/Harderian glands, larynx, liver, lungs, mammary gland (females only), mediastinal lymph node, mediastinal tissues, mesenteric lymph node, mesenteric tissues, nasal tissues/pharynx, oesophagus, oral tissues, ovaries, oviducts, pancreas, parathyroid glands, peripheral nerve - tibial, pituitary, prostate, rectum, salivary glands, seminal vesicles, skeletal muscle, skin and subcutis, skin - dermal site, skin - adjacent to dermal test site, spinal cord (cervical, thoracic, lumbar), spleen, stomach, testes, thymus, thyroid gland, tongue, trachea, urinary bladder, uterus, vagina.
Paraffin embedded tissues were sectioned approximately 6 μm thick, stained with haematoxylin and eosin and examined using a light microscope. The following tissues from the remaining groups were processed and histopathologically examined: liver, lungs, kidneys, dermal test site, skin adjacent to the dermal test site, and relevant gross lesions. - Statistics:
- Means and standard deviations were calculated for all continuous data. Body weights, feed consumption, organ weights, urine specific gravity, clinical chemistry data, coagulation, and appropriate haematologic data were evaluated by Bartlett's test (alpha = 0.01; Winer, 1971) for equality of variances. Based on the outcome of Bartlett's test, exploratory data analyses were performed by a parametric (Steel and Torrie, 1960) or nonparametric (Hollander and Wolfe, 1973) analysis of variance (ANOVA). If significant at alpha = 0.05, the ANOVA was followed respectively by Dunnett's test (alpha = 0.05; Winer, 1971) or the Wilcoxon Rank-Sum test (alpha = 0.05; Hollander and Wolfe, 1973) with a Bonferroni correction (Miller, 1966) for multiple comparisons to the control. The experiment-wise alpha level was reported for these two tests. Detailed clinical observations incidence scores were statistically analysed by a z-test of proportions comparing each treated group to the control group (alpha = 0.05; Bruning and Kintz, 1987). Data collected at different time points were analysed separately. Descriptive statistics only (means and standard deviations) were reported for body weight gains, RBC indices, and differential WBC counts. Statistical outliers were identified by a sequential test (alpha = 0.02; Grubbs, 1969), but routinely excluded only from feed consumption statistics. Outliers, if identified, were excluded from other analyses only for documented, scientifically sound reasons.
As numerous measurements were statistically compared in the same group of animals, the overall false positive rate (Type I errors) will be greater than the nominal alpha levels. Therefore, the final interpretation of the data considered statistical analyses along with other factors, such as dose-response relationships and whether the results are consistent with other biological and pathological findings and historical control values.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- refer to the field "Details on results" for further information
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- MORTALITY AND CLINICAL SIGNS
There were no deaths during this study.
There were no treatment-related clinical findings during the study. Examinations revealed infrequent occurrences of red periocular soiling, decreased quantity of faeces and focal or multifocal scabs on the skin. Since these observations did not occur in a dose-responsive manner, they were interpreted to not be treatment related.
EVALUATION OF DERMAL SITES
There were no treatment-related gross signs of dermal irritation throughout the entire study for any dose level. One male in the 1000 mg/kg/day group had scabs on the dermal test site on day 28 of study, thought to be associated with the clipping procedure.
BODY WEIGHTS
There were no treatment differences in the body weights or body weight gains of any treated groups when compared to their respective controls.
FEED CONSUMPTION
There were no treatment differences in the feed consumption of any treated groups when compared to their respective controls.
OPHTHALMOLOGY
Examinations performed on all animals pre-exposure and during week 4 revealed no treatment-related findings. Ophthalmic observations (periocular soiling, cloudy cornea, and pale fundus) did not occur in a dose-related manner. Therefore, all ophthalmologic observations were interpreted to be spontaneous alterations.
CLINICAL PATHOLOGY
There were no treatment related changes in any of the haematologic, clinical chemistry, or uninalysis parameters for male and female rats.
Females given 1000 mg/kg/day had a statistically identified decrease in mean cholesterol, relative to controls. However the mean cholesterol value of females given 1000 mg/kg/day (66 mg/dL) was within the historical control range of 58 - 74 mg/dL from other 4-week dermal toxicity studies conducted in the same laboratory, and therefore, was interpreted to be of no toxicological significance.
ANATOMIC PATHOLOGY
> Organ weights: There were no treatment-related changes in any of the organ weight parameters for male and female rats. Males given 100 or 500 mg/kg/day had statistically identified increases in absolute and relative full cecum weights, relative to controls. These alterations in cecum weights were interpreted to not be treatment-related because of the lack of cecal weight increase in males given 1000 mg/kg/day. In addition, there were no statistically identified alterations in empty cecal weights, and there were no histopathologic alterations of the cecum in males and females given 1000 mg/kg/day.
> Gross pathology: There were no treatment-related gross pathologic observations. A few males and females given 0 or 1000 mg/kg/day, and one male given 500 mg/kg/day, had mottling or necrosis of the papillary process of the liver. These gross liver alterations were interpreted to be caused by compressive effects of the elastic bandages used to hold the test material in place. All other gross pathologic observations were considered to be spontaneous alterations, not associated with exposure to the test material.
> Histopathology: The only treatment-related histopathologic observation was slight epidermal hyperplasia at the dermal test site in 2 males given 500 and 3 males given 1000 mg/kg/day. The epidermis of animals with slight hyperplasia was approximately twice as thick as the epidermis of unaffected control animals. There was no microscopic evidence of systemic toxicity at any dose level. A few animals from the control and 1000 mg/kg/day group, and one male given 500 mg/kg/day, had infarction or necrosis with accompanying inflammation of the papillary process of the liver. These liver lesions were interpreted to be caused by compressive effects of the elastic bandages used to hold the test material in place. All other histopathologic observations were considered to be spontaneous alterations, not associated with exposure to test material.
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- (systemic effects)
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no systemic effects at highest dose tested
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 2: Treatment-related Histopathology Findings at the Dermal Test Site
Sex |
Males |
Females |
||||||
Dose (mg/kg/day) |
0 |
100 |
500 |
1000 |
0 |
100 |
500 |
1000 |
Dermal test sites (no. examined) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Within normal limits |
3 |
2 |
1 |
0 |
7 |
9 |
5 |
6 |
Hyperplasia, epidermis, very slight |
7 |
8 |
7 |
7 |
3 |
1 |
5 |
4 |
Hyperplasia, epidermis, slight |
0 |
0 |
2 |
3 |
0 |
0 |
0 |
0 |
Bold type indicates incidence of effects judged to be treatment-related.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, the no-observed-effect level (NOEL) for Fischer 344 rats following 28-days of 6 hour/day dermal exposure to the test material was the targeted concentration of 100 mg/kg/day for males and 1000 mg/kg/day for females. The NOEL for systemic effects was 1000 mg/kg/day for both males and females.
- Executive summary:
The toxicity of the test material, following repeated dermal exposure, was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines OECD 410, EU Method B.9, EPA OPPTS 870.3200 and JMAFF (1985).
During the study, ten male and ten female Fischer 344 rats per group were dermally exposed at a semi-occluded skin test site to 0, 100, 500, or 1000 mg test material/kg body weight/day, 6 hours/day, 7 days/week, for at least 28 days. Parameters evaluated were daily cage-side observations, weekly detailed clinical observations, weekly dermal grading, ophthalmologic examinations, body weights, body weight gains, feed consumption, haematology, clinical chemistry, urinalysis, organ weights, and gross and histopathologic examinations. The only treatment-related effect was slight epidermal hyperplasia at the dermal test site of two males given 500 mg/kg/day, and 3 males given 1000 mg/kg/day. The slight epidermal hyperplasia was indicative of minimal irritation in response to dermal application of the test material. Under the conditions of this study, the no-observed-effect level (NOEL) for Fischer 344 rats following 28-days of 6 hour/day dermal exposure to the test material was the targeted concentration of 100 mg/kg/day for males and 1000 mg/kg/day for females. The NOEL for systemic effects was 1000 mg/kg/day for both males and females.
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