Sodium dimethyldithiocarbamate

Endpoint summary

Description of key information

Subchronic gavage study, rat, SDDC: NOAEL =24.4 mg SDDC/kg bw/day, LOAEL = 122 mg SDDC/kg bw/day
Read-across from ziram
Chronic feeding study, dog, ziram: NOAEL = 3.6 mg SDDC/kg bw/day, LOAEL = 14.9 mg SDDC/kg bw/day
subchronic feeding study, dog, ziram: NOAEL = 9.2 mg SDDC/kg bw/day, LOAEL = 27.4 mg SDDC/kg bw/day
Subchronic feeding study, rat, ziram: NOAEL < 16.7 mg SDDC/kg bw/day, LOAEL = 16.7 mg SDDC/kg bw/day
Subacute dermal toxicity study, rabbit, ziram: NOAEL = 225.8 mg SDDC/kg bw/day, LOAEL = 667.5 mg SDDC/kg bw/day
(NOAELs are corrected for differences in molecular weight and for the differences in the concentration of ziram tested and SDDC (41.44%))

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

yes

Remarks:

The highest dose level produced one fatality and had therefore to be adjusted.

GLP compliance:

yes

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna UK Limited, Huntingdon, UK.
- Age at study initiation: 3-5 months
- Weight at study initiation: (♂) 8.8 - 11.5 kg, (♀) 8.2 – 10.7 kg

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

52 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 50*, 185, 500# ppm (* Concentration was increased to 57.5 ppm to compensate losses during storage; # reduced from 700 to 500 ppm in week 12 because of treatment-related mortality)
Basis:
nominal in diet

No. of animals per sex per dose:

4 per sex

Control animals:

yes, plain diet

Positive control:

none

Observations and examinations performed and frequency:

CLINICAL SIGNS
- Daily

MORTALITY
- Daily

BODY WEIGHT
- Weekly

FOOD CONSUMPTION
- Daily

ACHIEVED INTAKE
- Calculated weekly

OPHTHALMOSCOPIC EXAMINATIONS
- Pre-exposure and in weeks 13, 26 and 52

NEUROLOGICAL EXAMINATIONS
GENERAL
- Pre-exposure and in weeks 34 and 50
- Parameters: behaviour and gait

CRANIAL NERVE FUNCTION
- Pre-exposure and in weeks 34 and 50
- Parameters: head tilt, facial muscle, muscles of mastication, blink reflex (l & r), pupillary light reflex (l & r),eye position, strabismus, abnormal nystagmus, corneal reflex (l & r), palpebral reflex (l & r), ear movement, position of philtrum, commissure of lips, jaw closure, open jaw resistance, tongue, gag reflex

SPINAL REFLEXES
- Pre-exposure and in weeks 34 and 50
- Parameters: muscle tone, patellar reflex (l & r), triceps reflex (l & r), flexor reflex (all 4 limbs individually), crossed extensor reflex, perineal reflex

POSTURAL AND ATTITUDINAL REACTIONS
- Pre-exposure and in weeks 34 and 50
- Parameters: wheelbarrowing, thoracic hopping, pelvic hopping, extensor postural thrust, tactile placing, visual placing, tonic neck reaction, righting reaction

HAEMATOLOGY (jugular or cephalic vein)
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), platelet count, reticulocyte count, total leukocyte count, differential leukocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), cell morphology
erythrocyte sedimentation rate (ESR) was performed only in two cases as part of diagnostic screen

CLINICAL CHEMISTRY
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: total protein, albumin, sodium, potassium, glucose, urea (BUN), alanine aminotransferase (ALT, GPT), aspartate aminotransferase (GOT), alkaline phosphatase (AP), creatinine, calcium, phosphorus, chloride, total cholesterol, total bilirubin, gamma-glutamyltransferase (GT), creatine phosphokinase (CPK), ornithine carbamoyltransferase (OCT), -hydroxybutyrate dehydrogenase (-HBDH), tri-iodothyronine (T3), thyroxine (T4)

URINALYSIS
- Pre-exposure and in weeks 13, 26 and 52
- Parameters: protein, glucose, pH, specific gravity, volume, ketones, haem pigments, bile pigments, urobilinogen, total reducing substances (TRS), epithelial cells (E), polymorphonuclear leukocytes (P), mononuclear leukocytes (M), erythrocytes (R), organisms (O), renal tubule casts (C), other abnormal constituents (A)

ORGAN WEIGHTS
- Yes
- Organs: adrenals, brain, heart, lung, kidneys, liver, ovaries/testes (with epididymides), spleen, pituitary, thymus, thyroids/parathyroids, uterus/prostate, pancreas

Sacrifice and pathology:

GROSS AND HISTOPATHOLOGY
- Gross pathology: all dose groups
- Adrenals, aorta, bones (sternum and femur), bone marrow (sternum), brain, caecum, colon, duodenum, eyes, gall bladder, heart, jejunum, ileum, kidneys, liver, lungs, lymph nodes, mammary gland, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic nerves, skeletal muscle, skin, spleen, stomach, testes (with epididymides), thymus, thyroids/parathyroids, tongue, trachea, urinary bladder, uterus, vagina
Additionally: one bone marrow smear per dog.

Statistics:

All analyses were carried out both together and separately for male and female. In view of the small number of animals and to confirm possible effects, analyses were also performed on combined data.
Data relating to food consumption were analysed as totals over selected time periods, expressed on a weekly basis. Bodyweight data were analysed using weight gains.
The following tests were used for food consumption, bodyweight, organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- For pre-dose data, analyses of variance were followed by Student’s ‘t’ test. For data from the dosing period, analyses of variance were followed by Williams’ test for a dose-related response. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate, analysis of covariance was used in place of analysis of variance. Statistical analysis in histopathological examination was performed using Fisher’s exact and Mantel’s tests.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
- Occasional liquid faeces was noted in all dose-groups including controls during the entire study and was considered to be not related to treatment.
- One treatment-related death occurred at the initial high dosage level of 700 ppm during week 11. After a convulsion, the female showed a collapsed state with excessive salivation, trembling, champing of the jaws and jerking of the limps. Pathological findings demonstrated changes consistent with the collapsed state. As a result the high dosage level was reduced to 500 ppm.
One further mortality was treatment-unrelated (suspected polyarteritis) and a replacement dog was obtained.

BODY WEIGHT AND WEIGHT GAIN
- After 26 weeks all females at 185 und 500 ppm showed some weight loss, such that overall gain after 52 weeks was significantly reduced.

COMPOUND INTAKE
- Calculated on a weekly basis by (ppm x food consumption)/(mid-week bodyweight x 7).
The means over the treatment period are:
1.6, 6.6, 17.4 mg/kg bw/day for males
1.9, 6.7, 20.6 mg/kg bw/day for females

CLINICAL CHEMISTRY
- ALT values had intergroup differences amongst males (not statistically significant): 1 dog (185 ppm) and 2 dogs (500 ppm) showed elevated ALT in week 26 and 52. Since these animals showed the most marked changes in the liver microscopic examination, it was considered that these changes were treatment-related.
- AP values showed an apparent dosage-related increase amongst males receiving 185 or 500 ppm in week 26 and 52, although differences were not statistically significant but considered as a result of treatment and are probably associated with the pathological findings seen in the liver of these dogs at termination.
- The decrease in albumin was not supported by any significant corroborative pathological finding at termination and was considered of equivocal toxicological importance.

ORGAN WEIGHTS
- Liver weights for males receiving 500 ppm were increased but didn’t show any histopathological changes.
- Group mean heart weights were decreased for animals at 500 ppm.
- Group mean prostate weights showed a dosage-related decrease compared with the control data, although the differences did not attain statistical significance. There were no macro- or microscopic findings for these tissues.

GROSS PATHOLOGY
- Multiple red discoloured linear depressions of gastric mucosa for 1 female at 185 ppm and a single oval, flat friable choleliths in the gall bladders of 2 males at 185 ppm. No similar findings were seen in any dog at the 500 ppm treatment level.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Liver and spleen are the target organs. Foci of degenerate hepatocytes were seen to a moderate degree at 500 ppm and at 185 ppm with a single cell necrosis in one male at 500 ppm. Inflammatory cell infiltration around central veins and sometimes around the branches of the hepatic vein was seen in some dogs. An apparent increase in centrilobular fibrocytes was seen in 3/4 male dogs treated with 500 ppm and in 1/4 male dog treated with 185 ppm. There was an increased incidence and degree of aggregates of pigmented Kupffer cells and macrophages in the livers of male and female dogs and an increased incidence of pigmented macrophages in the spleen of male dogs treated with 500 ppm or 185 ppm when compared to control male dogs.
- The initial appeared to be increased pigmentation of Kupffer cells and /or macrophages with Perls’ positive material, possibly reflecting increased iron metabolism and turnover. These changes were evident at all dosages in the liver, and for males at 185 or 500 ppm in the spleen. At 185 and 500 ppm, more marked associated changes were seen in the liver, chiefly hepatocyte degeneration and inflammatory cell infiltration. The only change identified at the low dose that could be possibly related to treatment, was aggregates of pigmented Kupffer cells and macrophages in one male and one female.

Dose descriptor:

LOAEL

Effect level:

ca. 185 ppm

Sex:

male/female

Basis for effect level:

other: = 6.6 mg ziram/kg bw/day = 6.2 mg SDDC (a.s.)/kg bw/day = 14.9 mg SDDC (41.44% solution as supplied)/kg bw/day, based on decrease in body weight gain, albumin and histopathology in spleen and liver.

Dose descriptor:

NOAEL

Effect level:

ca. 50 ppm

Sex:

male/female

Basis for effect level:

other: = 1.6 mg ziram/kg bw/day = 1.5 mg SDDC (a.s.)/kg bw/day = 3.6 mg SDDC (41.44%)/kg bw/day

Critical effects observed:

not specified

Table A6_5-1.         Results of chronic toxicity study
Parameter	Control		50 ppm		185 ppm		500 ppm		Dose-response +/–
	♂	♀	♂	♀	♂	♀	♂	♀	♂	♀
Mortality								1	–	–
Body weight gain						↓ 68%		↓ 81%	–	+
Clinical chemistry
Albumin				↓ 12%		↓ 16%	↓ 13%	↓ 16%	–	–
Cholesterol							↑ 51%		–	–
T3							↑ 33%		–	–
Organ weight							2/4
Liver							↑ 16%		+	–
Histopathology of liver
Foci degenerated hepatocytes	1/4	3/4	2/4	0/4	2/4	3/4	3/4	2/3	+	–
Aggregates of pigmented Kuppfer cells	0/4	0/4	1/4	1/4	2/4	3/4	3/4	2/3	+	–
Histopathology of spleen
Increased pigmented macrophages	1/4	2/4	1/4	2/4	3/4	2/4	3/4	3/3	–	–
↓ ↑: statistical significance

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

3.6 mg/kg bw/day

Study duration:

chronic

Species:

dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

1989

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 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

Data about the area covered by the test material and occlusion are not reported.

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England
- Age at study initiation: 10-12 weeks on arrival
- Weight at study initiation: fehlt noch

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day
- For solids, paste formed: Yes. Powder was moistened with water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

purity of ziram was analysed

Duration of treatment / exposure:

21 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5

Control animals:

yes

Positive control:

no

Observations and examinations performed and frequency:

CLINICAL SIGNS
- Time schedule: once daily

MORTALITY
- Time schedule: once daily

DERMAL IRRITATION
- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .

BODY WEIGHT
- Time schedule for examinations: Prior to dosing and then once weekly.

FOOD CONSUMPTION
- Time schedule for examinations: Once weekly.

HAEMATOLOGY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotest

CLINICAL CHEMISTRY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio

Sacrifice and pathology:

ORGAN WEIGHTS
From all animals sacrificed at termination.
- Organs: adrenals, liver, kidneys, testes with epididymides/ovaries

GROSS AND HISTOPATHOLOGY
All animals were sacrificed at study termination and a gross pathological examination was performed.
- Histopathology: from all animals of the control and highest dose group
- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver

Statistics:

All analyses were carried out separately for male and female.
The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.

Clinical signs:

no effects observed

Dermal irritation:

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:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN
Bodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day.

FOOD CONSUMPTION
Reduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.

HAEMATOLOGY
Significant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.

CLINICAL CHEMISTRY
Liver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.
Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.

GROSS PATHOLOGY
Increased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.

Dose descriptor:

LOAEL

Effect level:

300 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 281.1 mg SDDC (a.s.)/kg bw/day = 677.5 mg SDDC (41.44% solution as supplied)/kg bw/day, based on significantly increased GOT-levels for females

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 93.7 mg SDDC (a.s.)/kg bw/day = 225.8 mg SDDC (41.44%)/kg bw/day

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

226 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

One subchronic gavage study on rats has been performed with SDDC. The study has identified the bone marrow as target organ for SDDC with subsequent effects on spleen, kidneys and liver. In addition, less specific effects like hypertrophy or hyperplasia of stomach, urinary bladder, duodenum and thyroids were noted.

Repeated dose studies with ziram have been conducted in dogs, rabbits and rats.

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 attached in IUCLID section 13.

In rats ziram decreased body weight gain, food intake and food efficiency. Dogs presented a subdued behaviour and/or unsteady gait, with slight alterations in body weight and food efficiency, increase in liver weight, they vomited and had diarrhoea. In the rat, T4 serum level after four weeks showed a dose related reduction, T3 and TSH were not significantly affected. Moreover, minor, but consistent, changes in biochemical parameters were observed (total protein, albumin, Ca²⁺, RBC, urea nitrogen, creatinine and MCHC). In the rat, the target organs were liver and kidneys, as shown by the presence of degenerative alterations. Dogs showed an increased liver weight.

In the subchronic experiment (90 day study), the non-glandular stomach was the target organ with minimal epithelial hyperplasia in rats. No effects indicative of neurotoxicity were apparent when FOB tests were performed in the rat. In dogs, the target organs were liver and spleen, with at the start increased pigmentation of Kupffer cells and/or macrophages with Perls’ positive material, possibly reflecting increased iron metabolism and turnover. A slight lowering of red cell indices, acute inflammatory cell infiltration in the lungs, decreases in heart weight, likely related to convulsions were also observed.

In a 21-day percutaneous test, ziram affected the liver in rabbits. This effect occurred at 300 mg/kg bw/d. No dermal reactions were observed.

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. The studies are not strictly comparable because SDDC was dosed by gavage whereas ziram was administered via food.

Comparison of SDDC and Ziram

The principal effects caused by both substances are identical. Haemolysis indicated by a decrease in red blood cells and haemoglobin and by an increase in the mean corpuscular volume and mean corpuscular haemoglobin concentration is accompanied by subsequent effects on spleen, kidneys and liver. Among these effects are increased pigmentation of Kupffer cells, haemosiderosis and extramedullary haematopoiesis.

The quantitative difference between the LOAELs/NOAELs found in the studies might arise from a difference in bioavailability associated with the different application techniques. Bioavailability from the food matrix used in the ziram studies might be lower or delayed compared to SDDC which was applied undiluted.

The subchronic NOAEL for SDDC is 24.4 mg/kg bw/day based on the gavage study with SDDC. From the 13-week feeding study with ziram, a NOAEL for SDDC of less than 16.7 mg/kg bw/day for rats and 9.2 mg/kg bw/day for dogs is estimated.

Both chronic studies in dogs and rats (please refer to IUCLID section 7.7) provide NOAELs equivalent to 3.6 mg/kg bw/day and less than 5.7 mg SDDC/kg bw/day, respectively.

In the 21 -day toxicity study with ziram using the dermal route of administration in rabbits the only finding at 678 mg/kg bw/day was increase GOT level in females. The subacute dermal NOAEL for ziram is equivalent to 226 mg/kg bw/day for SDDC.

Classification for repeated-dose toxicity: none based on the subchronic toxicity study with SDDC in its manufactured form.

Derivation of relevant NOAEL: 

Long-term studies have not been conducted with SDDC, but with the closely related substances, ziram and thiram.

The dog appears to be the most sensitive species for ziram toxicity. A one-year study with ziram (Smith et al., 1993) revealed effects on body and prostate weight as well as histopathological findings in liver and spleen. The long-term LOAEL and NOAEL are equivalent to 14.9 and 3.6 mg technical a.s./kg bw/day, respectively.

Likewise, the most sensitive short-term NOAEL was also found in a dog study. The critical effects in a 90-day feeding study in dogs with ziram (Mc Lean et al., 1992) were focal necrosis and Kupffer cell pigmentation in the liver. The short-term LOAEL and NOAEL are equivalent to 27.5 and 9.2 mg technical a.s./kg bw/day, respectively.

Thiram

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.

Range-finding studies for dietary administration were performed for short periods of exposure in mice and in dogs for 28 days. The studies were used to set dose levels for the subsequent 90-day studies.

Rats and dogs received thiram in their diet either for a 90-day period or for 52 weeks. In both species, oral administration of thiram produced changes in the liver, increase in liver weight, blood cholesterol and decrease of plasma proteins, decreases in food consumption and body weight gain, local irritation to the non-glandular stomach, and macrocytic anaemia. The NOEL and NOAEL are lower for the dog than for the rat. The lowest NOAEL is 0.84 mg/kg bw/day (1 year dog study).

The chronic NOAEL based on a combined chronic/carcinogenicity study in rats (for study records see 7.7). Taking in account the results of the first year and the interim sacrifices, mainly changes in bodyweight, food/water consumption and haematology, the NOAEL was set at 1.5 mg/kg bw/d.

In rabbits, signs of systemic toxicity (liver effects) after dermal exposure to 1000 mg/kg bw/d thiram for 21 days were seen. Thus, the NOAEL for systemic toxicity is established at 300 mg/kg bw/d. Local skin reactions such as erythema with or without oedema and acanthosis were seen at all dose levels. The NOEL local was set lower than 100 mg/kg bw/d.

In one rat test, published in the open literature, a slight dysfunction of the testes following thiram, 25 mg/kg bw/d over 90 days, is suggested.

These effects on liver and liver enzyme parameters were shown to be completely reversible with full recovery observable, which was agreed upon in the evaluation by the RMS Belgium. In light of the reversibility of effects on liver and liver enzymes, in the absence of other severe systemic effects and in view of the occurrence of effects in an individual animal only (see thiram one-year study), a classification with R48/22 is not considered to be appropriate. Effects mediated by local contact at the site of first contact will be mitigated by consideration of suitable protective equipment and are not within the scope of the R48. Such effects are rather addressed by R phrases applicable for local effects (i.e. R34/35-R38/37/38).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest exposure duration (52 weeks) and the lowest NOAEL was chosen.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No study required since exposure of humans via inhalation is unlikely taking into account the physico-chemical properties of the substances and the lack of exposure to aerosols, particles or droplets of inhalable size under normal conditions of use.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
No study required since exposure of humans via inhalation is unlikely taking into account the physico-chemical properties of the substances and the lack of exposure to aerosols, particles or droplets of inhalable size under normal conditions of use.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The study with the relevant source substance was chosen.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The target substance is not classified for eye and skin irritating properties. The source substance, Ziram, did not induce local effects in the 21 day dermal toxicity study. Therefore no study is required.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

Based on the subchronic toxicity study performed with the relevant substance, technical SDDC, no classification for repeated dose toxicity is needed.