Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:   deaths occurred in rats at 2000 mg/kg bodyweight with no deaths seen at 300 mg/kg bodyweight.

Acute inhaled toxicity:  no data available.

Acute dermal toxicity:  no deaths seen in rats exposed at 2000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study carried out in compliance with an internationally recognised guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Crl:CD (SD) albino
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: reputable supplier
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 224 to 262 g
- Fasting period before study: no
- Housing: solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved softwood bark-free fibre bedding.
- Diet (e.g. ad libitum): free access to a standard rodent diet
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes
- Acclimation period: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23C
- Humidity (%): 40 to 70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): Artificial lighting was controlled to give a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours.

IN-LIFE DATES: From: To: 7 February to 7 March 2013
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle (if gavage): 10ml
- Justification for choice of vehicle: solubility

MAXIMUM DOSE VOLUME APPLIED: 10mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the dose levels for the study were chosen in compliance with the study guidelines. As no reliable previous toxicological information was available the initial dose level was 300 mg/kg.
Doses:
300 mg/kg and 2000mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical - twice daily; bodyweight - Days 1, 8, and 15
- Necropsy of survivors performed: yes


There were no deviations from protocol.
Sex:
female
Dose descriptor:
LD50
Effect level:
300 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
2000 mg/kg one animal on Day 3 and one on Day 4. The test was terminated on Day 4 for the remaining animal on humane grounds.











Clinical signs:
There were no clinical signs of reaction to treatment seen in any animal dosed at 300 mg/kg throughout the study.

Prior to death - underactivity, hunched posture, tremors, partially closed eyelids and irregular breathing, vocalising in two animals, unsteady gait, increased body tone, reduced body temperature, loose faeces, fast breathing noted in one animal and thin build in one animal and salivation, piloerection and red coloured urine seen in one animal. All of these signs (except for salivation which was seen after dosing on Day 1) were seen from Day 3. No signs were observed for the animal which was found dead on Day 3.
Body weight:
A low bodyweight gain was noted on Day 15 for one animal. All other surviving animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
Macroscopic examination of the decedents revealed congestion (characterised by darkened tissues/organs) of the subcutaneous tissue, heart and lungs, small (atrophy) spleen, stomach and caecum, pallor of kidneys and live, enlarge swollen stomach, gaseous distension of the caecum, brown yellow fluid content of the stomach, duodenum, small and large intestines, pale areas on the liver and kidneys.

At the macroscopic examination at study termination on Day 15 pallor and dark patches were seen on the lungs in one female dosed at 300 mg/kg, no abnormalities were noted in any of the remaining animals receiving 300 mg/kg.
Other findings:
- Other observations: a loss in bodyweight was noted for all decedents.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute median lethal oral dose (LD50) to rats of DMI was demonstrated to be between 300 and 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
500 mg/kg bw
Quality of whole database:
Two available studies, one disregarded the other a well conducted study performed under GLP in accordance with a recognised guideline.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
One disregarded study.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 January 2005 - 28 April 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted in accordance with international guidelines.
Qualifier:
according to
Guideline:
OECD Guideline 434 (Acute Dermal Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Species:
rabbit
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9 weeks (at the time of start of quarantine acclimation)
- Weight at study initiation: 1.79 – 2.21 kg (at the time of grouping)
- Housing: Stainless steel or aluminium cages. 1 rabbit/cage
- Diet (e.g. ad libitum): Solid fodder (CR-1, Lot No. R1024, available from CLEA Japan, Inc.) Approx. 120 g were given once a day.
- Water (e.g. ad libitum): The rabbits were allowed to freely drink the water conforming to the water standards under the water supply law through an automatic water supply device (available from Edstrom Industries, Inc.)
- Acclimation: Yes


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Actual measurement values: 20.6 – 22.5°C; allowable range: 19 - 25°C
- Humidity (%): Actual measurement values: 43 – 77%; allowable range: 30 – 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours/day artificial lighting (06:00 – 19:00 lamp-lighting)

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back area 12 cm x 14 cm
- Type of wrap if used: The applied area was covered with paraffin film and gauze and fixed with non-irritating tape and bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the application, the applied area was wiped with gauze dipped in slightly warm water
- Time after start of exposure: 24 hours
Duration of exposure:
24 hours
Doses:
1000 and 2000mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Frequency of observations and weighing: On the day of administration, 10 times a day (once before administration, once immediately after administration, once every 15 or 30 minutes after administration); 1 to 13 days after administration, twice a day; once on the day of autopsy (for Group 2, once a day from the day following the day of grouping to the day preceding the administration, in addition to the above times of administration)
- Necropsy of survivors performed: yes
- Other examinations performed: bodyweight, organ weights, other: the external surface, internal organs and tissues were visually observed.
Organs removed: Liver, kidneys (right and left) and administered section (skin of the back)
Statistics:
No statistical verification was carried out in this test.
Dose descriptor:
LD50
Effect level:
> 2 000 other: mg/kg
Based on:
test mat.
Mortality:
During the observation period, there was no death observed.
Clinical signs:
No abnormal signs were observed on the day of administration. Day after administration a decrease in stool volume at 1000 and 2000 mg/kg and decreased appetite at 2000mg/kg were observed.
Body weight:
In the group to which a dose of 2000 mg/kg was given, the rabbits began to show a decline in appetite and a fall in the amount of feces after one day from the administration and continued to fall in body weight until after two days from the administration. A decline in appetite and a fall in the amount of feces continued up to four days from the administration in 4 animals (in one animal, a fall in the amount of feces alone was observed two days from the administration.) No abnormality was observed after five days from the administration to the final day of observation. With regard to the body weight, the body weight value decreased one day after the administration, compared with the before-test value, and there was no abnormality after three days from the administration to the final day of observation.
Gross pathology:
In autopsy, no abnormality was observed in any of the animals of any group.

In the group to which a dose of 2000 mg/kg was given, the rabbits began to show a decline in appetite and a fall in the amount of feces after one day from the administration and continued to fall in body weight until after two days from the administration. A decline in appetite and a fall in the amount of feces continued up to four days from the administration in 4 animals (in one animal, a fall in the amount of feces alone was observed two days from the administration.)

No abnormality was observed after five days from the administration to the final day of observation.

In the group to which a dose of 1000 mg/kg was given, one animal showed a decline in appetite after one day from the administration, and two animals showed a decline in appetite and a fall in the amount of feces two days after the administration. With regard to the body weight, the body weight value decreased one day after the administration, compared with the before-test value,

and there was no abnormality after three days from the administration to the final day of observation.

Interpretation of results:
Category 5 based on GHS criteria
Remarks:
Migrated information
Conclusions:
On the basis of the results described above, it was judged under the conditions of the test that the single dermal DMI dose LD50 for rabbits was a dose higher than 2000 mg/kg.
Furthermore, the test substance was classified under “Category-5/Unclassified” according to the classification of acute toxicity under the Globally Harmonized System of Classification and Labelling of Chemicals.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute oral toxicity

An acute toxicity test was performed to determine the acute toxicity by oral exposure to DMI. The study was conducted in accordance with a relevant test guideline and in compliance with GLP.

Two groups of three fasted female rats received a single oral gavage dose of the test substance, formulated in purified water, at a dose level of 300 mg/kg bodyweight. As results at this dose level indicated the acute (median) lethal oral dose of the test substance to be greater than 300 mg/kg bodyweight, in compliance with the study guidelines a further group of three fasted females were similarly dosed at 2000 mg/kg bodyweight to complete the study. At 2000 mg/kg one animal died on Day 3 and one on Day 4. The test was terminated on Day 4 for the remaining animal on humane grounds. There were no deaths and no clinical signs of reaction to treatment in any animal dosed at 300 mg/kg throughout the study. Clinical signs prior to death comprised underactivity, hunched posture, tremors, partially closed eyelids and irregular breathing seen in two females, vocalising, unsteady gait, increased body tone, reduced body temperature, loose faeces, fast breathing and thin build noted in one female and salivation, piloerection and red coloured urine seen in one female. All of these signs (except for salivation which was seen after dosing on Day 1) were seen from Day 3. No signs were observed for the female which was found dead on Day 3. At the macroscopic examination at study termination on Day 15 pallor and dark patches were seen on the lungs in one female dosed at 300 mg/kg, no abnormalities were noted in any of the remaining animals receiving 300 mg/kg.

The acute median lethal oral dose (LD50) to rats of DMI was demonstrated to be between 300 and 2000 mg/kg bodyweight.

Acute inhalation toxicity

No data available

Acute dermal toxicity

Doses of DMI of 2000 and 1000 mg/kg were given to each of five groups of rabbits at a single time. During the observation period, there was no death in any of the groups to which doses of 2000 or 1000 mg/kg were given. In the group to which a dose of 2000 mg/kg was given, the rabbits began to show a decline in appetite and a fall in the amount of feces after one day from the administration and continued to fall in body weight until after two days from the administration. A decline in appetite and a fall in the amount of feces continued up to four days from the administration in 4 animals (in one animal, a fall in the amount of feces alone was observed two days from the administration.) No abnormality was observed after five days from the administration to the final day of observation. In the group to which a dose of 1000 mg/kg was given, one animal showed a decline in appetite after one day from the administration, and two animals showed a decline in appetite and a fall in the amount of feces two days after the administration. With regard to the body weight, the body weight value decreased one day after the administration, compared with the before-test value, and there was no abnormality after three days from the administration to the final day of observation. No abnormality was observed in any of the animals of any group.

On the basis of the results described, it was judged under the conditions of the test that the single dermal DMI dose LD50 for rabbits was a dose higher than 2000 mg/kg.

 

Justification for selection of acute toxicity – oral endpoint

One valid study available.

Justification for selection of acute toxicity – dermal endpoint

Two available studies, one disregarded the other a well conducted study performed under GLP in accordance with a recognised guideline.

Justification for classification or non-classification

The acute toxicity results for DMI were reviewed with reference to the EU interpretation of CLP, EU Regulation 1272/2008. On the basis that the available tests confirmed the oral LD50 value to be greater than 300 mg/kg but less than 2000 mg/kg, and the dermal LD50 value to be greater than 2000 mg/kg bodyweight, DMI is classified as category 4 for oral exposure but does not require classification as toxic by dermal exposure.