1-[2-fluoro-6-(trifluoromethyl)benzyl]-5-iodo-6-methylpyrimidine-2,4(1H,3H)-dione

Endpoint summary

Description of key information

The results from the acute oral, acute inhalation, and acute dermal toxicity studies indicated that there was no indication of toxicity.

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:

4th June 2018 to 29th October 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: Acute Oral Toxicity - Acute Toxic Class Method (423) published by the Ministry of Environmental Protection of Peoples Republic of China in the year 2013

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Physical check up and acclimation were made to all animals on arrival. Healthy young animals were acclimatised to the laboratory conditions and paired housed per cage in the facility of Room D101 for 7 days prior to the test. All animals were weighed and marked on the hair. Clinical observations were performed daily until grouping. Animals were raised in suspended stainless steel cages. Animals were housed individually during the test.
Temperature: 20-25oC
Humidity: 40-70%
Light sequence: 12 hour light / 12 hour dark
Food: Sterilised diet with complete nutrition (Beijing keaoxieli Feed Co. Ltd.)
Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

Dose volume
A-1298540: 10 mL/kg (all concentrations)
Dose levels:
300 mg/kg, 2000 mg/kg (female)

No. of animals per sex per dose:

3

Details on study design:

The test item was tested using a stepwise procedure, each group using 3 female animals. The first and second step dosing were both 300 mg/kg. As there were no deaths, the third and fourth steps were both 2000 mg/kg and all animals survived. Clinical observations and body weights were monitored during the study. All animals were subject to gross necroscopy.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality

Clinical signs:

other: There were no abnormal findings during the test

Gross pathology:

There were no findings during gross necropsy in any of the main study animals at the end of study.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the test item was defined to have an estimated LD50 > 2000 mg/kg and therefore classified as a Hazard Category of 5 according to Globally Harmonized System (GHS). However, since category 5 for acute oral tox has not been adopted by the EU, the classification will be GHS criteria not met.

Executive summary:

Objective
The study was performed to assess the acute oral toxicity of methyl iodouracil in  the Sprague Dawley rat.  The method was designed to meet the guidelines for the Testing of Chemicals - Acute Toxic Class Method (423) published by the Ministry of Environmental Protection of Peoples Republic of China in the year 2013. 

General Procedure
The test item was tested using a stepwise procedure, each group using 3 female animals. The first and second step dosing were both 300 mg/kg. As there were no deaths, the third and fourth steps were both 2000 mg/kg and all animals survived. Clinical observations and body weights were monitored during the study. All animals were subject to gross necroscopy.

There were no deaths during the study (mortality 0/3).

There were no abnormal findings during the study and all animals gained weight over the course of the study. There were no findings during gross necropsy. 

Conclusions: Based on the results, the test item was determined to have an estimated LD50 > 2000 mg/kg and therefore classified as a Hazard Category of 5 according to Globally Harmonized System (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 09, 2018 to August 23, 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

other: TG 436

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test System
Species: Rat
Strain: Sprague Dawley Grade: SPF
Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd. Animal Production License: SCXK. (Jing) 2016-0006
Animal Certificate No.: 11400700321610
Number of Animals: 6 animals (3 males and 3 females) were ordered and used. The females were nulliparous and non-pregnant.
Age and Body Weight: The age was between 63-69 days, and the body weights were between 257-281 g for male rats and 225-240 g for female rats. The
body weights were within ±20% of the mean weight for each sex when exposure.

Physical Examination and Acclimatization: A physical examination, weighing and marking on the hair and cage card identifying was made in 24 hours after animals' arrival. After the physical examination more than 5 days' acclimatization period started. Animals were acclimated to the restraining tubes twice prior to dosing in order to minimize stress and uncomfortableness about restraining tubes. First pre-adaption was about 1 h. Second pre-adaption was about 2 h. No abnormalities were found during both restraining. One or two animals were paired housed per cage during the acclimatization period.

Test conditions:
Husbandry: Animals were housed in Room Al20-1 of the facility. Animals were raised in suspended, stainless steel cages on cage racks. There were 10 cages per layer, and 4 layers per rack. Animals were housed individually after expsoure.

Environmental Controls: The temperature and humidity were automatically controlled and recorded. The target value of animal room temperature was 19°C -25°C,
of the relative humidity was 40%- 70% and light cycle was 12 hour light and 12 hour dark.

Food and Water: Animals were provided with rodent complete nutrition pellet diet supplied by Beijing keaoxieli Feed CO., LTD. Analysis report of diet was provided by the supplier. Water was purified using the HT-ROlOOO purity system. Drinking water was routinely analyzed. Diet and drinking water were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. During the test, diet and water were available to theanimals ad libitum except exposure and pre-adaption.

Animal Welfare: The animal use for this study complies with the national animal welfare laws and regulations (instructive notions with respect to caring for laboratory animals) (2006, PRC Ministry of Science). The animal care and use activities required for conduct of this study were reviewed and approved by the testing facility Animal Care and Use Committee (IACUC).

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

snout only

Vehicle:

other:

Mass median aerodynamic diameter (MMAD):

ca. 1.89 µm

Geometric standard deviation (GSD):

ca. 1.54

Remark on MMAD/GSD:

Actual mean concentration in the cabinet for four times measurement was 5035±68mg/m^3. The mass median aerodynamic diameters (MMAD) for two times measurement were 1.91µm and 1.87µm, respectively. The geometric standard deviations (GSD) were 1.56 and 1.52, respectively. The aerodynamic particle sizes less than 4 micron (mass%) for two times measurement were both 99.86% and 99.95%

Details on inhalation exposure:

Test Equipment and Administration Method:

Equipment: HOPE-MED 8052H dynamic snout only aerosol inhalation instrument was used.

Atmosphere Generation System: The test item was aerosolized using a stainless steel aerosol generation system. The test item was infused into generation system through peristaltic pump and mixed with compressed air. Target concentration was achieved by adjusting air flow rate and pump infusion velocity.

Exposure Method: Test item preparation: Test item had been grinded before exposure. Before exposure, each rat was restrained in a confined transparent polycrylic tube. The exposure tubes were installed in the portholes of the inhalation chamber and the chamber was sealed up. Filtered and compressed air was mixed with quantitative test item and aerosol was sent to exposure chamber (0.04m^3). The test item moving speed and exposure airflow rate had been adjusted. The aerosol had been continuously generated from generation system on the top of the chamber with an aerosol producer. A slight negative pressure was maintained in outer plenum of chamber to prevent leakage of the test substance into the surrounding area. The exhausted air was removed from the outlet at the bottom of the chamber to absorption unit.

Concentration Trial: Before commencement of the exposure, technical trial had been conducted (without animals) using the inhalation system. The two concentrations' error were within + 20%, so the exposure had been done.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Actual mean concentration in the cabinet for four times measurement was 5035 +/- 68 mg/m^3.

No. of animals per sex per dose:

1 dose at 5,000 mg/m^3: 3 males & 3 females in group

Control animals:

no

Details on study design:

Clinical Observations:
Clinical observations were recorded once during the exposure and twice with more than 30 minutes interval after exposure on the exposure day and then once daily for up to the end observation. Observation and record was conducted including animal fur changes, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behaviour patterns. Attention was directed to tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Body Weights:
The animals were weighed in the first 24 hours after arrival, on the day of exposure prior to exposure (day 0), and on day 1, day 3, day 7 and day 14.

Necropsy:
All surviving animals were dissected at the end of the study after anesthetizing with C02 inhalation and killed by bloodletting. Nose, pharynx, larynx, trachea and
lung were examined. The necropsy included following examinations such as the external features of the carcass, external body orifices, the abdominal, thoracic and their contents of all animals, and the location, size, hardness and the color. No abnormalities were found in female and male animals at the gross necropsy, so histopathological examination was not performed.

Evaluation of Data:
Animal number, sex, bodyweight, necropsy and histopathology abnormal findings were summed up. The mean and standard deviations of body weight at different times were calculated.
The inhalation toxicity LC50 range was found. According to GHS criteria for the acute inhalation toxicity (as shown in Table 3 below) the test item category was given. Because unit of LC50 was mg/m3, the LC50 divided by 1000 was converted to mg/L units when test item classification was conducted.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 035 mg/m³ air

Based on:

test mat.

Remarks on result:

other: 5035 + 68mg/m^3

Mortality:

No animals were found dead during test period and the mortality was zero.

Clinical signs:

other: No abnormalities were found during the whole observation period

Body weight:

The body weight of male and female animals showed an increased trend during the observation period.

Gross pathology:

No abnormalities were found in female and male animals at the gross necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on above results, the acute inhalation LC50 (4 h) in rats for the test material is more than 5035 +/- 68mg/m3. According to GHS's classification criteria of acute inhalation toxicity, the test item is classified as "Unclassified".

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 035 mg/m³ air

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:

4th June 2018 to 29th October 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: Acute Dermal Toxicity (TG402) published by the Ministry of Environmental Protection of Peoples Republic of China in the year 2013

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Physical check up and acclimation were made to all animals on arrival. Healthy young animals were acclimatised to the laboratory conditions and housed two per cage in the facility of Room D101 for 7 days prior to the test. All animals were weighed and marked on the hair. Clinical observations were performed daily until grouping. Animals were raised in suspended stainless steel cages. Animals were housed individually during the test.
Temperature: 20-25oC
Humidity: 40-70%
Light sequence: 12 hour light / 12 hour dark
Food: Sterilised diet with complete nutrition (Beijing keaoxieli Feed Co. Ltd.)
Water: ad libitum

Type of coverage:

semiocclusive

Vehicle:

corn oil

Details on dermal exposure:

According to body weights, the theoretical amounts of the test item were calculated.

Theoretical Weighed Test Item (mg/animal) = Body Weight (kg) x Dose (mg/kg)

The test item was weighed on a piece of gauze (6cm x 6cm) stuck on a small piece of medical tape (non-irritating) moistened with 0.5ml vehicle. Approximately 24 hours before the test, fur was removed from the dorsal area of the trunk of the test animal by clipping. Only animals with healthy and intact skin were used. The gauze was placed over the treatment area and wrapped with a piece of self-adhesive bandage. Shortly after dosing, the dressings were examined to ensure that the animals cannot ingest test item.

Duration of exposure:

14 days

Doses:

One dose

No. of animals per sex per dose:

5 males
5 females

Details on study design:

Clinical observations were performed once during the first 30 mins and at 1, 2 and 4 hours, then once each day for 14 days.

Careful observations and records of fur changes, eye & mucosa, respiratory, circulatory, nervous system, limb activity and behavioural changes.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality

Clinical signs:

other: There were no abnormal findings during the test

Gross pathology:

There were no findings during gross necropsy in any of the animals at the end of study.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the acute dermal toxicity of Methyl iodourcil was estimated to be above 2000 mg/kg and therefore classified as a Hazard Category of 5 according to Globally Harmonized System (GHS). However, since category 5 for acute dermal tox has not been adopted by the EU, the classification will be GHS criteria not met.

Executive summary:

Objective
The study was performed to assess the acute dermal toxicity of methyl iodouracil in  the Sprague Dawley rat.  The method was designed to meet the guidelines for the Testing of Chemicals - Acute Dermal Toxicity (TG402) published by the Ministry of Environmental Protection of Peoples Republic of China in the year 2013. 

General Procedure
A limit test at one dose level of 2000 mg/kg bw was carried out via a dermal route in a group of 10 animals (5 male, 5 female).  Clinical observations were performed once during the first 30 mins and at 1, 2 and 4 hours, then once each day for 14 days. Individual weights were determined within 24 hours after arrival, at grouping, on Day 0, Day 7 and Day 14. At the end of the test, a gross necroscopy was performed on all animals under test.

Results

Mortality: No deaths or moribund states were observed during the study. 

Clinical observations: There were no abnormal findings during the study. 

Skin Reactions: No signs of dermal irritation were observed during the study.

Body Weights:All animals gained weight over the course of the study.

Gross necropsy: There were no findings during gross necropsy. 

Conclusions: Based on the results, the acute dermal toxicity of Methyl iodourcil was estimated to be above 2000 mg/kg and therefore classified as a Hazard Category of 5 according to Globally Harmonized System (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw