dinotefuran (ISO); 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

Repeated dose toxicity: inhalation

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Version / remarks:

(1981)

Deviations:

no

Test guideline 2

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

Test material information

Constituent 1

Reference substance name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

EC Number:

605-399-0

Cas Number:

165252-70-0

Molecular formula:

C7H14N4O3

IUPAC Name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2.89 mg/L
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
16.02 mg/L
Basis:
nominal conc.

Doses / concentrations 3

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.