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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study, tested with the source substance sodium dimethyldithiocarbamate (CAS No. 128-04-1). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on an read-across substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Sodium dimethyldithiocarbamate
EC Number:
204-876-7
EC Name:
Sodium dimethyldithiocarbamate
Cas Number:
128-04-1
IUPAC Name:
sodium dimethyldithiocarbamate
Details on test material:
- Name of test material (as cited in study report): SDDC
- Purity: 41.44%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, Margate, Kent, UK
- Age at study initiation: 5-8 weeks (at start of treatment)
- Weight at study initiation: 164-217 g (♂) and 143-193 g (♀)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
24.4, 122, 610 mg testmaterial/kg/day (incorporating a correction factor for 41% purity; equivalent to 10, 50, 250 mg active ingredients/kg/day)
Basis:
other: nominal in vehicle
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Dose volume: 5 mL/kg bw
Positive control:
No

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Immediately before dosing and one and five hours after dosing (working week). Immediately before dosing and one hour after dosing at weekends and public holidays.

BODY WEIGHT: Yes
- On Day 0 and then once weekly. Also recorded at terminal kill.

FOOD AND WATER CONSUMPTION: Yes
- Once weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- For control and high-dose animals at pre-test and during week 12.

HAEMATOLOGY: Yes
- On Day 90. Where necessary repeated on Day 91.
- Parameters: erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, reticulocyte count, total leucocyte count, differential leukocyte count, thromboplastin time (= prothrombin time), activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- On Day 90. Where necessary repeated on Day 91.
- Parameters: glucose, urea, creatinine, total bilirubin, total cholesterol, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio, cholinesterase

NEUROBEHAVIOURAL EXAMINATION: Yes
- Behavioural assessments prior to start of treatment, then once weekly.
Parameters: gait, tremors, twitches, convulsions, bizarre/abnormal/stereotypic behaviour, salivation, pilo-erection, exophthalmia, lachrymation, hyper/hypothermia, skin colour, respiration, palpebral closure, urination, defaecation, transfer arousal, tail elevation

- Functional performance tests
Forelimb/hindlimb grip strength and motor activity were assessed during week 12.

- Sensory Reactivity during week 12.
Parameters: grasp response, vocalisation, toe pinch, tail pinch, finger approach, touch escape, pupil reflex, startle reflex (using ST1058 startle test meter from Benwick Electronics), blink reflex
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organs: brain, heart, liver, spleen, thymus, kidneys, adrenals, uterus, testes, epididymides, ovaries

HISTOPATHOLOGY: Yes
- all dose groups
- The following tissues were removed from all animals and preserved in buffered 10% formalin:
adrenals, aorta (thoracic), bone & bone marrow (sternum, femur including stifle joint), brain (cerebrum, cerebellum, pons), caecum, colon, duodenum, epididymides, eyes (fixed in Davidson's fluid), gross lesions, heart, ileum with Peyer’s patches, jejunum, kidneys, liver, lungs with bronchi (inflated with formalin before immersion in fixative), lymph nodes (cervical, mesenteric), mammary glands, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (submaxillary), sciatic nerve, seminal vesicles, skeletal muscle, skin (hind limb), spinal cord (cervical, mid-thoracic, lumbar), spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder, uterus
Statistics:
Data were processed to give group mean values and standard deviations where appropriate.
- Haematological; blood chemical, organ weight (absolute and relatie to terminal bodyweight), weekly bodyweight gain and quantitative functional performanceand sensory reactivity data were assessed for control and test material treatment groups for dose response relationships by linear regression analysis followed one way analysis variance (ANOVA) incorporating Levene’s test for homogeneity of variance.
- Where variances were shown to be homogenous pairwise comparisons were conducted using Dunnett’s test.
- Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test.
- For histopathological data chi squared analysis was used for differences in the incidence of lesions occurring with an overall frequency of 1 or greater and Kruskal-Wallis one way non-parametric analysis of variance for the comparison of severity grades for the more frequently observed graded conditions.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
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
Increased salivation of short duration were detected in either sex treated with 250 mg/kg/day together with associated findings of soiled body fur, accompanied in females from Day 28 by infrequent episodes of hunched posture and tiptoe gait. Instances of transient increased salivation were also seen in either sex treated with 50 mg/kg/day.
Excessive visible salivation and findings associated with abdominal discomfort are commonly reported following the oral administration of a test material and are considered to be attributable to the repeated administration of an unpalatable or locally irritant test material formulation by gavage rather than an indication of systemic toxicity.
No death.

BODY WEIGHT AND WEIGHT GAIN
No treatment-related adverse effects on bodyweight development.

FOOD & WATER CONSUMPTION
Reduced food consumption in the high-dose group of either sex was clearly related to the reduced bodyweight. Food efficiency (bodyweight/dietary uptake) was also reduced, indicating impaired food utilisation.
Daily visual inspection of water bottles revealed no overt intergroup differences.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related ocular effects.

HAEMATOLOGY
A clear haemolytic effect was identified for animals of both sexes treated with 50 and 250 mg/kg/day accompanied by an increase in mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). Males also showed a slight increase in mean corpuscular haemoglobin concentration (MCHC) at 250 mg/kg/day.

CLINICAL CHEMISTRY
Increases in plasma levels of total protein, sodium and cholesterol were found in males treated with 250 mg/kg/day.
Females treated with 250 mg/kg/day or animals of either sex treated with lower doses revealed no intergroup differences.

NEUROBEHAVIOUR
- Behavioural assessments
Detailed open-field observations from the fourth week of treatment confirmed the clinical signs of hunched posture and tiptoe gait detected in 250 mg/kg/day females. No treatment-related effects were detected at 50 or 10 mg/kg/day.
- Functional performance tests
Changes in total activity in male rats treated with 50 and 250 mg/kg/day were considered to be an indirect effect of abdominal discomfort associated with the irritancy of the test material formulation.
- Sensory reactivity assessments
Changes were considered to be associated with abdominal discomfort resulting from the irritancy of the test material formulation.

ORGAN WEIGHTS
Increases in kidney, liver and spleen weight when expressed relative to body weight were evident in both sexes treated with 250 mg/kg/day. Females also showed an increase in absolute spleen weight.

GROSS PATHOLOGY
Treatment-related gastric changes were detected in the majority of male animals treated with 250 mg/kg/day.

HISTOPATHOLOGY
- Spleen: Increased extramedullary haemopoiesis: ♂ at all doses/ ♀ at 250 mg/kg/day
Increased haemosiderin deposition in female dosed at 50 mg/kg/day
- Kidneys: Increased haemosiderin deposition: ♂ at 50 and 250 mg/kg/day / ♀ at 250 mg/kg/day
- Urinary Bladder: Indications for hyperplasia of the transitional epithelium in males at 250 mg/kg/day
- Thyroids: Increased follicular cell hypertrophy and associated colloid depletion in males at 250 mg/kg/day
- Stomach: Acanthosis and hyperkeratosis of forestomach epithelium: ♂ at 50 and 250 mg/kg/day / ♀ at 250 mg/kg/day
- Duodenum: Mucosal hypertrophy at 250 mg/kg/day in males was considered to be treatment-related
- Salivary Glands: Atrophy of the serous acini of the submaxillary salivary glands: ♂ / ♀ at 250 mg/kg/day
- Bone marrow: Indirect indication of bone marrow hyperplasia in females at 250 mg/kg/day and 50 mg/kg/day

All findings not described above were considered to be within the range of background lesions which may be recorded in rats of this strain and age.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
122 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: = 112 mg KDDC (50% solution as supplied)/kg bw/day, based on impaired functional performance, haemolysis, haemosiderosis in spleen and kidney
Dose descriptor:
NOAEL
Effect level:
24.4 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: = 22.5 mg KDDC (50% solution as supplied)/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 7.5.1 -A1 Results of haematology and blood chemistry (after 90 days)

 

Parameter

Control

10 mg/kg

50 mg/kg

250 mg/kg

Dose-response

+/–

Number of animals examined

10

10

10

10

10

10

10

10

Haematology

RBC count

+

+

MHC

+

+

MCV

+

+

MCHC

+

Blood chemistry

Total protein

+

Na+

+

Cholesterol

+

↑, ↓: statistically significant increase and decrease, respectively
– : no significant difference from control values

 

Table 7.5.1 -A2 Results of repeated dose toxicity study (after 90 days)

 

Parameter

Control

10 mg/kg

50 mg/kg

250 mg/kg

Dose-response

+/–

Number of animals examined

10

10

10

10

10

10

10

10

Organ weights

Kidney, rel.

+

+

Liver, rel.

+

+

Spleen, rel.

+

+

Spleen, abs.

+

Gross necropsy

Stomach – non glandular region thickened

0

0

0

0

0

0

7

3

+

+

Stomach – non glandular region sloughing

0

0

0

0

0

0

6

2

+

+

Histopathology

Spleen,
extramedullary haemopoiesis, slight a

1

0

6

0

6

3

9

8

+

+

Spleen,
haemosiderin deposition

moderate

2

6

4

7

7

9

9

1

+

+

marked

0

0

0

0

0

1

1

8

Kidneys,
haemosiderin deposition

minimal

0

7

2

9

5

6

4

3

+

slight

0

0

0

0

0

3

0

5

Urinary Bladder,
hyperplasia, minimal (
)/ slight ()

0

0

0

0

0

0

4

2

+

+

Thyroids,
follicular cell hypertrophy, moderate (
)/ slight ()

1

1

0

0

1

1

4

2

+

Stomach,
Acanthosis, slight

0

0

0

0

0

0

7

7

+

+

Stomach,
Hyperkeratosis, slight

0

0

0

0

0

0

6

5

+

+

Duodenum,
mucosal hypertrophy, minimal

0

0

1

0

2

0

4

1

+

Salivary Glands,
atrophy serous acini, present

0

0

0

0

0

1

7

7

+

+

Bone marrow,
adipose infiltration, slight

1

7

0

4

0

2

1

1

+

a  number of animals affected

Applicant's summary and conclusion