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EC number: 428-040-8 | CAS number: 138261-41-3
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 08 Oct 1987 - 08 Feb 1988
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 2018
- Deviations:
- yes
- Remarks:
- methodological deficiencies (please refer to "Principles of methods if other than guideline")
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 1981
- Deviations:
- no
- Principles of method if other than guideline:
- Rats were housed individually instead of in groups per sex, phytoestrogens were not determined in the diet, no lipid analysis was done in blood, no weight was determined for epididymides, prostate, uterus, ovaries, thymus, pituitary gland, thyroid and heart, brain histopathology was not specified, mammary glands were not examined in histopathology, T4, T3 and TSH were not assessed, sensory reactivity was not investigated
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 428-040-8
- EC Name:
- -
- Cas Number:
- 138261-41-3
- Molecular formula:
- C9H10ClN5O2
- IUPAC Name:
- 2-chloro-5-{[2-(nitroimino)imidazolidin-1-yl]methyl}pyridine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- common species, used often for toxicological studies, historical data are available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 64 - 102 g (males), 63 - 91 g (females)
- Fasting period before study: not applicable
- Housing: individually caged in Makrolon7 type II cages on low-dust wood granulate (supplied by
Ssniff Spezialdiaten GmbH, Soest, Germany) during trial period
- Diet: acclimatisation period: AltrominR 1324 pellets, study period: AltrominR 1321 meal, supplied by Altromin GmbH, Lage, Germany, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 10 days
DETAILS OF FOOD AND WATER QUALITY: food was regularly checked for contaminants and spot-checked, tap water was of drinking quality (Drinking Water Statute of 22.5.86, Federal Office Gazette No. 16, issued on 28.5.86, page 760, with effect from 1.10.86)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): approx. 50
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 28 Sep 1987 To: 08 Feb 1988
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet: weekly
- Mixing appropriate amounts with: AltrominR 1321 meal (supplied by Altromin GmbH, Lage, Germany), supplemented with 1% groundnut oil to prevent dust formation
- Storage temperature of food: room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Both concentration of the acitve substance in the feed as well as homogenity were tested before, during and at the end of the study. The first analysis determined the concentrations to be 164, 618 and 2380 ppm (Oct 1987), the last 153, 606 and 2540 ppm (Jan 1988), the mean was 129, 599 and 2410 ppm. During analytical checks on the target contents, a content of only 60 % was detected midway through the study in the 150 ppm group. No error could be found in the records from when the feed mix was weighed out. Analysis of 2 reserve samples prior to this point and 2 thereafter yielded correct target contents. A potential source of error for this low finding could not therefore be identified. Evaluation of the results for this dose group is thus not questionable.
Homogenity was also verified. - Duration of treatment / exposure:
- 13 weeks (up to 96 days, minimum 91 days)
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 150 ppm
- Remarks:
- corresponding to 14.0 and 20.3 mg/kg bw/day for males and females, respectively
- Dose / conc.:
- 600 ppm
- Remarks:
- corresponding to 60.9 and 83.3 mg/kg bw/day for males and females, respectively
- Dose / conc.:
- 2 400 ppm
- Remarks:
- corresponding to 300.2 and 422.2 mg/kg bw/day for males and females, respectively
- No. of animals per sex per dose:
- 10 (plus 10 in recovery group)
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: A pilot feeding study was performed administering 0, 120, 600 or 3000 ppm to Wistar rats for 14 weeks. At 3000 ppm, weight reduction was marked, evidence of liver damage and enlarged testicular tubules occurred. At 600 ppm, body weight was slightly reduced. The NOAEL was set to 120 ppm. Therefore, concentrations of 150, 600 and 1000 ppm were selected for this study
- Fasting period before blood sampling for clinical biochemistry: no
- Satellite groups: a recovery group of 10 animals/sex was included in the study for the control and high dose group
- Post-exposure recovery period in satellite groups: 4 weeks - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at leat twice daily (once at weekends and bank holidays)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily, detailed examinations were carried out weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
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: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule: at start of the study and prior to necropsy (before collection of blood sample)
- Parameters checked: pupillary reflex of both eyes, area around the eye and the anterior regions of the eye were assessed, the pupils were dilated with Mydriaticum-Roche eye-drops and the refractive sections of the eye and the fundus were examined (using an indirect ophthalmoscope)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 5 and 14 weeks (all animals) and in Week 17 for the satellite groups
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: all animals
- Parameters checked: differential blood count, erythrocyte count and morphology, haemoglobin concentration, haematocrit, leucocyte count, MCH (mean corpuscular haematology), MCHC (mean corpuscular haemoglobin concentration), MCV (mean corpuscular cell volume), platelet count, thromboplastin time, reticulocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 5 and 14 weeks (all animals) and in Week 17 for the satellite groups
- Animals fasted: No
- Anaesthetic used for blood collection: No (for glucose determination), yes for all other parameters (ether)
- How many animals: all animals
- Parameters checked: alkaline phosphatase, aspartate-aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), creatine kinase, glucose, albumin, bilirubin, cholesterol, creatinine, total protein, urea, triglycerides, phosphate, calcium, potassium, sodium, chloride, cholinesterase activity (in plasma, erythrocytes and brain (for brain, only 5 of 10 animals per groups were tested)
PLASMA/SERUM HORMONES/LIPIDS: Yes (see above)
URINALYSIS: Yes
- Time schedule for collection of urine: after 14 weeks (all animals) and in Week 17 for the satellite groups
- Metabolism cages used for collection of urine: not specified
- Animals fasted: Yes, during collection (over a period of 16 h)
- Parameters checked: blood, bilirubin, glucose, ketone bodies, pH, protein, urobilinogen, sediment, specific gravity (density), volume, creatinine, protein
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Organ weight was reported for brain, testes (both), liver, spleen, kidneys (both) and adrenal glands (both)
HISTOPATHOLOGY: Yes
Organs/tissues that were fixed in Bouin's solution: aorta, eyes (one or both), eyelids, caecum, colon, duodenum, femur, brain, bladder, Harder's glands, ureter, urethra, skin, heart, testes, pituitary, ileum, jejunum, larynx, bone marrow (in femur and sternum), head, liver, lymph nodes (mesenteric and mandibular), stomach, mammary glands, spleen, muscles (thigh), epididymis, adrenal glands, sciatic nerve, optic nerve, kidneys, oesophagus, tattooed auricles, ovaries, oviduct, pancreas, prostate, rectum, residual intestine, spinal cord (cervical, thoratic and lumbar), seminal vesicle, thyroid, salivary glands, sternum, thymus (if present), trachea, extraorbital lacrimal glands, uterus, vagina, tongue
Organs that were fixed in 10% buffered formaldehyde solution: one lobe of the liver and a lung - Other examinations:
- None
- Statistics:
- Arithmetic group means, standard deviation and, sometimes, upper and lower confidence limits (1 - a = 95% and 1 - a = 99%) were calculated for medical laboratory tests, measurement, body weight, feed and water intake and organ weights. Groups were compared using the significance test (U test, two-sided) according to Mann, H.B. and Whitney, D.R. and after Wilcoxon, F. (significance was set to p<0.05).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- not applicable
- Mortality:
- no mortality observed
- Description (incidence):
- not applicable
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - 600 ppm: slight reduction in body weight in males (8%)
- 2400 ppm: statistically significant lower body weight (14-16%, males and females) until the end of the study period, not reversible during the recovery period
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):
- - 2400 ppm: 33% (males) to 42 % (females) increased food consumption relative to body weight, not reversible during the recovery period (males and females still consumed more feed than the control animals in the last week of the follow-up period)
Summarized data 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):
- no effects observed
- Description (incidence and severity):
- not applicable
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- not applicable
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - 2400 ppm: slightly longer thromboplastin times and depressed thrombocyte counts, both findings were only partially reversible within the recovery period; plasma, erythrocyte and brain cholinesterase activities were not affected to a toxicologically significant extent in males and females, lower platelet count at Week 5 and 14, reaching statistical significance only in females in Week 5. This finding was reversible in the recovery group.
The effect on platelet counts and thromboplastin times suggest a weak impairment of blood clotting. Prolonged thromboplastin times were recorded even after the recovery period.
Occasional statistically significant differences were found for reticulocyte count, erythrocyte parameters (red cell count, mean cell volume, cellular haemoglobin content, mean cell haemoglobin concentration), haematocrit and haemoglobin concentration but these changes were small and not of toxicological relvance since all individual data were within the normal degree of scatter and not dose-dependent.. Moreover, leucocyte count was decreased in treated females but no dose-relationship was observed, all individual values were within the relatively broad reference range for this parameter and this finding was not reported for the previous range-finding study, so the finding was considered incidental.
Summarized data can be found in Attachment 3 and 5 in the attached background material. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - 150 ppm: reduced protein concentration in males (-3.6% in Week 14)
- 600 ppm: reduced protein concentration in males (-6.1% in Weeks 5, -4.8% in Week 14)
- 2400 ppm: slight but statistically significant increase in alkaline phosphatase activity in males in Week 5 (+14.6%) and significantly raised levels of ALAT activity in Week 14 only (+24.5%), lower triglycerides in males after 14 (-51.9%) and 17 (-14.7%) weeks, and in females after 17 weeks (-17.6%), reduced protein level in males (-5.1% in week 5, -7.6% in Week 14) and females (-7.7% in Week 5, -5.4% in Week 14), reduced albumin levels in males (-2.9%) and females (-6.0%) in Week 14.
The slightly depressed protein, albumin and cholesterol levels are indicatve for functional liver impairment
Other statistically significant differences were not considered of toxicological concern because they were slight and/or transient. These included raised creatinine concentration in females (600 and 2400 ppm) only in Week 5, and in males in Week 14 (2400 ppm), increased and decreased creatine phosphokinase activity for males (2400 ppm, Week 5) and females (2400 ppm recovery group), respecitvely. Also, differences in electrolyte concentrations in serum or plasma were not severe enough to be considered toxicologically relevant. Cholinesterase activity in erythrocytes was increased for males and females in Week 5 and for males in Week 14 and 17 but this was considered statistically but not biologically significant.
Summarized data can be found in Attachment 4 and 5 in the attached background material. - Urinalysis findings:
- no effects observed
- 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, non-treatment-related
- Description (incidence and severity):
- - 2400 ppm: reduced absolute liver weight for males (-11.6%) and females (-8.5%), reduced absolute kidney weights for males (-13.7%) and females (-9.1%), reduced absolute weights of adrenal glands of females (-15.5%), increased relative weights of brain for males (+13.0%) and females (+11.6%), spleen for females (+39.3%), and testes for males (+14.1%)
These findings were considered to be secondary effects to reduced body weight and therefore not directly treatment-related. However, since clincial chemistry investigations (see above) and histopathological findings (see below) show hepatic alterations in males caused by treatment, the lower liver weight is indicative for a treatment-related effect. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- not applicable
- Neuropathological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - 600 ppm: slight changes in the plasma of hepatocytes (3/10 males), interpreted as margina functional increase
- 2400 ppm: round cell infiltrates in liver (all males in 14 weeks group), isolated cell necrosis in liver (8/10 males in 14 weeks group), focal necrosis (4/10 males in 14 weeks group), higher incidence of cytoplasmic changes and swollen liver cell nuclei in males in 14 weeks group; no morphological effects were visible in males at the end of the recovery period thus suggesting reversible liver effects - Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- not applicable
- Other effects:
- not examined
- Description (incidence and severity):
- not applicable
- Details on results:
- Historical reference values can be found in Attachment 6.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects observed at this concentration
- Remarks on result:
- other: corresponds to 14.0 mg/kg bw/day
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 600 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- other: effects indicative for liver hepatotxicity were reversible within the recovery group
- Remarks on result:
- other: corresponds to 60.9 mg/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 600 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects observed at this concentration
- Remarks on result:
- other: corresponds to 83.3 mg/kg bw/day
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 2 400 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- Remarks on result:
- other: corresponds to 422.2 mg/kg bw/day
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 600 ppm
- System:
- hepatobiliary
- Organ:
- liver
Applicant's summary and conclusion
- Conclusions:
- The study was performed under GLP conditions and according to OECD TG 408 (adopted 1981). Deviations to the current version (adopted 2018) are minor. Thus, the study is considered reliable and valid. Due to decreased body weight gain, NOAELs of 150 and 600 ppm were derived for males and females, respectively (corresponding to 14.0 and 83.3 mg/kg bw/day in males and females, respectively). Reversible hepatotoxic effects were evident at 2400 ppm (corresponding to 300.2 mg/kg bw/day).
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