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EC number: 205-517-7 | CAS number: 141-98-0
- 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
Carcinogenicity
Administrative data
Description of key information
There are conclusive but not suffcient data for the classification of substance IPETC/O-isopropyl ethylthiocarbamate with regard to carcinogenicity. Carcinogenicity: IARC, NTP, ACGIH and OSHA do not classify this substance or its components as a carcinogen or suspect carcinogen.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- other: published data
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Dithiocarbamates are related compounds to Thionocarbamate . Zinc bis dimethyldithiocarbamate is closely related to the registered substance and it is considered that read-across is valid.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- The lowest dose level produced toxicity and was therefore too high. Clinical signs were examined daily only up to week 4.
- GLP compliance:
- yes
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: 24-34 g (males), 18-27 g (females) - Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on exposure:
- Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75, 225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and 75 ppm were greater than the nominal concentration in order to compensate for losses during storage.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 80 weeks
- Frequency of treatment:
- Daily
- Post exposure period:
- None
- Remarks:
- Doses / Concentrations:
0, 25, 75, 225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males )
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
0, 4, 11, 33, or 95 mg/kg bw per day for females
Basis:
nominal in diet - No. of animals per sex per dose:
- 50 per sex
- Control animals:
- yes, plain diet
- Positive control:
- no
- Observations and examinations performed and frequency:
- CLINICAL SIGNS
- Daily up to week 4, afterwards weekly
MORTALITY
- Twice daily
BODY WEIGHT
- Prior to start, then once weekly
FOOD CONSUMPTION
- Once weekly
WATER CONSUMPTION
- Daily by visual appraisal
BLOOD SMEARS
- No. of animals: 10 animals/sex/group
- Time points: At week 52 and prior to termination.
- Parameters: Differential leukocyte count, cell morphology
ORGAN WEIGHTS
- All animals
- Organs: Brain, kidneys, liver, testes (with epididymides - Sacrifice and pathology:
- GROSS PATHOLOGY
- All surviving animals at scheduled sacrifice.
HISTOPATHOLOGY
- All animals
- Organs: 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, other macroscopic abnormalities, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal column, spleen, stomach, testes (with epididymides), thymus, thyroids/parathyroids, trachea, urinary bladder, uterus - Statistics:
- All analyses were carried out separately for male and female.
Data relating to food consumption were analysed on a cage basis. For all other parameters, analyses were carried out using the individual animal as the basic experimental unit.
Food consumption data were analysed using cumulative totals and bodyweight data were analysed using weight gains.
The following tests were used for food consumption, bodyweight, blood smear and organ weight 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 Fisher and Mantel. 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.
- Analyses of variance were followed by Student’s ‘t’ test and 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. Mortality was analysed using log rank methods, Mantel. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- BODY WEIGHT
- After week 1 a dosage-related reduction among animals receiving 225 or 675 ppm was apparent. After 80 weeks, with exception of the gain of females receiving 225 ppm, these reductions were statistically significant.
FOOD CONSUMPTION
- A dosage-related, statistically significant reduction in food intake was apparent for animals receiving 225 or 675 ppm.
COMPOUND INTAKE
- Calculated on a weekly basis by (ppm x food consumption)/(mid-week bodyweight x 7).
The means over the main treatment period are:
3, 9, 27, 82 mg/kg bw/day for males
4, 11, 33, 95 mg/kg bw/day for females
ORGAN WEIGHTS
- The increased body weight-related kidney and testes + epididymides weights were considered to be an effect of the lower body weight and of no toxIcological significance.
HISTOPATHOLOGY
- Liver: An increased incidence of centrilobular enlargement of hepatocytes, sometimes with vacuolisation, and/or generalised enlargement of hepatocytes was seen in all treated animals. A dose-relationship did not occur.
- Urinary bladder: The incidence of epithelial hyperplasia was increased in animals receiving 675 ppm and males receiving 225 ppm.
All other changes reported were within the normal background range for mice of this strain. - Relevance of carcinogenic effects / potential:
- Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75,225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and75 ppm were greater than the nominal concentration in order to compensate for losses during storage. Statistically significant reductions in body-weight gain and food intake were seen in males and females receiving 225 or 675 ppm. Dose-related, statistically significant decreases in the absolute brain weight of males receiving 225 or 675 ppm and the brain weight adjusted for final body weight of females receiving 75, 225, or 675 ppm were noted. Macroscopic examination of all animals that died or were killed at termination revealed increased incidences of reduced adipose tissue in males that died, irregular cortical scarring of the kidneys in males at terminal sacrifice, brown kidneys in males, and roughened and white forestomachs in females, all receiving the highest dose. An increased incidence of centrilobular and/or generalized hepatocellular enlargement was seen in all treated groups, and an increased incidence of urinary bladder epithelial hyperplasia was seen in males and females receiving 675 ppm and in males at 225 ppm. No treatment- related neoplastic effects were seen.
- Dose descriptor:
- NOAEL
- Effect level:
- 675 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of neoplastic lesions
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- 82 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of neoplastic lesions
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- < 25 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: = 4.0 mg ziram/kg bw/day, based on an increased incidence of centrilobular and/or generalised hepatocellular enlargement.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified. Effect type:toxicity (migrated information)
- Conclusions:
- Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance and it is considered that read-across is valid. No treatment- related neoplastic effects were seen.
- Executive summary:
Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75,225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and75 ppm were greater than the nominal concentration in order to compensate for losses during storage. Statistically significant reductions in body-weight gain and food intake were seen in males and females receiving 225 or 675 ppm. Dose-related, statistically significant decreases in the absolute brain weight of males receiving 225 or 675 ppm and the brain weight adjusted for final body weight of females receiving 75, 225, or 675 ppm were noted. Macroscopic examination of all animals that died or were killed at termination revealed increased incidences of reduced adipose tissue in males that died, irregular cortical scarring of the kidneys in males at terminal sacrifice, brown kidneys in males, and roughened and white forestomachs in females, all receiving the highest dose. An increased incidence of centrilobular and/or generalized hepatocellular enlargement was seen in all treated groups, and an increased incidence of urinary bladder epithelial hyperplasia was seen in males and females receiving 675 ppm and in males at 225 ppm. No treatment- related neoplastic effects were se
Reference
Table 7.7 -B1 Histopathology of the relevant tissues |
|
|||||||||||
Parameter / Dose |
Control |
25 ppm |
75 ppm |
225 ppm |
675 ppm |
Dose-response +/– |
||||||
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
|
Liver / number examined |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
||
Centrilobular hepatocye enlargement |
2 |
0 |
21 |
12 |
21 |
19 |
25 |
16 |
19 |
13 |
– |
– |
Centrilobular hepatocye enlargement and vacuolation |
0 |
0 |
7 |
0 |
9 |
2 |
5 |
1 |
5 |
1 |
– |
– |
Generalised enlargement |
1 |
1 |
9 |
10 |
12 |
10 |
15 |
7 |
6 |
7 |
– |
– |
Urinary bladder / number examined |
50 |
48 |
50 |
50 |
46 |
48 |
50 |
49 |
50 |
49 |
||
Epithelial hyperplasia |
7 |
0 |
7 |
5 |
9 |
1 |
20 |
5 |
31 |
14 |
+ |
– |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 82 mg/kg bw/day
- Study duration:
- chronic
- Species:
- mouse
Carcinogenicity: via inhalation route
Link to relevant study records
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/O-isopropyl ethylthiocarbamate . Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/f O-isopropyl ethylthiocarbamate .
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- Not monitoring food consumption
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Sprague Dawley Inc. Indianapolis, IN
- Age at study initiation: 28-30 days old
- Weight at study initiation: 121.2-165 g (males) and 93.6 - 124.3 g (females) on the first day of exposure
- Fasting period before study: None
- Housing: 2 per cage in stainless steel, wire mesh cages
- Diet (e.g. ad libitum): Pelleted, certified AGWAY PROLAB animal diet rat 3000 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 3 weeks
ENVIRONMENTAL CONDITIONS
- Temperature : 17 - 26 °C
- Humidity (%): 40-70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12-12 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation chamber (Wahmann Manufacting company, Timonium, MD)
- System of generating particulates/aerosols: liquid isopropanol was metered from a container by piston pump
- Temperature in air chamber: 22 ± 4 degrees
- Air flow rate: 1000 l/min for first month and 900 l/min thereafter
- Air change rate: 14 air changes/hr for first month and 12.5 air changes/hr thereafter
- Method of particle size determination: not reported
- Treatment of exhaust air: not reported
TEST ATMOSPHERE
- Brief description of analytical method used: liquid isopropanol was metered from a container by piston pump into a heated glass evaporator and the temperature of the evaporators was maintained at the lowest level to sufficiently vaporize the test substance.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Each exposure chamber was analyzed for isopropanol twice each hour by flame ionization gas chromatography.
- Duration of treatment / exposure:
- At least 104 weeks
- Frequency of treatment:
- 6 hours/day, 5 days/week
- Remarks:
- Doses / Concentrations:
0, 500, 2500, or 5000 ppm
Basis:
nominal conc. - No. of animals per sex per dose:
- 65 sex/dose for the core group and 10 sex/dose for the interm sacrifice
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Rationale for animal assignment (if not random): animals were assigned to 3 exposure groups and a control group using a stratified randomization procedure based on body weight
- Rationale for selecting satellite groups: 10 sex/group were sacrified in the middle of the study - Positive control:
- None
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks and then every other week after
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
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 data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to experiment, and during weeks 71, 80, 104, and 107
- Dose groups that were examined: all rats
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 13 months, 19 months, and 25 months
- Anaesthetic used for blood collection: Yes (identity) methoxyflurane
- Animals fasted: No
- How many animals: 10 sex/dose level
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 57
- Animals fasted: No
- How many animals: 10 sex/dose group
URINALYSIS: Yes
- Time schedule for collection of urine: week 57, 59, 74, and 104
- Metabolism cages used for collection of urine: No
- Animals fasted: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- None
- Statistics:
- The data for the 3 treatment groups and the control group were compared with Levene's test for equality of variances, analysis of variance (ANOVA), and t-tests. The nonparmetric data were statistically evaluated with the Kruskal-Wallis test followed by the Mann-Whitney U-test. Mortality was analysed by life-table analyses. Incidence data were compared using Fishers exact test.
- 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):
- not examined
- 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:
- effects observed, treatment-related
- 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:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Mortality rates for males in the 0, 500, 2500, and 5000 ppm groups were 82, 83, 91, and 100%, respectively. For females, 54, 48, 55, and 69%. No significant differences were noted for male rats from 500 or 2500 groups or any female rats.
-In males and females exposed to 5000 ppm; hypoactivity, lack of a startle reflex, and narcosis were identified. In males and females exposed to 2500 ppm; hypoactivity, and a lack of a startle reflex were observed. No effects in 500 ppm group. During non-exposure periods in males 5000 ppm group emaciation and dehydration was observed. In males and females in 5000 ppm there was greater numbers of rats with urine stains and swollen periocular tissue (females only). Females in the 2500 ppm group also had increased incidence of urine stains.
BODY WEIGHT AND WEIGHT GAIN
-Decreased body weights were observed for male rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 6 body weights were increased significantly over the control group. Increased body weights were also noted for male rats from the 2500 ppm group.
-Decreased body weights were observed for female rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 5 body weights were increased significantly over the control group. Increased body weights were also noted for female rats from the 500 ppm group. At week 72, all female body weights were significantly increased when compared to the control group.
URINALYSIS
-In males in the 5000 ppm group, in weeks 57, 59, 74, and 104 decrease in osmolality and increase in total protein and total volume were reported.
-In females rats in the 5000 ppm group, a decrease in osmolality and an increase in total volume was reported. At week 74, total glucose excreted in the urine was increased for females in the 5000 ppm group.
ORGAN WEIGHTS
- At the interim sacrifice, absolute and relative kidney weights were increased for male rats in the 5000 ppm group. Relative liver weights were increased for male rats in the 2500 ppm group. Concentration-related increases in absolute and relative testes weight was reported for male rats in 5000 ppm group. In females, increases in absolute and relative lung weight for rats in the 5000 ppm was reported.
-At the terminal sacrifice, increase in relative liver weight was noted for male rats in 2500 ppm group. In females, an increase in absolute and relative liver and kidney weights were noted for the 5000 ppm group.
GROSS PATHOLOGY
- At the interim sacrifice, an increase in granular kidneys in male rats from the 2500 and 5000 ppm groups were noted
- At the terminal sacrifice, an increase in granular kidneys in male rats from the 2500 ppm group was noted. Increased frequencies of gross lesions for male rats that died included increase incidence of thickened stomachs, granular kidneys, and color change of the kidneys for animals in 2500 and 5000 ppm groups.
- For females that died before the end of the study, an increased incidence of thickened stomachs was noted for animals from the 5000 ppm group and granular kidneys were noted for animals from the 2500 and 5000 ppm groups.
HISTOPATHOLOGY: NON-NEOPLASTIC
- At the interim sacrifice, male rats from the 5000 ppm group had an increased frequency of testicular seminiferous tubule atrophy.
-Increased frequencies of kidney lesions were observed in male rats in the 2500 and 5000 dose groups that died during the study. Increased in the frequency of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs, kidney, cornea, and testes was noted for male rats in the 2500 and 5000 ppm dose groups that died during the study. Additionally, basophilic cell foci in the liver, splenic hemosiderosis, rhinitis, and squamous metaplasisa of the respiratory epithelium in the nasal cavity were reported for male rats in the 5000 ppm group that died during the study.
-Increased severity of glomerulosclerosis was observered in female rats in the 5000 ppm group. Renal disease was also increased in female rats in the 5000 ppm group.
- For female rats that died during the study, increased frequencies of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs and kidney. Increase in myocardial degeneration, atrial thrombosis, splenic hemosiderosis, ocular keratitis, inflammatory and metaplastic changes in the nasal cavity, squamous metaplasia of the respiratory epithelium and glandular ectasia in the gastric mucosa was also evident in females in the 5000 ppm group that died during the study.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-Dose-related increase in interstitial cell adenomas of the testis in male rats at interim sacrifice, at the terminal sacrifice, and in male rats that died during the study. - Relevance of carcinogenic effects / potential:
- Concentrations of 5000 ppm is equal to 12.47 mg/m³ (molecular mass of 60.10 g/mol for Propan-2-ol)
- Dose descriptor:
- NOEL
- Effect level:
- 5 000 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The NOEL for oncogenicity effects for both mice and rats was determined to be greater than 5000 ppm
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOEL
- Effect level:
- 12.47 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Concentrations of 5000 ppm is equal to 12.47 mg/m³ (molecular mass of 60.10 g/mol for Propan-2-ol)
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Conclusions:
- The NOEL for oncogenicity effects for both mice and rats was determined to be greater than 5000 ppm.
Propan-2-ol (Isopropyl alcohol) as a main constituent of IPETC/ O-isopropyl ethylthiocarbamate need to be considered in the assessment of IPETC/O-isopropyl ethylthiocarbamate l .
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 12.47 mg/m³
- Study duration:
- chronic
- Species:
- mouse
Carcinogenicity: via dermal route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- other: published data
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Dithiocarbamates are related compounds to Thionocarbamate . Zinc bis dimethyldithiocarbamate is closely related to the registered substance and it is considered that read-across is valid.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- The lowest dose level produced toxicity and was therefore too high. Clinical signs were examined daily only up to week 4.
- GLP compliance:
- yes
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: 24-34 g (males), 18-27 g (females) - Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on exposure:
- Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75, 225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and 75 ppm were greater than the nominal concentration in order to compensate for losses during storage.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 80 weeks
- Frequency of treatment:
- Daily
- Post exposure period:
- None
- Remarks:
- Doses / Concentrations:
0, 25, 75, 225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males )
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
0, 4, 11, 33, or 95 mg/kg bw per day for females
Basis:
nominal in diet - No. of animals per sex per dose:
- 50 per sex
- Control animals:
- yes, plain diet
- Positive control:
- no
- Observations and examinations performed and frequency:
- CLINICAL SIGNS
- Daily up to week 4, afterwards weekly
MORTALITY
- Twice daily
BODY WEIGHT
- Prior to start, then once weekly
FOOD CONSUMPTION
- Once weekly
WATER CONSUMPTION
- Daily by visual appraisal
BLOOD SMEARS
- No. of animals: 10 animals/sex/group
- Time points: At week 52 and prior to termination.
- Parameters: Differential leukocyte count, cell morphology
ORGAN WEIGHTS
- All animals
- Organs: Brain, kidneys, liver, testes (with epididymides - Sacrifice and pathology:
- GROSS PATHOLOGY
- All surviving animals at scheduled sacrifice.
HISTOPATHOLOGY
- All animals
- Organs: 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, other macroscopic abnormalities, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal column, spleen, stomach, testes (with epididymides), thymus, thyroids/parathyroids, trachea, urinary bladder, uterus - Statistics:
- All analyses were carried out separately for male and female.
Data relating to food consumption were analysed on a cage basis. For all other parameters, analyses were carried out using the individual animal as the basic experimental unit.
Food consumption data were analysed using cumulative totals and bodyweight data were analysed using weight gains.
The following tests were used for food consumption, bodyweight, blood smear and organ weight 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 Fisher and Mantel. 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.
- Analyses of variance were followed by Student’s ‘t’ test and 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. Mortality was analysed using log rank methods, Mantel. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- BODY WEIGHT
- After week 1 a dosage-related reduction among animals receiving 225 or 675 ppm was apparent. After 80 weeks, with exception of the gain of females receiving 225 ppm, these reductions were statistically significant.
FOOD CONSUMPTION
- A dosage-related, statistically significant reduction in food intake was apparent for animals receiving 225 or 675 ppm.
COMPOUND INTAKE
- Calculated on a weekly basis by (ppm x food consumption)/(mid-week bodyweight x 7).
The means over the main treatment period are:
3, 9, 27, 82 mg/kg bw/day for males
4, 11, 33, 95 mg/kg bw/day for females
ORGAN WEIGHTS
- The increased body weight-related kidney and testes + epididymides weights were considered to be an effect of the lower body weight and of no toxIcological significance.
HISTOPATHOLOGY
- Liver: An increased incidence of centrilobular enlargement of hepatocytes, sometimes with vacuolisation, and/or generalised enlargement of hepatocytes was seen in all treated animals. A dose-relationship did not occur.
- Urinary bladder: The incidence of epithelial hyperplasia was increased in animals receiving 675 ppm and males receiving 225 ppm.
All other changes reported were within the normal background range for mice of this strain. - Relevance of carcinogenic effects / potential:
- Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75,225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and75 ppm were greater than the nominal concentration in order to compensate for losses during storage. Statistically significant reductions in body-weight gain and food intake were seen in males and females receiving 225 or 675 ppm. Dose-related, statistically significant decreases in the absolute brain weight of males receiving 225 or 675 ppm and the brain weight adjusted for final body weight of females receiving 75, 225, or 675 ppm were noted. Macroscopic examination of all animals that died or were killed at termination revealed increased incidences of reduced adipose tissue in males that died, irregular cortical scarring of the kidneys in males at terminal sacrifice, brown kidneys in males, and roughened and white forestomachs in females, all receiving the highest dose. An increased incidence of centrilobular and/or generalized hepatocellular enlargement was seen in all treated groups, and an increased incidence of urinary bladder epithelial hyperplasia was seen in males and females receiving 675 ppm and in males at 225 ppm. No treatment- related neoplastic effects were seen.
- Dose descriptor:
- NOAEL
- Effect level:
- 675 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of neoplastic lesions
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- 82 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of neoplastic lesions
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- < 25 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: = 4.0 mg ziram/kg bw/day, based on an increased incidence of centrilobular and/or generalised hepatocellular enlargement.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified. Effect type:toxicity (migrated information)
- Conclusions:
- Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance and it is considered that read-across is valid. No treatment- related neoplastic effects were seen.
- Executive summary:
Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75,225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80 weeks. The concentrations of ziram given to the groups at 25 and75 ppm were greater than the nominal concentration in order to compensate for losses during storage. Statistically significant reductions in body-weight gain and food intake were seen in males and females receiving 225 or 675 ppm. Dose-related, statistically significant decreases in the absolute brain weight of males receiving 225 or 675 ppm and the brain weight adjusted for final body weight of females receiving 75, 225, or 675 ppm were noted. Macroscopic examination of all animals that died or were killed at termination revealed increased incidences of reduced adipose tissue in males that died, irregular cortical scarring of the kidneys in males at terminal sacrifice, brown kidneys in males, and roughened and white forestomachs in females, all receiving the highest dose. An increased incidence of centrilobular and/or generalized hepatocellular enlargement was seen in all treated groups, and an increased incidence of urinary bladder epithelial hyperplasia was seen in males and females receiving 675 ppm and in males at 225 ppm. No treatment- related neoplastic effects were se
Reference
Table 7.7 -B1 Histopathology of the relevant tissues |
|
|||||||||||
Parameter / Dose |
Control |
25 ppm |
75 ppm |
225 ppm |
675 ppm |
Dose-response +/– |
||||||
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
♂ |
♀ |
|
Liver / number examined |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
||
Centrilobular hepatocye enlargement |
2 |
0 |
21 |
12 |
21 |
19 |
25 |
16 |
19 |
13 |
– |
– |
Centrilobular hepatocye enlargement and vacuolation |
0 |
0 |
7 |
0 |
9 |
2 |
5 |
1 |
5 |
1 |
– |
– |
Generalised enlargement |
1 |
1 |
9 |
10 |
12 |
10 |
15 |
7 |
6 |
7 |
– |
– |
Urinary bladder / number examined |
50 |
48 |
50 |
50 |
46 |
48 |
50 |
49 |
50 |
49 |
||
Epithelial hyperplasia |
7 |
0 |
7 |
5 |
9 |
1 |
20 |
5 |
31 |
14 |
+ |
– |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 0.64 mg/kg bw/day
- Study duration:
- chronic
- Species:
- mouse
- Quality of whole database:
- For dermal exposure we taken that:
-the average weight of mice is 80 g (60 -100 g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg
corrected dermal NOAEL= oral NOAEL
82 mg/kg bw/d x 0.008 kg = NOAECrat 0.64 mg/kg bw/day
Justification for classification or non-classification
Based on the hazard assessment of IPETC/O-isopropyl ethylthiocarbamate in section 2.1 and 2.2.in IUCLID 6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99)
and according to the criteria described in Directive 67/548 and in the CLP Regulation:
Directive 67/548 |
Carcinogenicity Carc. Cat. 1; R45 May cause cancer. Carc. Cat. 1; R49 May cause cancer by inhalation. Carc. Cat. 2; R45 May cause cancer. Carc. Cat. 2; R49 May cause cancer by inhalation. Carc. Cat. 3; R40 Limited evidence of a carcinogenic effect.
|
CLP |
Carcinogenicity Carc. 1A Carc. 1B Carc. 2 H350: May cause cancer <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H351: Suspected of causing cancer <state route of exposure if it is conclusively proven that no other routs of exposure cause the hazard>. |
It is concluded that the substance IPETC/O-isopropyl ethylthiocarbamate does not meet the criteria to be classified for human health hazards for Carcinogenicity.
Additional information
Oral effects:
Under the condition of the test in a reliable study of Powell, L.A.J.,.; et al.,1994, for a period of 80 weeks,.No evidence of a carcinogenic potential was seen in male and female mice fed dose levels up to 82 and 95 mg/kg bw/d Zinc bis dimethyldithiocarbamate, respectively, for males and females.
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance and it is considered that read-across is valid. No treatment- related neoplastic effects were seen.
NOAEL=82 mg/kg bw/day
Inhalation effects:
The NOEL for oncogenicity effects for both mice and rats was determined to be greater than 5000 ppm.
Propan-2-ol (Isopropyl alcohol) as a main constituent of IPETC/ O-isopropyl ethylthiocarbamate need to be considered in the assessment of IPETC/O-isopropyl ethylthiocarbamate . Concentrations of 5000 ppm is equal to 12.47 mg/m³ (molecular mass of 60.10 g/mol for Propan-2-ol)
NOAECmice 12.47 mg/m3
Dermal Effects:
For dermal exposure we taken that:
-the average weight of mice is 80 g (60 -100 g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg
corrected dermal NOAEL= oral NOAEL
82 mg/kg bw/d x 0.008 kg =
NOAECrat 0.64 mg/kg bw/day
Carcinogenicity: via oral route (target organ): other: all
gross lesions and masses
Carcinogenicity: via inhalation route (target organ): respiratory:
lung; other: all gross lesions and masses
Carcinogenicity: via dermal route (target organ): other: skin
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