Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: inhalation, other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09/10/2001 - 26/02/2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-methyl-2-nitro-3-(tetrahydrofuran-3-ylmethyl)guanidine
EC Number:
605-399-0
Cas Number:
165252-70-0
Molecular formula:
C7H14N4O3
IUPAC Name:
1-methyl-2-nitro-3-(tetrahydrofuran-3-ylmethyl)guanidine
Test material form:
solid: particulate/powder
Remarks:
powder

Test animals

Species:
rat
Strain:
other: Crl:WI(GlxBRL/Han)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: About 9 weeks old
- Weight at study initiation: 173.8-226.6 g for males. 144.9-182.2 g for females

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: The calculated MMAD ± GSD were 2.03 ± 3.31 µm, 1.80 ± 3.60 µm and 1.55 ± 2.96 µm, respectively.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE
- Exposure apparatus: Wright dust feed generator connected to a 40L-exposure chamber utilising a tangential, continuous air-flow system.
- See Table 7.5.2-1
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- The actual exposure concentrations were measured gravimetrically at least hourly during each exposure period for each concentration.
- The particle size of the atmospheres was determined gravimetrically pre-exposure and then once a week throughout the exposure period. The particle size of the highest atmosphere concentration was measured on a further 3 occasions during Week 1.
- Test atmospheres were sampled for up to 30 seconds by drawing through a 9-stage cascade impactor (0.52 - 100µm)
- The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated for each occasion.
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
Daily for 29 or 30 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
2.89 mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
16.02 mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
61.24 mg/L
Basis:
nominal conc.
No. of animals per sex per dose:
10 rats per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The target atmosphere chamber concentrations were selected by the Sponsor based on findings on a preceding 6 day prelliminary study. The highest exposure concentration (2 mg/L) was selected as this was considered to be the highest practical concentration obtainable in the respirable range and would result in a classification of Category IV in the single 4-hour exposure study (EPA OPPTS 870.1000 guideline). The intermediate and low exposure concentrations are fractions of the high exposure atmosphere concentration.
- Post exposure observation period: none
Positive control:
None

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed twice daily for morbidity and mortality. Animal observation following exposure was performed daily, generally immediately after exposure and several times up to 2 hours after exposure.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded before exposure on Day 1, at weekly intervals and at necropsy.

FOOD CONSUMPTION:
- Time schedule for examinations: Food consumption was determined weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmoscopic examinations were performed on all animals pre-exposure and on all animals treated at 0 or 2.08mg/L during Week 4.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During Week 4
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, overnight prior to sampling
- How many animals: All rats

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During Week 4
- Animals fasted: Yes, overnight prior to sampling
- How many animals: All rats

URINALYSIS: Yes
- Time schedule for collection of urine: During Week 4
- Animals fasted: Yes, overnight prior to sampling
- How many animals: All rats
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Where appropriate, data were subjected to statistical analysis using one-way ANOVA. Levene’s test was used to evaluate the homogeneity of variance. Where data were not heterogeneous Dunnett’s test was employed. Clinical chemistry data were analysed using non-parametric tests, Kruskal-Wallis ANOVA and the Terpstra-Jonckheere test. Organ weight data was analysed using ANCOVA followed by Dunnett’s test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
There were no deaths or treatment-related clinical signs in any exposure group. The body weight gains of all male treated groups were reduced during week 1. Since the overall effect on male body weight gain was minimal and transient, and associated with a slight decrease in food consumption, it is considered not to be an adverse effect. The weight gain of all female treated groups was comparable to the control values throughout the study. The mean weekly food consumption of all male treated groups in weeks 1 and 2, and in the high dose group in week 3, was slightly lower than the control consumption. However, the differences were not statistically significant. The food consumption of all female treated groups was unaffected by exposure to dinotefuran.
There were no treatment-related ophthalmological findings at the highest exposure concentration. There were no treatment-related effects on the hematological and plasma and urine clinical chemistry profiles in either sex at any exposure concentration. There were no treatment-related macroscopic findings, organ weight changes or histopathological alterations.
No target organs were identified in either sex at the highest dose level employed.

See Table 1.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
2.08 mg/L air
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table A6.3.3-1   Summary of body weight gain and food consumption

Study interval

Sex

Group mean body weight gain (g) at (mg/L):

 

 

0

0.22

0.66

2.08

Week 1

Male

26.7

17.1*

16.0**

14.3**

Week 2 - week 4

 

38.2

35.4

35.2

34.0

Overall (week 1 - week 4)

 

64.8

52.5

51.1*

48.3**

Week 1

Female

8.2

7.2

7.1

7.0

Week 2 - week 4

 

17.8

19.8

14.1

22.5

Overall (week 1 - week 4)

 

26.0

27.0

21.2

29.5

 

Group mean food consumption (g/week):

Week 1

Male

146.3

137.8

138.9

130.7

Week 2

 

155.1

148.4

147.0

140.0

Week 3

 

155.3

153.9

151.3

145.7

Week 4

 

134.7

137.3

138.9

135.9

Week 1

Female

109.5

110.1

109.0

109.7

Week 2

 

113.5

117.6

114.2

117.9

Week 3

 

117.2

122.8

119.2

120.2

Week 4

 

110.7

113.1

114.4

119.8

 

Applicant's summary and conclusion

Conclusions:
A no-observed-adverse-effect-level for respirable dinotefuran was established in both sexes as 2.08 mg/L, the maximum technically achievable aerosol concentration with a MMAD ± GSD of 1.55 ± 2.96 µm.