Potassium O-ethyl dithiocarbonate

Carcinogenicity

Description of key information

There are conclusive but not suffcient data for the classification of substance Potassium ethyl xanthate 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

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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

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:

not specified

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)

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, Potassium isobutyl xanthate, 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

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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

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:

not specified

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)

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, Potassium isobutyl xanthate, 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

Quality of whole database:

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

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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

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:

not specified

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)

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, Potassium isobutyl xanthate, 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

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 Potassium ethyl xanthate in section 2.1 and 2.2.in IUCLID 5.4., 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 Potassium ethyl xanthate 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, Potassium ethyl xanthate, 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