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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22/05/1996 - 09/12/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study: Some dose levels were repeated using a different treatment volume to investigate the influence of treatment volume on acute toxicity. The deviation does not affect the validity or integrity of the study results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Version / remarks:
(1982)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 59 NohSan No. 4200 (1985)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
powder

Test animals

Species:
rat
Strain:
other: Crl:CD[SD]BR (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Age at study initiation:
- Range finding study: 8 to 15 weeks old
- Definitive study phase I: 8 to 14 weeks old
- Definitive study phase II: 9 to 14 weeks old

Weight at study initiation:
- Range finding study: 273 to 292 g
- Definitive study phase I: 233 to 299 g
- Definitive study phase II: 239 to 299 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration of vehicle: 0.5 % CMC in distilled water
- Amount of vehicle (if gavage): 20 mL/kg for the range finding study and phase II of the definitive study; 10 mL/kg for phase I of the main study
- Justification for choice of vehicle: no data
Doses:
Range finding study: 500, 1000, 3000, 5000 mg/kg bw
Definitive study phase I: 1000, 3000 mg/kg bw (females only); 5000 mg/kg bw (males and females)
Definitive study phase II: 1000, 2000, 3000 mg/kg bw (males and females); 4000 mg/kg bw (females only); 5000 mg/kg bw (males only)
No. of animals per sex per dose:
Range finding study: 1 rat per sex per dose
Definitive study phase I: 5 rats per sex per dose for highest dose level; 5 female rates per dose for lower dose levels
Definitive study phase II: 5 rats per sex per dose for dose levels 1000 to 3000 mg/kg bw; 5 females per 4000 mg/kg bw dose level; 5 males per 5000 mg/kg bw dose level

Control animals:
no
Details on study design:
- Duration of test/exposure period: 14 days
- Rational for dose level selection: The definitive study dose levels were selected based on the results from the range finding study
- Post exposure observation period: 14 days
Statistics:
The LD50 and 95 % confidence limits for the individual sexes and the sexes combined were determined by a modified Behrens-Reed-Muench cumulant method.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
2 804 mg/kg bw
Based on:
test mat.
95% CL:
> 1 947 - < 4 037
Sex:
female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
95% CL:
> 1 354 - < 2 954
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 450 mg/kg bw
Based on:
test mat.
95% CL:
> 1 942 - < 3 090
Remarks on result:
other: male and female combined
Mortality:
- In the range-finding study, the females treated at 3000 or 5000mg/kg died on day 1. All other animals survived the observation period.
- In phase I of the main study, there were no deaths at any dose level administered at a treatment volume of 10mL/kg. The LD50 for dinotefuran administered at 10mL/kg was > 5000mg/kg.
- In phase II of the main study, deaths occurred in females treated at ≥2000mg/kg and in males treated at ≥3000mg/kg. All deaths in phase II occurred on the day of dosing or on the day following dosing (Table 1).
Clinical signs:
- In phase I of the main study, two females at 5000mg/kg showed transient staggering gait on the day of treatment only and red staining of the face persisting for up to 3 days. One female treated at 3000mg/kg also showed transient staggering gait on the day of treatment. A male at 5000mg/kg showed transient excessive salivation and a female at 1000mg/kg showed red staining of the face. All other animals were of normal appearance and behavior.
- In phase II of the main study, Treatment-related clinical signs were apparent at dose levels of ≥2000mg/kg and included hypoactivity, staggering gait, hunched posture, prostration, red-stained face, miosis, lacrimation, salivation, tachypnea, dyspnea, soft feces, yellow staining of the uro-genital area, tonic or clonic convulsions and tremors. Clinical signs were generally transient but occasionally persisted for up to 3 days after treatment.
Body weight:
- All survivors except one female at 5000mg/kg in phase I showed body weight gain during the observation period.
Gross pathology:
- Necropsy and post mortem examination did not reveal any treatment-related gross lesions in either decedents or survivors killed at the end of the observation period.

Any other information on results incl. tables

Table 1: Mortality and time of death

Dose level

Number dying / number tested

(mg/kg)

Dose range-finding study

(treatment volume 20mL/kg)

Main study - phase I

(treatment volume 10mL/kg)

Main study - phase II (treatment volume 20mL/kg)

 

Male

Female

Male

Female

Male

Female

500

0 / 1

0 / 1

-

-

-

-

1000

0 / 1

0 / 1

-

0 / 5

0 / 5

0 / 5

2000

-

-

-

-

0 / 5

3b/ 5

3000

0 / 1

1a/ 1

-

0 / 5

3b/ 5

4b/ 5

4000

-

-

-

-

-

5c/ 5

5000

0 / 1

1a/ 1

0 / 5

0 / 5

-

-

adied on day 1;

bdied on day of treatment;

c4 died on day of treatment and one on day 1;

- not tested

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits were calculated to be 2804 mg/kg and 1947-4037 mg/kg for males, 2000 mg/kg and 1354-2954 mg/kg for females and 2450 mg/kg and 1942-3090 mg/kg for the sexes combined.
Therefore, dinotefuran does not require classification according to Reg. (EC) No. 1272/2008.