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Toxicological information

Carcinogenicity

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Description of key information

There are conclusive but not suffcient data for the classification of substance Reaction mass of SIBX 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

Referenceopen allclose all

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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
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 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)

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

+

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

Endpoint:
carcinogenicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
The lowest dose level produced toxicity and was therefore too high.
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 157-192 g, ♀: 114-175 g
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Ad libitum
Post exposure period:
None
Remarks:
Doses / Concentrations:
0, 60*, 180, 540 ppm (* Concentration was increased to 66 ppm to compensate losses during storage)
Basis:
nominal in diet
No. of animals per sex per dose:
50 per sex (104 week sacrifice)
20 per sex (52 week sacrifice)
Control animals:
yes, plain diet
Positive control:
no
Observations and examinations performed and frequency:
CLINICAL SIGNS & MORTALITY
- At least twice daily

BODY WEIGHT
- Before start of treatment, then once weekly

FOOD CONSUMPTION
- Once weekly

WATER CONSUMPTION
- Daily by visual appraisal

OPHTHALMOSCOPIC EXAMINATION
- At pre-test for all rats and at sacrifice for high-dose and control group

HAEMATOLOGY
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: Differential leukocyte count, haematocrit (PCV), haemoglobin, erythrocyte count (RBC), total leukocyte count, platelet count, thrombotest, cell morphology
CLINICAL CHEMISTRY
- No. of animals: 10 rats/sex/group
- Time points: Weeks (4), 13, 26, 52, 78, 104
- Parameters: Glucose, total cholesterol, urea nitrogen, total bilirubin, total protein, albumin, creatinine, calcium, phosphorus, chloride, alanine aminotransferase (ALT, GPT), aspartate aminotransferase (GOT), alkaline phosphatase (AP)
In week 4 only tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH).

URINALYSIS
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: pH, protein, glucose, ketones, haem pigments, bile pigments, urobilinogen, total reducing substances (TRS), specific gravity, volume, microscopic examination

ORGAN WEIGHTS
- All surviving animals at weeks 52 and 104.
- Organs: Brain, adrenals, heart, kidneys, liver, ovaries, testes (with epididymides), thyroid
Sacrifice and pathology:
GROSS PATHOLOGY
- All surviving animals at scheduled sacrifice.

HISTOPATHOLOGY
- All surviving animals from control and high-dosage group at weeks 52 and 104.
- All surviving animals from low and intermediate group at weeks 52 and 104 organs indicated with * and organs indicated with # as treatment-related changes were seen at the high-dosage level.
- Organs: Adrenals#, aorta, bones (sternum and femur), bone marrow (sternum), brain, caecum, colon, duodenum, eyes, heart, jejunum, ileum, kidneys*, liver*, lungs*, lymph nodes#(males), 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 both together and separately for male and female.
Data relating to food and water 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 water consumption data were analysed as the total recorded intake 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 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:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
BODY WEIGHT
- Marked bodyweight gain reduction during week 1 in animals receiving 180 and 540 ppm. At 540 ppm reduced bodyweight gain continued until termination whereas at 180 ppm after week 1 the values were comparable to the controls for the majority of the dosing period.

FOOD CONSUMPTION
- Consistent with reduction in bodyweight gain, food intake by animals receiving 540 ppm, and to a lesser degree, those receiving 180 ppm was decreased during the first week. Subsequently food intake improved but remained lower than in the control.

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:
2.5, 7.7, 23.7 mg/kg bw/day for males
3.4, 10.2, 34.6 mg/kg bw/day for females

HAEMATOLOGY
- In week 13 in all treated groups the erythrocyte number was reduced with the effect persisting in females given 60 ppm in week 26 and those given 180 or 540 ppm up to termination.
- In consequence haematocrit values for females given 180 ppm in week 26 and 52 and in those receiving 540 ppm from week 26 to termination were decreased.
- Additionally reduced haemoglobin concentrations were apparent for males given 540 ppm at week 13 only and in females from week 26 to termination. Females given 180 ppm were also affected at weeks 26 and 52.
- Reductions in thrombotest times were noted for treated groups of males at weeks 13 and 26 only.
CLINICAL CHEMISTRY
- T3, T4 and TSH were dosage-related decreased in week 4. The reduction in T4 values was still apparent for treated males at weeks 13 and 26.
- Albumin values were reduced in week 13 amongst animals receiving 180 or 540 ppm with a corresponding reduction in total protein. This effect persisted in week 26 at 540 ppm. From week 52 there was a marginal decrease in total protein in males and a lower albumin fraction in females receiving 540 ppm.
- Blood urea nitrogen was increased at week 13 amongst males receiving 540 ppm and at week 26 additionally at 180 ppm. At week 52 and 78 an increase was also apparent for females at the same dosage.
- Decreased GPT values were noted from week 13 to termination for animals receiving 540 ppm and at week 13 and 26 for males given 180 ppm.

URINALYSIS
Effects seen were not considered to be associated with any histopathological changes in the kidney.

ORGAN WEIGHTS (relative)
- Decrease in adrenal weights in males receiving 180 or 540 ppm at interim kill at termination in all males.
- Liver and thyroid weights all treated females dose-related increase at interim and terminal kills.
- Additionally at interim kill a dose-related increase in heart weight were apparent in females and at terminal kill decreases were noted for pituitary and kidney weights in males.
PATHOLOGY
Termination kill:
- Depressions and thickening of the forestomach were seen in both sexes with raised areas noted in males and white discolouration noted in females. Depressions in the stomach antrum mucosa were found only in females as well as various cystic changes in the adrenals.
- Additionally the incidence of atrophied hindlimbs was greater among treated animals than controls.

HISTOPATHOLOGY
Results are displayed in table 7.7-A3
Relevance of carcinogenic effects / potential:
In a study of toxicity, involving groups of 20 CD(SD)BR rats of each sex, and carcinogenicity, involving groups of 50 rats of each sex, the animals were fed diets containing ziram (purity, 98.7%) providing concentrations of 0, 60, 180, or 540 ppm (equal to 0, 3.0/2.5, 9.1/7.7, or 27/24 mg/kg bw per day for males and 0, 3.9/3.4, 12/10, or 38/35 mg/kg bw per day for females), for 12 or 24 months.
Clinical signs, body weight, and food consumption were observed weekly, and ophthalmoscopic, haematological, biochemical, and urinary investigations were performed at certain intervals. At termination, the organ weights, haematological parameters, and the results of clinical chemical, urinary, and macroscopic and microscopic examinations were recorded. Body-weight gain, food intake, and food conversion ratios were reduced in a dose-dependent fashion in male and female rats at 180 and 540 ppm. The erythrocyte count was reduced dose-dependently in animals of each sex at 60, 180, and 540 ppm, and a dose-dependent decrease in thromboplastin time was observed in males at all three doses. At 180 and 540 ppm, packed cell volume and haemoglobin were reduced in females and thromboplastin time in males.
Tri-iodothyronine, thyroxine, albumin, total protein, and calcium levels were reduced and that of blood urea nitrogen was increased at 180 and 540 ppm in animals of each sex. Haemangiomata in the mesenteric lymph nodes, hypertrophy with vacuolation of the adrenals, and C-cell hyperplasia of the thyroids were observed in males at 540 ppm. In females, cortical cystic degeneration of the adrenals wasseen at 540 ppm. Dose-dependent adipose replacement, narrowing of the myofibres in skeletal muscle, haemosiderosis in the spleen, adipose tissue replacement in the pancreas, prominent ultimobranchial cysts in the thyroids, and epithelial hyperplasia and subepithelial oedema in the nonglandular part of the stomach were observed in animals at 60, 180, or 540 ppm.
Dose descriptor:
LOAEL
Effect level:
ca. 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
< 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: A no-observable-effect level could not be determined due to dose-related changes in organ weights and histopathological findings at the lowest dose.
Remarks on result:
not determinable
Remarks:
no NOAEL identified. Effect type:toxicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: = 23.7 mg ziram/kg bw/day, based on a higher incidence of haemangiomata was noticed.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: = 34.6 mg ziram/kg bw/day,absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 34.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Table 7.7-A1   Body weight, haematology and organ weights

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Body weight

(↓)

(↓)

(↓)

(↓)

(↓)

(↓)

Body weight gain

↓ 14%

↓ 26%

Haematology

Haematocrit (PCV)

Haemoglobin

RBC

Organ weight (rel.)

Testes + epididymides

↑ 12%

↑ 26%

Adrenals

↓ 34%

↑ 56%

Liver

↑ 12%

Brain

↑ 19%

Thyroid

↑ 33%

Heart

↑ 11%

↓ ↑: statistically significance ;   (↓ ↑): no statistical significance

Table 7.7-A2   Macroscopic pathology after 104 weeks

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Dose-response

+/–

No of animals examined

50

50

50

50

50

50

50

50

Forestomach

Depressions

11

8

16

7

20

14

20

31

+

Raised areas

0

0

0

1

3

1

4

0

Thickening

5

3

11

3

11

8

12

12

+

White discolouration

4

1

8

1

7

4

6

9

+

Stomach

Antrum mucosa depression

6

2

4

3

6

6

4

 

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD(SD)BR rats. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

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

Referenceopen allclose all

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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
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 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)

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

+

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

Endpoint:
carcinogenicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
The lowest dose level produced toxicity and was therefore too high.
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 157-192 g, ♀: 114-175 g
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Ad libitum
Post exposure period:
None
Remarks:
Doses / Concentrations:
0, 60*, 180, 540 ppm (* Concentration was increased to 66 ppm to compensate losses during storage)
Basis:
nominal in diet
No. of animals per sex per dose:
50 per sex (104 week sacrifice)
20 per sex (52 week sacrifice)
Control animals:
yes, plain diet
Positive control:
no
Observations and examinations performed and frequency:
CLINICAL SIGNS & MORTALITY
- At least twice daily

BODY WEIGHT
- Before start of treatment, then once weekly

FOOD CONSUMPTION
- Once weekly

WATER CONSUMPTION
- Daily by visual appraisal

OPHTHALMOSCOPIC EXAMINATION
- At pre-test for all rats and at sacrifice for high-dose and control group

HAEMATOLOGY
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: Differential leukocyte count, haematocrit (PCV), haemoglobin, erythrocyte count (RBC), total leukocyte count, platelet count, thrombotest, cell morphology
CLINICAL CHEMISTRY
- No. of animals: 10 rats/sex/group
- Time points: Weeks (4), 13, 26, 52, 78, 104
- Parameters: Glucose, total cholesterol, urea nitrogen, total bilirubin, total protein, albumin, creatinine, calcium, phosphorus, chloride, alanine aminotransferase (ALT, GPT), aspartate aminotransferase (GOT), alkaline phosphatase (AP)
In week 4 only tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH).

URINALYSIS
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: pH, protein, glucose, ketones, haem pigments, bile pigments, urobilinogen, total reducing substances (TRS), specific gravity, volume, microscopic examination

ORGAN WEIGHTS
- All surviving animals at weeks 52 and 104.
- Organs: Brain, adrenals, heart, kidneys, liver, ovaries, testes (with epididymides), thyroid
Sacrifice and pathology:
GROSS PATHOLOGY
- All surviving animals at scheduled sacrifice.

HISTOPATHOLOGY
- All surviving animals from control and high-dosage group at weeks 52 and 104.
- All surviving animals from low and intermediate group at weeks 52 and 104 organs indicated with * and organs indicated with # as treatment-related changes were seen at the high-dosage level.
- Organs: Adrenals#, aorta, bones (sternum and femur), bone marrow (sternum), brain, caecum, colon, duodenum, eyes, heart, jejunum, ileum, kidneys*, liver*, lungs*, lymph nodes#(males), 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 both together and separately for male and female.
Data relating to food and water 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 water consumption data were analysed as the total recorded intake 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 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:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
BODY WEIGHT
- Marked bodyweight gain reduction during week 1 in animals receiving 180 and 540 ppm. At 540 ppm reduced bodyweight gain continued until termination whereas at 180 ppm after week 1 the values were comparable to the controls for the majority of the dosing period.

FOOD CONSUMPTION
- Consistent with reduction in bodyweight gain, food intake by animals receiving 540 ppm, and to a lesser degree, those receiving 180 ppm was decreased during the first week. Subsequently food intake improved but remained lower than in the control.

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:
2.5, 7.7, 23.7 mg/kg bw/day for males
3.4, 10.2, 34.6 mg/kg bw/day for females

HAEMATOLOGY
- In week 13 in all treated groups the erythrocyte number was reduced with the effect persisting in females given 60 ppm in week 26 and those given 180 or 540 ppm up to termination.
- In consequence haematocrit values for females given 180 ppm in week 26 and 52 and in those receiving 540 ppm from week 26 to termination were decreased.
- Additionally reduced haemoglobin concentrations were apparent for males given 540 ppm at week 13 only and in females from week 26 to termination. Females given 180 ppm were also affected at weeks 26 and 52.
- Reductions in thrombotest times were noted for treated groups of males at weeks 13 and 26 only.
CLINICAL CHEMISTRY
- T3, T4 and TSH were dosage-related decreased in week 4. The reduction in T4 values was still apparent for treated males at weeks 13 and 26.
- Albumin values were reduced in week 13 amongst animals receiving 180 or 540 ppm with a corresponding reduction in total protein. This effect persisted in week 26 at 540 ppm. From week 52 there was a marginal decrease in total protein in males and a lower albumin fraction in females receiving 540 ppm.
- Blood urea nitrogen was increased at week 13 amongst males receiving 540 ppm and at week 26 additionally at 180 ppm. At week 52 and 78 an increase was also apparent for females at the same dosage.
- Decreased GPT values were noted from week 13 to termination for animals receiving 540 ppm and at week 13 and 26 for males given 180 ppm.

URINALYSIS
Effects seen were not considered to be associated with any histopathological changes in the kidney.

ORGAN WEIGHTS (relative)
- Decrease in adrenal weights in males receiving 180 or 540 ppm at interim kill at termination in all males.
- Liver and thyroid weights all treated females dose-related increase at interim and terminal kills.
- Additionally at interim kill a dose-related increase in heart weight were apparent in females and at terminal kill decreases were noted for pituitary and kidney weights in males.
PATHOLOGY
Termination kill:
- Depressions and thickening of the forestomach were seen in both sexes with raised areas noted in males and white discolouration noted in females. Depressions in the stomach antrum mucosa were found only in females as well as various cystic changes in the adrenals.
- Additionally the incidence of atrophied hindlimbs was greater among treated animals than controls.

HISTOPATHOLOGY
Results are displayed in table 7.7-A3
Relevance of carcinogenic effects / potential:
In a study of toxicity, involving groups of 20 CD(SD)BR rats of each sex, and carcinogenicity, involving groups of 50 rats of each sex, the animals were fed diets containing ziram (purity, 98.7%) providing concentrations of 0, 60, 180, or 540 ppm (equal to 0, 3.0/2.5, 9.1/7.7, or 27/24 mg/kg bw per day for males and 0, 3.9/3.4, 12/10, or 38/35 mg/kg bw per day for females), for 12 or 24 months.
Clinical signs, body weight, and food consumption were observed weekly, and ophthalmoscopic, haematological, biochemical, and urinary investigations were performed at certain intervals. At termination, the organ weights, haematological parameters, and the results of clinical chemical, urinary, and macroscopic and microscopic examinations were recorded. Body-weight gain, food intake, and food conversion ratios were reduced in a dose-dependent fashion in male and female rats at 180 and 540 ppm. The erythrocyte count was reduced dose-dependently in animals of each sex at 60, 180, and 540 ppm, and a dose-dependent decrease in thromboplastin time was observed in males at all three doses. At 180 and 540 ppm, packed cell volume and haemoglobin were reduced in females and thromboplastin time in males.
Tri-iodothyronine, thyroxine, albumin, total protein, and calcium levels were reduced and that of blood urea nitrogen was increased at 180 and 540 ppm in animals of each sex. Haemangiomata in the mesenteric lymph nodes, hypertrophy with vacuolation of the adrenals, and C-cell hyperplasia of the thyroids were observed in males at 540 ppm. In females, cortical cystic degeneration of the adrenals wasseen at 540 ppm. Dose-dependent adipose replacement, narrowing of the myofibres in skeletal muscle, haemosiderosis in the spleen, adipose tissue replacement in the pancreas, prominent ultimobranchial cysts in the thyroids, and epithelial hyperplasia and subepithelial oedema in the nonglandular part of the stomach were observed in animals at 60, 180, or 540 ppm.
Dose descriptor:
LOAEL
Effect level:
ca. 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
< 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: A no-observable-effect level could not be determined due to dose-related changes in organ weights and histopathological findings at the lowest dose.
Remarks on result:
not determinable
Remarks:
no NOAEL identified. Effect type:toxicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: = 23.7 mg ziram/kg bw/day, based on a higher incidence of haemangiomata was noticed.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: = 34.6 mg ziram/kg bw/day,absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 34.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Table 7.7-A1   Body weight, haematology and organ weights

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Body weight

(↓)

(↓)

(↓)

(↓)

(↓)

(↓)

Body weight gain

↓ 14%

↓ 26%

Haematology

Haematocrit (PCV)

Haemoglobin

RBC

Organ weight (rel.)

Testes + epididymides

↑ 12%

↑ 26%

Adrenals

↓ 34%

↑ 56%

Liver

↑ 12%

Brain

↑ 19%

Thyroid

↑ 33%

Heart

↑ 11%

↓ ↑: statistically significance ;   (↓ ↑): no statistical significance

Table 7.7-A2   Macroscopic pathology after 104 weeks

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Dose-response

+/–

No of animals examined

50

50

50

50

50

50

50

50

Forestomach

Depressions

11

8

16

7

20

14

20

31

+

Raised areas

0

0

0

1

3

1

4

0

Thickening

5

3

11

3

11

8

12

12

+

White discolouration

4

1

8

1

7

4

6

9

+

Stomach

Antrum mucosa depression

6

2

4

3

6

6

4

 

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD(SD)BR rats. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3.5 mg/m³
Study duration:
chronic
Species:
mouse

Carcinogenicity: via dermal route

Link to relevant study records

Referenceopen allclose all

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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
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 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)

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

+

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD-1 mice. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

Endpoint:
carcinogenicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
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 xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2 In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
The lowest dose level produced toxicity and was therefore too high.
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 157-192 g, ♀: 114-175 g
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Ad libitum
Post exposure period:
None
Remarks:
Doses / Concentrations:
0, 60*, 180, 540 ppm (* Concentration was increased to 66 ppm to compensate losses during storage)
Basis:
nominal in diet
No. of animals per sex per dose:
50 per sex (104 week sacrifice)
20 per sex (52 week sacrifice)
Control animals:
yes, plain diet
Positive control:
no
Observations and examinations performed and frequency:
CLINICAL SIGNS & MORTALITY
- At least twice daily

BODY WEIGHT
- Before start of treatment, then once weekly

FOOD CONSUMPTION
- Once weekly

WATER CONSUMPTION
- Daily by visual appraisal

OPHTHALMOSCOPIC EXAMINATION
- At pre-test for all rats and at sacrifice for high-dose and control group

HAEMATOLOGY
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: Differential leukocyte count, haematocrit (PCV), haemoglobin, erythrocyte count (RBC), total leukocyte count, platelet count, thrombotest, cell morphology
CLINICAL CHEMISTRY
- No. of animals: 10 rats/sex/group
- Time points: Weeks (4), 13, 26, 52, 78, 104
- Parameters: Glucose, total cholesterol, urea nitrogen, total bilirubin, total protein, albumin, creatinine, calcium, phosphorus, chloride, alanine aminotransferase (ALT, GPT), aspartate aminotransferase (GOT), alkaline phosphatase (AP)
In week 4 only tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH).

URINALYSIS
- No. of animals: 10 rats/sex/group
- Time points: Weeks 13, 26, 52, 78, 104
- Parameters: pH, protein, glucose, ketones, haem pigments, bile pigments, urobilinogen, total reducing substances (TRS), specific gravity, volume, microscopic examination

ORGAN WEIGHTS
- All surviving animals at weeks 52 and 104.
- Organs: Brain, adrenals, heart, kidneys, liver, ovaries, testes (with epididymides), thyroid
Sacrifice and pathology:
GROSS PATHOLOGY
- All surviving animals at scheduled sacrifice.

HISTOPATHOLOGY
- All surviving animals from control and high-dosage group at weeks 52 and 104.
- All surviving animals from low and intermediate group at weeks 52 and 104 organs indicated with * and organs indicated with # as treatment-related changes were seen at the high-dosage level.
- Organs: Adrenals#, aorta, bones (sternum and femur), bone marrow (sternum), brain, caecum, colon, duodenum, eyes, heart, jejunum, ileum, kidneys*, liver*, lungs*, lymph nodes#(males), 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 both together and separately for male and female.
Data relating to food and water 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 water consumption data were analysed as the total recorded intake 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 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:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
BODY WEIGHT
- Marked bodyweight gain reduction during week 1 in animals receiving 180 and 540 ppm. At 540 ppm reduced bodyweight gain continued until termination whereas at 180 ppm after week 1 the values were comparable to the controls for the majority of the dosing period.

FOOD CONSUMPTION
- Consistent with reduction in bodyweight gain, food intake by animals receiving 540 ppm, and to a lesser degree, those receiving 180 ppm was decreased during the first week. Subsequently food intake improved but remained lower than in the control.

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:
2.5, 7.7, 23.7 mg/kg bw/day for males
3.4, 10.2, 34.6 mg/kg bw/day for females

HAEMATOLOGY
- In week 13 in all treated groups the erythrocyte number was reduced with the effect persisting in females given 60 ppm in week 26 and those given 180 or 540 ppm up to termination.
- In consequence haematocrit values for females given 180 ppm in week 26 and 52 and in those receiving 540 ppm from week 26 to termination were decreased.
- Additionally reduced haemoglobin concentrations were apparent for males given 540 ppm at week 13 only and in females from week 26 to termination. Females given 180 ppm were also affected at weeks 26 and 52.
- Reductions in thrombotest times were noted for treated groups of males at weeks 13 and 26 only.
CLINICAL CHEMISTRY
- T3, T4 and TSH were dosage-related decreased in week 4. The reduction in T4 values was still apparent for treated males at weeks 13 and 26.
- Albumin values were reduced in week 13 amongst animals receiving 180 or 540 ppm with a corresponding reduction in total protein. This effect persisted in week 26 at 540 ppm. From week 52 there was a marginal decrease in total protein in males and a lower albumin fraction in females receiving 540 ppm.
- Blood urea nitrogen was increased at week 13 amongst males receiving 540 ppm and at week 26 additionally at 180 ppm. At week 52 and 78 an increase was also apparent for females at the same dosage.
- Decreased GPT values were noted from week 13 to termination for animals receiving 540 ppm and at week 13 and 26 for males given 180 ppm.

URINALYSIS
Effects seen were not considered to be associated with any histopathological changes in the kidney.

ORGAN WEIGHTS (relative)
- Decrease in adrenal weights in males receiving 180 or 540 ppm at interim kill at termination in all males.
- Liver and thyroid weights all treated females dose-related increase at interim and terminal kills.
- Additionally at interim kill a dose-related increase in heart weight were apparent in females and at terminal kill decreases were noted for pituitary and kidney weights in males.
PATHOLOGY
Termination kill:
- Depressions and thickening of the forestomach were seen in both sexes with raised areas noted in males and white discolouration noted in females. Depressions in the stomach antrum mucosa were found only in females as well as various cystic changes in the adrenals.
- Additionally the incidence of atrophied hindlimbs was greater among treated animals than controls.

HISTOPATHOLOGY
Results are displayed in table 7.7-A3
Relevance of carcinogenic effects / potential:
In a study of toxicity, involving groups of 20 CD(SD)BR rats of each sex, and carcinogenicity, involving groups of 50 rats of each sex, the animals were fed diets containing ziram (purity, 98.7%) providing concentrations of 0, 60, 180, or 540 ppm (equal to 0, 3.0/2.5, 9.1/7.7, or 27/24 mg/kg bw per day for males and 0, 3.9/3.4, 12/10, or 38/35 mg/kg bw per day for females), for 12 or 24 months.
Clinical signs, body weight, and food consumption were observed weekly, and ophthalmoscopic, haematological, biochemical, and urinary investigations were performed at certain intervals. At termination, the organ weights, haematological parameters, and the results of clinical chemical, urinary, and macroscopic and microscopic examinations were recorded. Body-weight gain, food intake, and food conversion ratios were reduced in a dose-dependent fashion in male and female rats at 180 and 540 ppm. The erythrocyte count was reduced dose-dependently in animals of each sex at 60, 180, and 540 ppm, and a dose-dependent decrease in thromboplastin time was observed in males at all three doses. At 180 and 540 ppm, packed cell volume and haemoglobin were reduced in females and thromboplastin time in males.
Tri-iodothyronine, thyroxine, albumin, total protein, and calcium levels were reduced and that of blood urea nitrogen was increased at 180 and 540 ppm in animals of each sex. Haemangiomata in the mesenteric lymph nodes, hypertrophy with vacuolation of the adrenals, and C-cell hyperplasia of the thyroids were observed in males at 540 ppm. In females, cortical cystic degeneration of the adrenals wasseen at 540 ppm. Dose-dependent adipose replacement, narrowing of the myofibres in skeletal muscle, haemosiderosis in the spleen, adipose tissue replacement in the pancreas, prominent ultimobranchial cysts in the thyroids, and epithelial hyperplasia and subepithelial oedema in the nonglandular part of the stomach were observed in animals at 60, 180, or 540 ppm.
Dose descriptor:
LOAEL
Effect level:
ca. 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
< 60 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: A no-observable-effect level could not be determined due to dose-related changes in organ weights and histopathological findings at the lowest dose.
Remarks on result:
not determinable
Remarks:
no NOAEL identified. Effect type:toxicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: = 23.7 mg ziram/kg bw/day, based on a higher incidence of haemangiomata was noticed.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 540 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: = 34.6 mg ziram/kg bw/day,absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
ca. 34.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: absence of neoplastic lesions
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Table 7.7-A1   Body weight, haematology and organ weights

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Body weight

(↓)

(↓)

(↓)

(↓)

(↓)

(↓)

Body weight gain

↓ 14%

↓ 26%

Haematology

Haematocrit (PCV)

Haemoglobin

RBC

Organ weight (rel.)

Testes + epididymides

↑ 12%

↑ 26%

Adrenals

↓ 34%

↑ 56%

Liver

↑ 12%

Brain

↑ 19%

Thyroid

↑ 33%

Heart

↑ 11%

↓ ↑: statistically significance ;   (↓ ↑): no statistical significance

Table 7.7-A2   Macroscopic pathology after 104 weeks

Parameter  / Dose

Control

60 ppm

180 ppm

540 ppm

Dose-response

+/–

No of animals examined

50

50

50

50

50

50

50

50

Forestomach

Depressions

11

8

16

7

20

14

20

31

+

Raised areas

0

0

0

1

3

1

4

0

Thickening

5

3

11

3

11

8

12

12

+

White discolouration

4

1

8

1

7

4

6

9

+

Stomach

Antrum mucosa depression

6

2

4

3

6

6

4

 

Conclusions:
Zinc bis dimethyldithiocarbamate was not carcinogenic in the CD(SD)BR rats. Zinc bis dimethyldithiocarbamate is closely related to the registered substance, Reaction mass of SIBX , 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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
0.64 mg/kg bw/day
Study duration:
chronic
Species:
mouse

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, Reaction mass of SIBX, and it is considered that read-across is valid. No treatment- related neoplastic effects were seen.

Inhalation effects:

The oral dose for the mice is converted to the corresponding air concentration using a standard breathing volume for the mice (1.15m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL mice              82 mg/kg bw/day

÷1.15m3/kgbw

÷20m3/mice

NOAECmice     3.5 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

Justification for classification or non-classification

Based on the hazard assessment of Reaction mass of SIBX 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 Reaction mass of SIBX does not meet the criteria to be classified for human health hazards for Carcinogenicity.