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Key value for chemical safety assessment

Acute toxicity: via oral route

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Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21/05/1996 - 09/12/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1981)
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
Species:
mouse
Strain:
other: Crl:CD1[ICR]BR (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Age at study initiation:
- Range finding study: 4 to 8 weeks old
- Definitive study: 4 to 10 weeks old

Weight at study initiation:
- Range finding study: 24.9 to 27.8 g
- Definitive study: 23.0 to 29.6 g
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
- Justification for choice of vehicle: no data
Doses:
Range finding study: 500, 1000, 3000, 5000 mg/kg bw
Definitive study: 1000, 2000, 3000 mg/kg bw
No. of animals per sex per dose:
Range finding study: 1 mouse per sex per dose
Definitive study: 5 mice per sex per dose
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.
Sex:
male
Dose descriptor:
LD50
Effect level:
2 450 mg/kg bw
Based on:
test mat.
95% CL:
> 1 801 - < 3 331
Sex:
female
Dose descriptor:
LD50
Effect level:
2 275 mg/kg bw
Based on:
test mat.
95% CL:
> 1 537 - < 3 369
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 371 mg/kg bw
Based on:
test mat.
95% CL:
> 1 884 - < 2 983
Remarks on result:
other: male and female combined
Mortality:
- In the range-finding study, both animals treated at 5000mg/kg and the male treated at 3000mg/kg died on the day of treatment. All other animals survived the observation period.
- In the main study, deaths occurred at dose levels of ≥2000mg/kg but not at 1000mg/kg (Table 1). All deaths in the main study occurred on the day of treatment.
Clinical signs:
Transient clinical signs of toxicity, on the day of treatment only, were apparent at dose levels of ≥2000mg/kg and included hypoactivity, staggering gait, dyspnea, tonic convulsions and tremors.
Body weight:
Survivors treated at 2000 or 3000mg/kg gained weight throughout the observation period.
Gross pathology:
Necropsy and post mortem examination revealed no gross lesions in either decedents or survivors killed at the end of the observation period.

Table 1: Mortality and time of death

Dose level

Number dying / number tested

(mg/kg)

Dose range-finding study

Main study

 

Male

Female

Male

Female

500

0 / 1

0 / 1

-

-

1000

0 / 1

0 / 1

0 / 5

0 / 5

2000

-

-

1a/ 5

2a/ 5

3000

1a/ 1

0 / 1

4a/ 5

4a/ 5

5000

1a/ 1

1a/ 1

-

-

adied on the day of treatment;

- not tested

Interpretation of results:
practically nontoxic
Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits were calculated to be 2450 mg/kg and 1801-3331 mg/kg for males, 2275 mg/kg and 1537-3369 mg/kg for females and 2371 mg/kg and 1884-2983 mg/kg for the sexes combined. Therefore, dinotefuran does not require classification according to Reg. (EC) 1272/2008.
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.
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
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
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.
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.

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

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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 450 mg/kg bw

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04/01/1999 - 03/08/1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study: The concentration employed is less than the specified limit concentration of 5mg/L, since 4.09mg/L is the highest technically achievable concentration with a particle size of approximately 5µm (MMAD of 4.74µm)
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
(1998)
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:
yes
Species:
rat
Strain:
other: Crl:WI[Glx/BRL/Han]BR (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: About 12 weeks old
- Weight at study initiation: 321-378 g for males. 188-207 g for females
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The exposure equipment comprised a Wright dust feed generator connected to a 40L-exposure chamber utilising a tangential, continuous air-flow system.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
The analytically determined mean achieved atmosphere concentration in the exposure chamber of the treated group was 4.09 mg/L, and MMAD ± GSD of 4.74 ± 2.79 µm. The range of MMAD values obtained is considered to be the minimum attainable.
Duration of exposure:
4 h
Concentrations:
4.09 mg/L
No. of animals per sex per dose:
5 rats per sex per dose
Control animals:
yes
Details on study design:
- Rational for dose level selection: The concentration employed is less than the specified limit concentration of 5mg/L, since 4.09mg/L is the highest technically achievable concentration with a particle size of approximately 5µm (MMAD of 4.74µm).
- Post exposure observation period: 14 days
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.09 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No deaths occurred during the exposure or observation periods (Table 1).
Clinical signs:
other: No clinical signs of an adverse reaction to treatment occurred during the exposure period and no treatment-related clinical signs of an adverse reaction to treatment were apparent.
Body weight:
Body weight gains were not affected by exposure to dinotefuran (Table 7.2.2-1).
Gross pathology:
Necropsy and post mortem examination did not reveal any treatment-related lesions in either sex. The group mean absolute and relative lung weights of the male treated group were 11 and 14%, respectively, higher than the control group (Table 1). However, the differences are considered to be incidental to treatment with dinotefuran since one control animal had an unusually low lung weight of 1.196g. The lung weights of the treated males were comparable to the lung weights of the other control males.

Table 1: Mortality, bodyweight and lungweight

Sex

Exposure

Mortality

Group mean body weight (g):

Mean lung weight

 

(mg/L)

(dying / tested)

Pre-test

Day 2

Day 8

Day 15

(g)

(%)

Male

0

0 / 5

352

348

356

373

1.68

0.454

 

4.09

0 / 5

342

336

350

366

1.87

0.516

Female

0

0 / 5

197

196

197

204

1.18

0.585

 

4.09

0 / 5

199

198

201

208

1.26

0.614

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The 4-hour inhalation lethal concentration (LC50) value for respirable dinotefuran in male and female rats is > 4.09 mg/L. Although this value falls within the classification category 4, higher concentrations of dinotefuran in the respirable range were not technically feasible after extensive atmosphere development. Since neither clinical signs of toxicity nor deaths occurred at the highest technically achievable concentration, it is considered that dinotefuran does not require classification in the EU according to the CLP regulation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
4 009 mg/m³

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06/01/1997 - 09/12/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Version / remarks:
(1982)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 59 NohSan No. 4200 (1985)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
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: 8 to 16 weeks old
- Weight at study initiation: 254 to 290 g
Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Details on dermal exposure:
VEHICLE
- Concentration of vehicle: 0.5 % CMC in distilled water
- Total volume applied: 0.5 mL
- Justification for choice of vehicle: no data

TEST SITE
- Area of exposure: The formulation was applied to the test sites at approximately 0.03 g/cm² to an area of 16 cm².
- Washing: Washed with tap water
- Total volume applied: 2 mL/ kg dinotefuran
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 rats per sex per dose
Control animals:
no
Details on study design:
- Duration of test/exposure period: 24 hours
- Rational for dose level selection: Based on the requirements of the regulatory test guidelines.
- Post exposure observation period: 14 days
Statistics:
None
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths
Clinical signs:
There were no treatment-related clinical signs of toxicity, although 2 females showed red-stained face on the day of treatment.
Transient slight to moderate erythema, associated with slight edema in one animal, occurred in 8 of the 10 animals on the day of patch removal (Table 1). Slight erythema persisted in 2 animals until day 7, but thereafter no dermal reactions were evident.
Body weight:
All male animals gained weight throughout the study, but 4 females during the first week and 2 females during the second week showed minor weight losses of up to 9g .
Gross pathology:
There were no macroscopic findings at necropsy in any animal.

Table 1: Mean group dermal irritation scores

Sex

Observation

Group mean dermal irritation scores on day:

 

 

1

3

7

10

14

Male

Erythema

1.60

1.0

0.40

0

0

 

Edema

0.20

0.40

0

0

0

 

Atonia

0

0

0

0

0

 

Desquamation

0

0

0

0

0

 

Coriaceousness

0

0

0

0

0

 

Fissuring

0

0

0

0

0

Female

Erythema

0.60

0.20

0

0

0

 

Edema

0

0

0

0

0

 

Atonia

0

0

0

0

0

 

Desquamation

0

0

0

0

0

 

Coriaceousness

0

0

0

0

0

 

Fissuring

0

0

0

0

0

 

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) was estimated to be greater than 2000 mg/kg in both sexes. Accordingly, in the EU dinotefuran does not require classification according to the CLP regulation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Justification for classification or non-classification