Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8 May to 22 May 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An acceptable, well-documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report date:
1980

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Acute oral LD50 determined in male rats.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Zinc bis[O-(6-methylheptyl)] bis[O-(sec-butyl)] bis(dithiophosphate)
EC Number:
298-577-9
EC Name:
Zinc bis[O-(6-methylheptyl)] bis[O-(sec-butyl)] bis(dithiophosphate)
Cas Number:
93819-94-4
Molecular formula:
C16H36O4P2S4Zn-C32H68O4P2S4Zn neutral salt; C48H108O13P6S12Zn4- C96H204O13P6S12Zn4 basic salt
IUPAC Name:
zinc bis[O-(6-methylheptyl)] bis[O-(sec-butyl)] bis(dithiophosphate)
Details on test material:
- Name of test material (as cited in study report): MRD-80-22
- Substance type: technical product
- Physical state: dark amber liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Sprague-Dawley CD
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts 01887
- Age at study initiation: "young adults"
- Weight at study initiation: 263-326 g
- Fasting period before study: overnight for approx. 18.5 h
- Housing: group-housed (6/cage) during acclimation period, individually-housed during study
- Diet: ad libitum, Purina Laboratory Rodent Diet
- Water: ad libitum
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): no data but monitored daily
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5.97 ml/kg bw

DOSAGE PREPARATION (if unusual): administered as received, no mixture required
Doses:
0.681, 1.00, 1.47, 2.15, 3.16, 4.64 and 6.81 g/kg bw
No. of animals per sex per dose:
5 males/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: viability checked twice daily; observations of pharmacological and toxicological signs checked approx. 1, 2 and 4 h after dosing and daily thereafter for 14 days; pre-fasted, post-fasted, day 7, day 14 and, for animals not surviving the 14-day observation period, terminal body weights recorded
- Necropsy of survivors performed: yes
- Other examinations performed: gross post mortem examination performed on all animals which died or were found dead during the study and on all animals surviving at termination of the observation period
Statistics:
LD50 calculated according to Miller L.C. and Tainter M.L. (1944). Estimation of the ED50 and its error by means of logarithmic-probit graph paper. Proc. Soc. Exp. Bio. Med. 57, 261-264.

Results and discussion

Preliminary study:
None
Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
2 600 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Confidence limits could not be calculated because of the distribution of mortality
Mortality:
All animals in the 4.64 and 6.81 g/kg bw groups died within 3 days of dosing and animals in the 3.16 g/kg bw dose group died within 7 days after dosing. No deaths were seen within the 14-day observation period amongst animals treated with 2.15 g/kg bw or below. See Table 1 under "any other information on results" below.
Clinical signs:
Signs seen on the day of dosing in some animals in all or most groups included excessive salivation, soft stool and faecal staining of the ano-genital area. Some animals also exhibited rales and/or motor activity decrease. Additional signs noted subsequently, primarily in animals which died spontaneously, included respiratory rate decrease, red nasal discharge, general poor condition, urinary staining, ataxia, hypothermia, decreased food consumption, prostration and, in single animals, tremors and cyanosis. Survivors in the 0.681 and 1.00 g/kg bw groups recovered from any clinical signs within 24 h after dosing, while those dosed with 1.47 and 2.15 g/kg bw recovered within 3 and 6 days, respectively. See Table 2 under "any other information on results below".
Body weight:
All animals surviving the 14-day observation period exhibited moderate body weight gains. Those dying prior to termination of the study showed body weight losses. See Table 3 under "any other information on results" below.
Gross pathology:
Gross necropsy at all dose levels revealed effects on the lungs (mottled pale or dark red, scattered dark red foci, red patch), spleen (slightly roughened), and adrenals (pale or mottled red). In addition, the cardiac region of the stomach was found to contain thin yellow fluid in one animal at each of the 1.0 and 2.15 g/kg bw dose levels and the testes were purple and slightly diminished in one animal and the kidneys were mottled pale in another animal at 2.15 g/kg bw. At 3.16 g/kg bw, pronounced vascularization in the brain, stomach and intestines (which also contained viscous pale, thick yellow (intestines), thick green-yellow or green-white (stomach) fluid), distended stomach, extremely diminished, pale and smooth spleen, dark red adrenals, empty urinary bladder and diminished or undescended testes were also noted. At 4.64 g/kg bw, the liver was also seen to be darkened in colour and the kidneys pale and, at the top dose, the liver was also mottled pale, the cardiac region of the stomach distended and the spleen dark and irregular.
Other findings:
No data

Any other information on results incl. tables

Table 1 - Mortality

 

Dose level (g/kg bw)

Overall mortality

Days of mortality

0.681

0/5

 -

1.00

0/5

 -

1.47

0/5

 -

2.15

0/5

 -

3.16

5/5

Days 2, 2, 3, 3 and 7, respectively

4.64

5/5

Days 2, 2, 2, 2 and 3, respectively

6.81

5/5

Days 2, 2, 2, 3 and 3, respectively

 

Table 2 - Clinical signs

 

Dose level (g/kg bw)

Clinical effects seen

0.681

Red oral discharge in 1 rat after 1 h, clear oral discharge in 2 and 1 rats after 1 and 2 h, respectively, faecal staining in 1 rat after 2 h, soft stool in 2 rats after 2 h

1.00

Clear oral discharge in 2 rats after 1 h, faecal staining in 1 and 3 rats after 2 and 4 h respectively, soft stool in 2 rats after 2 and 4 h, motor activity decrease in 1 rat after 2 h

1.47

Clear oral discharge in 3 rats after 1 h, faecal staining in 1, 2, 2 and 1 rats after 2, 4 and 24 h and 2 days respectively, soft stool in 1, 1 and 2 rats after 2, 4 and 24 h respectively, motor activity decrease in 2 rat after 2 and 24 h respectively, unthrifty in 1 rat after 24 h

2.15

Clear oral discharge in 2 rats after 1 h, red oral discharge in 2 rats after 3 days, clear oral discharge in 2 rats after 1 h, respiratory rate decrease in 2 rats after 24 h, red urinary staining in 1 rat after 2 and 3 days, faecal staining in 2, 4, 2, 4, 4, 2 and 1 rats after 1, 2, 4 and 24 h and 2, 3 and 5-7 days respectively, soft stool in 2, 4, 4, 2 and 2 rats after 1, 2 and 24 hrs and 2 and 3 days respectively, motor activity decrease in 5 rats after 24 h and 2 days, decreased food consumption and unthrifty in 2 rats after 4 days

3.16

Ataxia, red ocular discharge and prostration in 1 rat after 2 days, coarse tremors, red oral discharge and emaciation in 1 rat after 5-7 days, red nasal discharge in 1 rat after 3, 4 and 5-7 days, respiratory rate decrease in 3, 2 and 1 rats after 24 h and 2 and 5-7 days respectively, rales in 2, 1 and 1 rats after 1, 2 and 24 h, urinary staining in 1 rat after 4 and 5-7 days, faecal staining in 1, 2, 4, 4, 3, 1, 1, and 1 rats after 1, 2, 4 and 24 h and 2, 3, 4 and 5-7 days, general poor condition in 1 rat after 2, 4 and 5-7 days, soft stool in 1, 2, 2, 4, 2, 1, 1 and 1 rats after 1, 2, 4 and 24 h and 2, 3, and 5-7 days, piloerection in 1 rat after 24 h and 5-7 days, motor activity decrease in 2, 2, 1, 5, 1, 1 and 1 rats after 1, 2, 4 and 24 h and 2, 4 and 5-7 days respectively, decreased food consumption in 1 rat after 4 days, unthrifty in 1 rat after 3 and 4 days

4.64

Ataxia and red ocular discharge in 1 rat after 2 days, fine tremors in 1 rat after 24 hrs, clear oral discharge in 1 rat after 1 hr, respiratory rate decrease in 2 and 1 rats after 24 hrs and 2 days respectively, faecal staining in 2, 3, 5, 4 and 1 rats after 1, 2, 4 and 24 hrs and 2 days respectively, soft stool in 2, 4, 4 and 4 rats after 1, 2, 4 and 24 hrs respectively, motor activity decrease in 5 and 1 rats after 24 hrs and 2 days respectively

6.81

Ataxia and hypothermia in 1 rat and respiratory decrease in 3 and 2 rats, after 24 h and 2 days respectively, coarse tremors in 1 rat after 24 h, clear oral discharge in 2 rats after 1 h, faecal staining in 3, 3, 4, 3 and 2 rats and soft stool in 4, 4, 4, 3 and 2 rats after 1, 2, 4 and 24 h and 2 days respectively, cyanosis and prostration in 1 rat after 2 days, motor activity decrease in 1, 4 and 2 rats after 4 and 24 h and 2 days respectively

 

 Table 3 - Body weight change

 

Dose level (g/kg bw)

Pre-fast weight (g)

Post-fast weight (g)

Change from pre-fast weight (g)

Interim death

Survivors

 

terminal weight

Weight at day 7

Weight at day 14

0.681

274-316

252-287

 

+28 - +43

+53 - +80

1.00

263-325

238-293

 

+19 - +53

+48 - +117

1.47

290-311

267-283

 

+23 - +55

+75 - +104

2.15

281-326

254-292

 

+6 - +32

+65-+111

3.16

290-312

264-283

-54 - -107

 

 

4.64

280-322

262-296

-47 - -57

 

 

6.81

288-317

260-285

-46 - -64

 

 

 

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In a well reported, well-conducted, unpublished study, the oral LD50 of MRD-80-22 to the male rat was estimated to be 2.6 g/kg bw.
Executive summary:

In a well reported, well-conducted, unpublished study, groups of 5 male Sprague-Dawley CD rats were given a single oral intubation of MRD-80-22 at doses of 0.681, 1.00, 1.47, 2.15, 3.16, 4.64 or 6.81 g/kg bw. Mortality, clinical signs and body weights were monitored for a 14-day period, and gross necropsy was performed on all animals.

No deaths occurred at doses of up to 2.15 g/kg bw, but all of the animals at the higher doses died within 7, 3 and 3 days, respectively. The LD50, calculated according to Miller and Tainter (1944), was 2.6 g/kg bw.

Therefore, according to EU CLP Regulations and the Dangerous Substances Directive, this test material would not be classified for acute oral toxicity, under the conditions of this test.