Potassium dimethyldithiocarbamate

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: acute 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, tested with the source substance zinc(bis) dimethyldithiocarbamate (CAS No. 137-30-4). 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:

1994

Report date:

1994

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 418 (Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure)

Deviations:

yes

Remarks:

This study protocol is not fully in compliance with OECD guideline 418 (1995): • Rats instead of hens • 14 days observation and not 21 • No biochemical measurements • Tests were performed only once a week and not twice Histo

Test guideline 2

Deviations:

yes

Remarks:

• Histopathology was performed on solely 5 rats/sex from control group and maximal dose • No positive control

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ziram

EC Number:

205-288-3

EC Name:

Ziram

Cas Number:

137-30-4

IUPAC Name:

zinc bis(dimethyldithiocarbamate)

Constituent 2

Reference substance name:

zinc bis dimethyldithiocarbamate

IUPAC Name:

zinc bis dimethyldithiocarbamate

Details on test material:

Test material: Ziram
Lot/Batch number: V528/8331AA
Description: White powder
Purity: 97.8%
Stability: The stability of the test substance and test substance preparations in vehicle were confirmed by analysis.

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 Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 43 days
- Weight at study initiation: 189 - 253 g (males), 138 - 190 g (females)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Single oral dose

Frequency of treatment:

n.a.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 15, 300 and 600 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

12 per sex for 0, 15, 300 mg/kg bw
16 per sex for 600 mg/kg bw

Control animals:

yes, concurrent vehicle

Details on study design:

Concentration in vehicle: Not reported.
Total volume applied: 7.5 ml/kg bw
Postexposure period: 14 days

Examinations

Observations and clinical examinations performed and frequency:

MORTALITY
- Twice daily.

CLINICAL SIGNS
- Daily except on days were FOB was conducted.

BODY WEIGHT
- Pre-study and on days 7 and 14.

Specific biochemical examinations:

No anticholinergic substances used

Neurobehavioural examinations performed and frequency:

FUNCTIONAL OBSERVATIONAL BATTERY (FOB) & LOCOMOTOR ACTIVITY
- Pre-study, 4 h after treatment and on days 7 and 14.

Sacrifice and (histo)pathology:

Pathology
- All animals
- All central and peripheral tissues were preserved. Brain weight and dimensions were recorded as well as all gross abnormalities or changes in coloration.

HISTOPATHOLOGY
- Yes, on five animals per sex from control and high-dosage group.
- Nerve tissues: brain, spinal cord, gasserian ganglion/trigeminal nerves, lumbar dorsal/ventral root fibers and dorsal root ganglion at T13 – L4, cervical dorsal/ventral root fibers and dorsal root ganglion at C3 – C8, eyes with optic nerves, sciatic nerves, sural nerves, tibial nerves, peroneal nerves, forelimbs, tail

Other examinations:

no

Positive control:

none

Results and discussion

Results of examinations

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):

effects observed, treatment-related

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Clinical biochemistry findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

no effects observed

Details on results:

MORTALITY
- Four males (= 25%) and seven females (= 44%) died following dose administration with 600 mg test material. In the 300 mg/kg bw group one female (= 8%) died.

CLINICAL SIGNS
- Signs observed in the 300 and 600 mg/kg bw groups included gait alterations, abnormal respiration and excreta and a distended abdomen during the first days after exposure.
- Other treatment-related signs in the 300 and 600 mg/kg bw groups consisted of staining/material on various body surfaces during the first week.
- Additional observations on two males in the mid-dose group included cyanosis, hypothermia, enophthalmus, unkempt appearance hypoactivity and ptosis.

BODY WEIGHT
- Transient significant reductions were apparent in the 300 and 600 mg/kg bw group during week 1. For animals receiving 300 mg/kg bw this effect persisted up to termination.

FOB & LOCOMOTOR ACTIVITY
- Administration of 300 and 600 mg test material/kg bw produced alterations in posture, palpebral closure and feces consistency. Out of these only the alterations in posture persisted up to termination.
- Further on animals receiving 300 and 600 mg/kg bw showed lacrimation, salivation, changes in fur appearance, changes in respiratory rate and/or character, red deposits around mouth and crusty deposits around mouth and nose on the day of administration. Additionally at 600 mg/kg bw decreased muscle tone was noticed. The only findings observed on days 7 and 14 were limited to the already mentioned two males in the mid-dose group.
- Moreover ziram induced at a level of 300 and 600 mg/kg bw impaired mobility and altered gait at day 0, which persisted partly in two males receiving 300 mg/kg bw up to termination.
- Sensory observations revealed test article related effects at 300 and 600 mg/kg bw including absent tail pinch and olfactory responses as well as an absent or only slight startle response. In addition absent forelimb and/or hindlimb extensions in females were attributed to the treatment.
- For neuromuscular parameters no treatment-related effects were observed.
- Physiological observations showed a decrease in body temperature at 300 and 600 mg/kg bw at day 0 and 7. On day 14 the decrease was limited on the already mentioned males receiving 300 mg/kg bw.
- Finally treatment with ziram caused decreases in mean ambulatory and total motor activity counts in animals receiving 300 and 600 mg/kg bw with full recovery until day 14.

PATHOLOGY
Unscheduled sacrifice:
- White contents in the stomach and/or intestine were observed at 300 and 600 mg/kg bw as well as distention of the stomach and/or intestine. Two females of the 600 mg/kg bw group were emaciated (no abdominal adipose tissue was present).

Scheduled sacrifice:
No treatment-related effects on brain weight or dimensions were noticed.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

ca. 300 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 312.6 mg KDDC (a.s.)/kg bw = 625.2 mg KDDC (50% solution as supplied)/kg bw, based on reduction of brain and body weight and body temperature, impairment of walk, tiptoe gait and mobility

Remarks on result:

other:

2

Dose descriptor:

NOAEL

Effect level:

ca. 15 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: = 15.6 mg KDDC (a.s.)/kg bw = 31.2 mg KDDC (50%)/kg bw

Remarks on result:

other:

Any other information on results incl. tables

Table 7.9.1-A1         Acute neurotoxic effects
Parameter / Dose	0 mg/kg		15 mg/kg		300 mg/kg		600 mg/kg		Dose-response +/–
	♂	♀	♂	♀	♂	♀	♂	♀	♂	♀
Clinical signs					Yes	Yes	Yes	Yes	–	–
Body weight					↓		↓		–	–
Changes in FOB					Yes	Yes	Yes	Yes	–	–