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EC number: 204-876-7 | CAS number: 128-04-1
- 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:
- chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1993
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- GLP guideline study; According to the ECHA guidance document “Practical guide 6, V2: How to report read-across and categories” (Dec 2012), the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Deviations:
- yes
- Remarks:
- The highest dose level produced one fatality and had therefore to be adjusted.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Ziram
- EC Number:
- 205-288-3
- EC Name:
- Ziram
- Cas Number:
- 137-30-4
- Molecular formula:
- C6H12N2S4Zn
- IUPAC Name:
- zinc bis(dimethyldithiocarbamate)
- Reference substance name:
- zinc bis dimethyldithiocarbamate
- IUPAC Name:
- zinc bis dimethyldithiocarbamate
Constituent 1
Constituent 2
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Interfauna UK Limited, Huntingdon, UK.
- Age at study initiation: 3-5 months
- Weight at study initiation: (♂) 8.8 - 11.5 kg, (♀) 8.2 – 10.7 kg
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 52 weeks
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50*, 185, 500# ppm (* Concentration was increased to 57.5 ppm to compensate losses during storage; # reduced from 700 to 500 ppm in week 12 because of treatment-related mortality)
Basis:
nominal in diet
- No. of animals per sex per dose:
- 4 per sex
- Control animals:
- yes, plain diet
- Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- CLINICAL SIGNS
- Daily
MORTALITY
- Daily
BODY WEIGHT
- Weekly
FOOD CONSUMPTION
- Daily
ACHIEVED INTAKE
- Calculated weekly
OPHTHALMOSCOPIC EXAMINATIONS
- Pre-exposure and in weeks 13, 26 and 52
NEUROLOGICAL EXAMINATIONS
GENERAL
- Pre-exposure and in weeks 34 and 50
- Parameters: behaviour and gait
CRANIAL NERVE FUNCTION
- Pre-exposure and in weeks 34 and 50
- Parameters: head tilt, facial muscle, muscles of mastication, blink reflex (l & r), pupillary light reflex (l & r),eye position, strabismus, abnormal nystagmus, corneal reflex (l & r), palpebral reflex (l & r), ear movement, position of philtrum, commissure of lips, jaw closure, open jaw resistance, tongue, gag reflex
SPINAL REFLEXES
- Pre-exposure and in weeks 34 and 50
- Parameters: muscle tone, patellar reflex (l & r), triceps reflex (l & r), flexor reflex (all 4 limbs individually), crossed extensor reflex, perineal reflex
POSTURAL AND ATTITUDINAL REACTIONS
- Pre-exposure and in weeks 34 and 50
- Parameters: wheelbarrowing, thoracic hopping, pelvic hopping, extensor postural thrust, tactile placing, visual placing, tonic neck reaction, righting reaction
HAEMATOLOGY (jugular or cephalic vein)
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), platelet count, reticulocyte count, total leukocyte count, differential leukocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), cell morphology
erythrocyte sedimentation rate (ESR) was performed only in two cases as part of diagnostic screen
CLINICAL CHEMISTRY
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: total protein, albumin, sodium, potassium, glucose, urea (BUN), alanine aminotransferase (ALT, GPT), aspartate aminotransferase (GOT), alkaline phosphatase (AP), creatinine, calcium, phosphorus, chloride, total cholesterol, total bilirubin, gamma-glutamyltransferase (GT), creatine phosphokinase (CPK), ornithine carbamoyltransferase (OCT), -hydroxybutyrate dehydrogenase (-HBDH), tri-iodothyronine (T3), thyroxine (T4)
URINALYSIS
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: protein, glucose, pH, specific gravity, volume, ketones, haem pigments, bile pigments, urobilinogen, total reducing substances (TRS), epithelial cells (E), polymorphonuclear leukocytes (P), mononuclear leukocytes (M), erythrocytes (R), organisms (O), renal tubule casts (C), other abnormal constituents (A)
ORGAN WEIGHTS
- Yes
- Organs: adrenals, brain, heart, lung, kidneys, liver, ovaries/testes (with epididymides), spleen, pituitary, thymus, thyroids/parathyroids, uterus/prostate, pancreas - Sacrifice and pathology:
- GROSS AND HISTOPATHOLOGY
- Gross pathology: all dose groups
- Adrenals, aorta, bones (sternum and femur), bone marrow (sternum), brain, caecum, colon, duodenum, eyes, gall bladder, heart, jejunum, ileum, kidneys, liver, lungs, lymph nodes, mammary gland, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerves, skeletal muscle, skin, spleen, stomach, testes (with epididymides), thymus, thyroids/parathyroids, tongue, trachea, urinary bladder, uterus, vagina
Additionally: one bone marrow smear per dog. - Statistics:
- All analyses were carried out both together and separately for male and female. In view of the small number of animals and to confirm possible effects, analyses were also performed on combined data.
Data relating to food consumption were analysed as totals over selected time periods, expressed on a weekly basis. Bodyweight data were analysed using weight gains.
The following tests were used for food consumption, bodyweight, organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- For pre-dose data, analyses of variance were followed by Student’s ‘t’ test. For data from the dosing period, analyses of variance were followed by Williams’ test for a dose-related response. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate, analysis of covariance was used in place of analysis of variance. Statistical analysis in histopathological examination was performed using Fisher’s exact and Mantel’s tests.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- 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:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Occasional liquid faeces was noted in all dose-groups including controls during the entire study and was considered to be not related to treatment.
- One treatment-related death occurred at the initial high dosage level of 700 ppm during week 11. After a convulsion, the female showed a collapsed state with excessive salivation, trembling, champing of the jaws and jerking of the limps. Pathological findings demonstrated changes consistent with the collapsed state. As a result the high dosage level was reduced to 500 ppm.
One further mortality was treatment-unrelated (suspected polyarteritis) and a replacement dog was obtained.
BODY WEIGHT AND WEIGHT GAIN
- After 26 weeks all females at 185 und 500 ppm showed some weight loss, such that overall gain after 52 weeks was significantly reduced.
COMPOUND INTAKE
- Calculated on a weekly basis by (ppm x food consumption)/(mid-week bodyweight x 7).
The means over the treatment period are:
1.6, 6.6, 17.4 mg/kg bw/day for males
1.9, 6.7, 20.6 mg/kg bw/day for females
CLINICAL CHEMISTRY
- ALT values had intergroup differences amongst males (not statistically significant): 1 dog (185 ppm) and 2 dogs (500 ppm) showed elevated ALT in week 26 and 52. Since these animals showed the most marked changes in the liver microscopic examination, it was considered that these changes were treatment-related.
- AP values showed an apparent dosage-related increase amongst males receiving 185 or 500 ppm in week 26 and 52, although differences were not statistically significant but considered as a result of treatment and are probably associated with the pathological findings seen in the liver of these dogs at termination.
- The decrease in albumin was not supported by any significant corroborative pathological finding at termination and was considered of equivocal toxicological importance.
ORGAN WEIGHTS
- Liver weights for males receiving 500 ppm were increased but didn’t show any histopathological changes.
- Group mean heart weights were decreased for animals at 500 ppm.
- Group mean prostate weights showed a dosage-related decrease compared with the control data, although the differences did not attain statistical significance. There were no macro- or microscopic findings for these tissues.
GROSS PATHOLOGY
- Multiple red discoloured linear depressions of gastric mucosa for 1 female at 185 ppm and a single oval, flat friable choleliths in the gall bladders of 2 males at 185 ppm. No similar findings were seen in any dog at the 500 ppm treatment level.
HISTOPATHOLOGY: NON-NEOPLASTIC
- Liver and spleen are the target organs. Foci of degenerate hepatocytes were seen to a moderate degree at 500 ppm and at 185 ppm with a single cell necrosis in one male at 500 ppm. Inflammatory cell infiltration around central veins and sometimes around the branches of the hepatic vein was seen in some dogs. An apparent increase in centrilobular fibrocytes was seen in 3/4 male dogs treated with 500 ppm and in 1/4 male dog treated with 185 ppm. There was an increased incidence and degree of aggregates of pigmented Kupffer cells and macrophages in the livers of male and female dogs and an increased incidence of pigmented macrophages in the spleen of male dogs treated with 500 ppm or 185 ppm when compared to control male dogs.
- The initial appeared to be increased pigmentation of Kupffer cells and /or macrophages with Perls’ positive material, possibly reflecting increased iron metabolism and turnover. These changes were evident at all dosages in the liver, and for males at 185 or 500 ppm in the spleen. At 185 and 500 ppm, more marked associated changes were seen in the liver, chiefly hepatocyte degeneration and inflammatory cell infiltration. The only change identified at the low dose that could be possibly related to treatment, was aggregates of pigmented Kupffer cells and macrophages in one male and one female.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 185 ppm
- Sex:
- male/female
- Basis for effect level:
- other: = 6.6 mg ziram/kg bw/day = 6.2 mg SDDC (a.s.)/kg bw/day = 14.9 mg SDDC (41.44% solution as supplied)/kg bw/day, based on decrease in body weight gain, albumin and histopathology in spleen and liver.
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 50 ppm
- Sex:
- male/female
- Basis for effect level:
- other: = 1.6 mg ziram/kg bw/day = 1.5 mg SDDC (a.s.)/kg bw/day = 3.6 mg SDDC (41.44%)/kg bw/day
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table A6_5-1. Results of chronic toxicity study |
||||||||||
Parameter |
Control |
50 ppm |
185 ppm |
500 ppm |
Dose-response +/– |
|||||
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
|
Mortality |
1 |
– |
– |
|||||||
Body weight gain |
↓ 68% |
↓ 81% |
– |
+ |
||||||
Clinical chemistry |
||||||||||
Albumin |
↓ 12% |
↓ 16% |
↓ 13% |
↓ 16% |
– |
– |
||||
Cholesterol |
↑ 51% |
– |
– |
|||||||
T3 |
↑ 33% |
– |
– |
|||||||
Organ weight |
2/4 |
|||||||||
Liver |
↑ 16% |
+ |
– |
|||||||
Histopathology of liver |
||||||||||
Foci degenerated hepatocytes |
1/4 |
3/4 |
2/4 |
0/4 |
2/4 |
3/4 |
3/4 |
2/3 |
+ |
– |
Aggregates of pigmented Kuppfer cells |
0/4 |
0/4 |
1/4 |
1/4 |
2/4 |
3/4 |
3/4 |
2/3 |
+ |
– |
Histopathology of spleen |
||||||||||
Increased pigmented macrophages |
1/4 |
2/4 |
1/4 |
2/4 |
3/4 |
2/4 |
3/4 |
3/3 |
– |
– |
↓ ↑: statistical significance |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.