Sodium dimethyldithiocarbamate

Carcinogenicity

Description of key information

No indication for a carcinogenic effect

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:

key study

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP guideline study; According to the ECHA guidance document “Practical guide 6, V2: How to report read-across and categories” (Dec 2012), the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

equivalent or similar to guideline

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 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: ♂: 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

Dose descriptor:

LOAEL

Effect level:

ca. 60 ppm (nominal)

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)

Sex:

male/female

Basis for effect level:

other: A no-observable-effect level could not be determinded 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)

Sex:

male

Basis for effect level:

other: = 23.7 mg ziram/kg bw/day = 22.2 mg SDDC (a.s.)/kg bw/day = 53.5 mg SDDC (41.44% solution as supplied)/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)

Sex:

female

Basis for effect level:

other: = 34.6 mg ziram/kg bw/day = 32.4 mg SDDC (a.s.)/kg bw/day = 78.1 mg SDDC (41.44% solution as supplied)/kg bw/day

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
Table 7.7-A3   Micropathology 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
Neoplastic changes
Spleen
Haemangioma	0	0	0	0		0	0	1	0	–	–
Lymphnodes
Haemangioma	0	0	0	0		0	0	5*	0	–	–
Non-neoplastic changes
Spleen
Haemosiderosis	10	24	22*	29		29*	38*	23*	39*	–	–
Skeletal muscle
Adipose replacement	5	0	10	4		27*	21*	43*	26*	+	+
Narrowing of fibres	2	0	10*	4		30*	15*	37*	22*	+	+
Sciatic nerve
Axonal degeneration	14	3	12	5		15	4	22	16*	–	–
Liver
Bile duct hyperplasia	7	5	7	6		13	9	15	17*	+	+
Pigmented sinusoidal cells	2	0	5	3		22*	13*	26*	15*	+	+
Kidneys
Brown pigment in tubular epithelial cells	2	5	6	8		6	9	4	19*	–	–
Pancreas
Replacement by adipose tissue	7	0	14	2		15*	4	21*	3	+	–
Adrenals
Vacuolation	4	1	11*	1		11*	0	12*	2	–	–
Cortical cystic degeneration	2	7	3	9		1	12	2	29*	–	+
Thyroid
Prominent ultimobranchial cyst	4	3	5	12*		14*	22*	15*	27*	–	+
C-cell hyperplasia	1	5	3	5		5	5	8*	3	+	–
Forestomach
Non-glandular hyperplasia	6	7	18*	6		25*	15*	25*	37*	–	+
Non-glandular ulceration or oedema	5	3	8	5		14*	6	14*	12*	–	–
* statistical significance (Fisher’s exact test)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

78.1 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The occurrence of a benign tumour in only one sex of only one species is of low toxicological significance and does not justify classification of SDDC as a carcinogen.

Additional information

According to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, substances may be considered as analogues provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The target (SDDC) and source substance (ziram) are considered to apply to these general rules. The assumed similarity is justified on basis that both, SDDC and ziram, represent salts of dimethyl dithiocarbamic acid (DDC) which have similar physico-chemical properties, exhibit a similar environmental fate and ecotoxicity profile, similar metabolic pathways and comparable systemic effects in mammals. There is convincing evidence that these chemicals lie in the overall common profile with respect to the present analogue approach. For a detailed discussion please refer to the analogue justification.

Summary of carcinogenicity studies in mice and rats with ziram

Carcinogenicity studies with SDDC have not been performed. It is proposed to read across the respective available data on the similar active substance, ziram, to SDDC.

The similarity of SDDC and ziram with regard to their toxicological properties can be established by comparison of the outcome of the subchronic oral study in rats with SDDC and the subchronic oral study with dogs and the chronic oral study with rats with ziram.

A 2-year rat study and an 80-week mouse study, both using dietary administration, have been conducted with ziram. In the rat, benign haemangiomata were seen in the mesenteric lymph nodes of five male terminal kill rats receiving 540 ppm ziram. Haemangiomata are benign multilocular tumours occasionally seen in low numbers of rats of this strain and age range, mesenteric lymph nodes and the spleen being the most common sites for their detection. These haemangiomata were not pronounced, did not show evidence of malignancy and were confined to this group and sex only. The incidence was statistically significant in comparison to the control group and was not observed in other tissues of these animals and or seen in any rats receiving lower doses of ziram. Therefore it can be considered that the presence of these haemangiomata at a dosage level of 540 ppm in male animals was a consequence of the administration of ziram.

In contrast the incidence of the various neoplasms observed in the mouse study showed no significant deviation from the expected tumour profile of laboratory-maintained mice of this strain.

On the basis of the increased incidence of haemangiomata, a tumorigenic effect of high doses of ziram in the rat cannot be excluded. Since the overall conclusion with regard to mutagenicity is negative, also in the case of SDDC, the possible tumorigenic mechanism remains unclear.

Data for thiram were submitted in the initial registration dossier. However, as detailed in the analogue justification, ziram is the more relevant source substance. The data on thiram are provided for sake of completeness.

Summary of carcinogenicity studies in mice and rats with thiram

Thiram was administered to rats up to the MTD in the diet for 2 years. At 7.31/8.86 mg/kg bw/d (♂/♀), the animals showed signs of systemic toxicity indicated by reduced bodyweight gain, changes in some haematology and liver parameters and increased thyroid C-cell hyperplasia. The incidence of benign tumours showed a statistically positive trend, although their number is not statistically different between control and treated groups. In view of the overall results obtained in this carcinogenicity study, it can be concluded that thiram is not carcinogenic in rats. A NOEL was established at 1.46/1.80 mg/kg bw/d (♂/♀).

Male and female mice received thiram (3 to 112 mg/kg bw/d) in their diet for 97 weeks. Starting at 2.5/3.1 mg/kg bw/d (♂/♀), systemic toxic effects (bw, bw gain, skin reactions and changes in blood parameters) could be observed. Treatment-related non-neoplastic findings were observed in the non-glandular stomach, eye, urinary bladder, adrenal gland, spleen of mid- and high-dose animals, most remarkable in high-dose females.There is no tumour induction in the mouse. A NOEL was set at 50/112 mg/kg bw/d (♂/♀).

 

Justification for selection of carcinogenicity via oral route endpoint:
The study with the lowest effect level was chosen.

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: other