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Description of key information

An Acute Oral (9 females rats): LD50 = 1000mg/kg

An acute Dermal (5 males and 5 females rats): LD50 > 2000mg/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
Study period:
17 september 2009 to 08 October 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD guideline and in compliance with GLP
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan
- Age at study initiation: 9 weeks
- Weight at study initiation: 194 to 227 g
- Fasting period before study: 16 to 17 hours
- Housing: individual
- Diet (e.g. ad libitum): ad libitum from 4 hours afer dosing
- Water (e.g. ad libitum): adlibitum from 4 hours after dosing
- Acclimation period: >6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 deg C
- Humidity (%): 55%
- Air changes (per hr): 10-20 changes per hour
- Photoperiod (hrs dark / hrs light):12 hrs dark/12 hrs light

IN-LIFE DATES: From: 17 September 2009 To: 15 October 2009
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bodyweight
- Justification for choice of vehicle:
- Lot/batch no. (if required): V8A6289
- Purity:

MAXIMUM DOSE VOLUME APPLIED: 10ml/kg bodyweight

DOSAGE PREPARATION (if unusual):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: guideline
Doses:
Experiments 1 and 2: 300 mg/kg
Esperiment 3: 2000 mg/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 Obs: pre-dose, 0.5, 1, 2, 3 and 4 hrs on day of dosing, daily from Days 2 to 15.
Body weight measurements: before administration and 1, 3, 7 and 14 days after administration.
Pathology of organs and tisues on Day 15
- Necropsy of survivors performed: yes
Preliminary study:
Experiments 1 and 2 (300 mg/kg bodyweight): mucous stool observed in 1 and 2 animals in experiments 1 and 2 respectively at 1 or 4 hours after dosing. Soiled periproctal regoin in 2 animals in Experiments 1 at 2 hrs after dosing or on day following administration. The findings disappeared by 2 days after administration.

Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 Cut-off value based on 0/6 deaths seen at 300 mg/kg and 2/3 deaths at 2000 mg/kg.
Mortality:
Two animals died in experiment 3 (2000 mg/kg bodyweight)
Clinical signs:
Experiments 1 and 2:
Mucous stool observed in 1 and 2 animals in experimetns 1 and 2 respectively, at 1 or 4 hours after dosing. soiled periproctal region in 2 animals in experiment 1 at 2 hours after dosing.

Experiment 3:
For the dead animals, one showed hypoactivity at 3 hours after dosing and tremor at 3 and 4 hours after dosing, this and on other animal showed hypoactivity, lateral position and bradypnea on the day following administration.
Body weight:
Supressed bodyweight gain was noted on the day follwoing administration, however, favourable increased gain was seen 3 days after administration or later.

In experiment 3, decreased bodyweight was noted on the day following administration in the dead animals. Supressed bodyweight gain noted the day follwoing administration in the surviving animal, however, favourable increased gain was seen on day 3 after administration.
Gross pathology:
No abnormalities observed at necropsy in any experiment including dead animals.
Conclusions:
The LD50 cut off value of MTF was estimated to be 1000 mg/kg under the conditions of this study since death occurred in 2 animals at 2000 mg/kg.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
02 April to 16 April 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD, EEC, EPA and JMAF guidelines and in compliance with GLP
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Guideline:
other: JMAFF 12 Nousan No 8147, 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Certificate of Compliance from UK GLP Monitoring Authority.
Test type:
fixed dose procedure
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: UK
- Age at study initiation: approximately 8-12 weeks prior to dosing
- Weight at study initiation: Males: 295 - 308 g; Females 185 - 207 g
- Fasting period before study:
- Housing: individually form Days -1 until Day 11 and then group housed (5 rats of same sex) until end of study.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 Days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 °C
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

IN-LIFE DATES: From: 02 April 2013 To: 16 April 2013
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:

TEST SITE
- Area of exposure:50mm x 50mm
- % coverage: 10%
- Type of wrap if used: porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the
trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, weak solution of detergenr in warm water.
- Time after start of exposure: 24 hrs after start of exposure

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.89 ml/kg bodyweight
- Concentration (if solution): 1.061 g/ml
- Constant volume or concentration used: yes


Duration of exposure:
24 hours
Doses:
2000 mg/kg bodyweight
No. of animals per sex per dose:
5 per sex
Control animals:
not required
Details on study design:
A group of ten rats (five males and five females) received a single topical application of the test substance, as supplied, at a dose level of 2000 mg/kg
bodyweight, for duration of 24 hours. The animals were retained for a 14 day observation period during which clinical signs, dermal reaction and bodyweight investigations were performed. All animals were humanely killed and examined macroscopically on Day 15, the end of the observation period.
Preliminary study:
There were no deaths and no systemic response to treatment in any animal. Very slight erythema (barely perceptible) was seen in four males and five females. These reactions had resolved by Day 11. A bodyweight loss was noted for four females on Day 15. All other animals were considered to
have achieved satisfactory bodyweight gains throughout the study.
No abnormalities were noted in any animal at the macroscopic examination at study
termination on Day 15.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths
Clinical signs:
Very slight erythema (barely perceptible) was seen in four males and five females. These reactions had resolved by Day 11.
Body weight:
A bodyweight loss was recorded for four females (EE6 - EE9) on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Conclusions:
The acute median lethal dermal dose (LD50) to rats of MTF was demonstrated to be greater than 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50

Additional information

An acute oral toxicity study (Kumamoto Laboratory, 2009) was conducted to assess the toxicity of MTF following a single oral administration to rats.

The study was conducted according to OECD test guideline 423 and in compliance with GLP.

A single dose of the test substance was administered by oral route to female rats Crl:CD(SD) rats.

Dose levels in both experiments 1 and 2 were set at 300 mg/kg, and that in experiment 3 was set at 2000 mg/kg. Three animals were used in each experiment. Clininal observation and body weight measurement were conducted during the observation period and necropsy was performed at the completion of the observation period.

Three animals in experiment 3 (2000 mg/kg) died 2 days after administration (day 3).

In observation for clinical signs, mucous stool or soiled periproctal region was observed in experiments 1 and 2. Besides the findings, hypoactivity, tremor, lateral position, or bradypnea was observed in dead animal in experiment 3.

In surviving animals in experiments 1 and 2, mucous stool or soiled periproctal region all disappeared by 2 days after administration.

There were also changes to the body weights after administration and in dead animals.

An acute dermal toxicity study (Huntingdon Life Sciences, 2013) was conducted to assess the toxicity of MTF following a single dermal exposure to rats.

The study was conducted according to OECD test guideline 402, EC test guideline B3, and US EPA OPPTS 870.1200, and in compliance with GLP.

A group of ten rats (five males and five females) received a single topical application of the test substance, as supplied, at a dose level of 2000 mg/kg bodyweight, for duration of 24 hours. The animals were retained for a 14 day observation period during which clinical signs, dermal reaction and bodyweight investigations were performed.

There were no deaths and no systemic response to treatment in any animal. Very slight erythema (barely perceptible) was seen in four males and five females. These reactions had resolved by Day 11. A bodyweight loss was noted for four females on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

No inhaled toxicity study was conducted, as the requirement for an acute toxicity study by a second route of exposure was satisfied by the dermal toxicity study, noted above. It is considered unlikely that MTF will be available in a vapour or other airborne / inhalable state.

Justification for classification or non-classification

The LD50 by oral administration was determined to be 1000 mg/kg bodyweight in rats.

According to the CLP Regulation (Regulation (EC) 1272/2008), classification as Acute Toxiticy Category IV applies when the LD50 is greater than 300 mg/kg but equal to or less than 2000 mg/kg. On this basis, MTF, will be calssified Acute Toxicity (oral) category IV; the signal word "Warning" and the Hazard statement "H302: Harmful if swallowed" are applicable. The corresponding classification according to the Dangerous Substances Directive (Directive 67/548/EEC, DSD) is "R22, Harmful if swallowed", applicable when the acute oral LD50 is between 200 and 2000 mg/kg.

The LD50 by dermal administration to rats was determined to be greater than 2000 mg/kg; on this basis no classification is required for dermal toxicity according to either the CLP regulation, or the DSD.