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EC number: 601-147-9 | CAS number: 111988-49-9
- 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: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19 Jan - 14 Feb 2000
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
- Reference Type:
- other: Amendment
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
- Reference Type:
- other: Amendment
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 2008
- Deviations:
- yes
- Remarks:
- The study was conducted to investigate the mechanism of thyroidal changes after treatment with the test material. Therefore, the examinations were limited. For details please refer to "Principles of method if other than guideline".
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 1995
- Deviations:
- yes
- Remarks:
- The focus was set on the mechanism of test substance-related thyroidal changes.
- Principles of method if other than guideline:
- The study period was 3 weeks instead of 4, animals were housed individually instead of in groups, and were checked for morbidity and moribundity only once per day. Sensory reactivity was not assessed and no haematology was performed. Regarding clinical chemistry, only T3, T4, TSH, UDP-GT-levels and activity and plasma hormone levels were assessed. Organ weights were recorded for liver, uterus and the left thyroidal lobe only and histopathology was performed only for thyroid.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3-(2-chlor-5-pyridyl-methyl)-cyanimino-1,3-thiazolidin
- EC Number:
- 601-147-9
- Cas Number:
- 111988-49-9
- Molecular formula:
- C10H9ClN4S
- IUPAC Name:
- 3-(2-chlor-5-pyridyl-methyl)-cyanimino-1,3-thiazolidin
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Common strain for toxicological studies and recommended by the guideline.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: mean of male groups: 173-178 g, mean of female groups: 131-135 g
- Fasting period before study: not applicable
- Housing: individually under conventional conditions in type IIa polycarbonate cages on low-dust wood granulate (S sniff Spezialdiäten GmbH, Soest, Germany), during acclimatization rats were kept in groups (about 5 animals per type III cage, separated by sex)
- Diet: fixed-formula standard diet (Altromin® 1321 powder supplied by Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days
DETAILS OF FOOD AND WATER QUALITY: feed and water were regularly checked for contaminations.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): approx. 55
- Air changes (per hr): 15.20
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- peanut oil
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): fixed-formula standard diet (Altromin® 1321 powder supplied by Altromin GmbH, Lage, Germany)
- Storage temperature of food: room temperature
VEHICLE
- Justification for use and choice of vehicle: peanut oil was mixed in the feed to prevent dust-formation
- Amount of vehicle in feed: 1% - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Data on homogeneity and stability of the test substance in the administration vehicle covering the concentration range used were obtained. It was found that the test substance was stable in the diet for 8 days.
- Duration of treatment / exposure:
- 21 days
- Frequency of treatment:
- continuously via the diet
Doses / concentrationsopen allclose all
- Dose / conc.:
- 25 ppm
- Remarks:
- corresponding to 2.6 and 3.1 mg/kg bw/day actual dose ingested for males and females, respectively
- Dose / conc.:
- 100 ppm
- Remarks:
- corresponding to 9.0 and 12.3 mg/kg bw/day actual dose ingested for males and females, respectively
- Dose / conc.:
- 400 ppm
- Remarks:
- corresponding to 36.9 and 44.6 mg/kg bw/day actual dose ingested for males and females, respectively
- Dose / conc.:
- 1 600 ppm
- Remarks:
- corresponding to 145.1 and 190.8 mg/kg bw/day actual dose ingested for males and females, respectively
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The same doses had been administered in a subchronic feeding study in rats. In the present study, particular emphasis was given to the effects in thyroids and on thyroid hormones.
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS/DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: Body surfaces and orifices, posture, general behavior, breathing and excretory products
BODY WEIGHT: Yes
- Time schedule for examinations: Before beginning of the study and weekly thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Days -2 through 14 (retroorbital plexus) and Day 21 and 22 (cardiac puncture)
- Anaesthetic used for blood collection: Yes (deep diethylether anesthesia)
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked: Triiodothyronine (T3), thyroxine (total) (T4), thyroxine binding capacity (TBC) and thyroid stimulating hormone (TSH) levels and protein content (from heparinized plasma), UDP-glucuronyl transferase (UDP-GT, from liver samples at time of necropsy)
PLASMA/SERUM HORMONES/LIPIDS: Yes, see above
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- Sacrifice of surviving animals was performed by exsanguination under deep ether anesthesia,
GROSS PATHOLOGY: Yes
Organ weights were recorded for liver, uterus and the left thyroidal lobe.
HISTOPATHOLOGY: Yes
tissues collected: liver, thyroid, uterus and pinnae were fixed in aqueous 10% formalin solution, tissues investigated: thyroid - Optional endpoint(s):
- Optional endpoints: No
- Other examinations:
- None
- Statistics:
- The quantitative results for individual animals were used to calculate group means, median and standard deviations. The results for the groups that received the test substance were compared with those for the control group and significant differences indicated by '+' for p < 0.05 and '++' for p < 0.01.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The only effect observed was bright feces of one female (high dose) after 2 and 3 weeks. This finding was considered incidental.
- Mortality:
- no mortality observed
- Description (incidence):
- not applicable
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1600 ppm: decreased transient body weight (males, Week 1 and 2, -10.5 and -8.4%) and decreased body weight in females (throughout the study, -12.5 to -13.0%), reduced body weight gains in males (-14.9%) and females (-43.5%), all compared to controls.
Summarized data can be found in Attachment 1 in the attached background material. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - 1600 ppm: reduced feed consumption and daily feed intake compared to controls during Week 1 for both sexes
Not treatment related:
Decreased daily feed intake for the 100 and 400 ppm male rats compared to controls was not considered biologically relevant because of a lack of dose response.
Summarized data for the 21-day interval can be found in Attachment 2 in the attached background material. - Food efficiency:
- not examined
- Description (incidence and severity):
- not applicable
- Water consumption and compound intake (if drinking water study):
- not examined
- Description (incidence and severity):
- not applicable
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Haematological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Thyroid parameters
- 1600 ppm: significant reduction in T3 levels on Day 2 in male and female rats, significant reduction in total T4 levels on Days 2 and 7 in male rats and on Day 2 in female rats, increase in the level of TSH in males on Day 14 and in females on Days 7 and 22, all compared to controls.
As can be expected, there was variation within the observations made in the control groups at different times. Hormone levels underlie a wide intra-individual variation. For relative changes, the pre-treatment data of each treatment group was used instead of the control group as reference. Therefore, analysis of covariance has been made. Treatment-related results were
- 400 ppm: increased thyroid stimulating hormone (TSH) in males from Day 7-21 (not statistically significant but in dose-dependency with results seen at 1600 ppm) compared to controls.
- 1600 ppm: reductions in T3 and T4 on Day 2 for males (-21.2 and -32.0%, respectively) and females (-30.9 and -34.4%, respectively) compared to controls, reduction of T4 continued for males throughout the study (-11.31 to -38.88%) and for females at Day 7 and 22 (-21.8 and -41.6%, respectively) compared to controls, increased TSH throughout the study in males and females, statistically significant at Day 14 in males (532.8%) and Day 7 (127%) and Day 22 (247.7%) in females compared to controls.
Summarized data can be found in Attachment 3.
UDP levels
- 400 ppm: increased UDP-GT levels in males (+98.2%) and females (+64.1%) compared to controls.
- 1600 ppm: increased UDP-GT levels in males (+252%%) and females (+221%%) compared to controls.
Summarized data can be found in Attachment 4. Reference values for total protein and thyroid parameters are presented in Attachment 5.
Further findings not considered to be treatment-related:
Changes in plasma protein levels were statistically significant compared to controls at some instances (females at 1600 ppm, males at all dose levels). However, these were not dose-dependent and close to control values and were therefore not considered treatment-related. - Endocrine findings:
- not examined
- Description (incidence and severity):
- not applicable
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- not applicable
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- not applicable
- Immunological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - 400 ppm: increased absolute liver weight in males compared to controls (+14.2%)
-1600 ppm: increased absolute (+32.2% in males, +22.9% in females) and relative (+40.6% in males, +39.4% in females) liver weight compared to controls
Further findings not considered to be treatment-related:
The decreased thyroid weights in females (absolute at > 400 ppm, relative at 400 ppm) compared to controls were not regarded as treatment-related, as there was no dose response for the relative thyroid weight.
Summarized data can be found in Attachment 6. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1600 ppm: increased liver (10/10 males, 9/10 females), marked lobular pattern (7/10 females)
Summarized data is presented in Attachment 7. - Neuropathological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - 400 ppm: minimal to slight hypertrophy of the follicular epithelium compared to controls (males)
- 1600 ppm: minimal to slight hypertrophy of the follicular epithelium compared to controls (males/females)
Summarized data can be found in Attachment 8 (attached background material). - Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- not applicable
- Other effects:
- not examined
- Description (incidence and severity):
- not applicable
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed at this dose level.
- Remarks on result:
- other: corresponding to 9.0 mg/kg bw/day for males and 12.3 mg/kg bw/day for females
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 400 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- gross pathology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Remarks on result:
- other: corresponding to 36.9 mg/kg bw/day for males and 44.6 mg/kg bw/day for females
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 400 ppm
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
Applicant's summary and conclusion
- Conclusions:
- The present study was conducted according to the OECD guideline 407 (dated 1995), however with the focus being set on the mechanism of thyroidal changes related to the test substance; the study conduct was GLP compliant. It was shown that the test substance induces the hepatic enzyme UDP-glucuronyl transferase (UDP-GT). In general, induction of UDP-GT leads to increased T4 glucuronide formation and excretion of T4, resulting in decreased T3 and T4 levels, which was also found in this study. TSH levels increased to compensate for decreased T4 and T3 levels and led to a continuous activation of the thyroid as already seen by hypertrophy of the follicular epithelium of the thyroid. Moreover, changes in the liver and on body weight and feed consumption were observed. It was concluded that the activation of UDP-GT was seen as a primary effect of the test substance and the consequent changes in hormone level and thyroid histopathology secondary effects due to activation of the hypothalamic-pituitary-thyroidal (HPT) axis. A dietary concentration of 100 ppm (equivalent to 9.0 and 12.3 mg/kg body weight per day, for males and females, respectively) was determined as a clear no-observed-effect level.
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