Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 January 2014 - 25 February 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
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:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 11063
- Expiration date of the lot/batch: 31 December 2014

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark

Test animals

Species:
rat
Strain:
other: Crl:CD (SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approximately 8-12 weeks
- Weight at study initiation: 207 g - 242 g
- Fasting period before study:
- Housing: The animals were allocated without conscious bias to cages within the treatment groups. They were housed in groups of three rats of the same sex. Animals were housed inside a barriered rodent facility (Building F21, Room 044/045). The facility was designed and operated to minimise the entry of external biological and chemical agents and to minimise the transference of such agents between rooms.
- Diet (e.g. ad libitum): The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet), except for overnight prior to and approximately four hours after dosing.This diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottlesfitted with sipper tubes.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 to 70%
- Air changes (per hr): Periodic checks were made on the number of air changes in the animal rooms. Temperature
and humidity were monitored daily.
- Photoperiod (hrs dark / hrs light): 12h dark / 12h light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2000 and 300 mg/mL

MAXIMUM DOSE VOLUME APPLIED:
administered at a volume of 10 mL/kg body weight
Doses:
2000 and 300 mg/mL
No. of animals per sex per dose:
3 female rats per 2000 mg/kg
6 female rats per 300 gm/kg
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: All animals were subject to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two females (An. Nos. A1 and A2) dosed at 2000 mg/kg died on Day 2 and a further female (An. No. A3) was sacrificed on Day 2 due to deteriorating condition.
Clinical signs:
Clinical signs prior to death comprised loose faeces, elevated gait, underactivity, reduced body temperature, unsteady gait, partially closed eyelids, irregular breathing, shallow breathing, blue extremities and piloerection. Loose faeces were seen from approximately 30 minutes after dosing, elevated gait was noted approximately 3 hours after dosing and the remaining signs were seen from Day 2. A loss in body weight was noted for all decedents. Macroscopic examination of decedents revealed congestion (characterised by darkened tissues/organs) of the subcutaneous tissue, heart and liver (all decedents), congestion (blood vessels injected) of the brain (all decedents) and lungs (An. No A1), pallor of the spleen and kidneys (all decedents), enlarged swollen or thickened stomach (all decedents) and caecum (An. No. A1), small (atrophy) spleen (all decedents), gaseous distension of the stomach (An. Nos A2 and A3) and yellow or green fluid contents of the duodenum, large and small intestines and caecum (all decedents).
Clinical signs of reaction to treatment seen in females dosed at 300 mg/kg comprised of loose faeces, seen in five females. These signs were first noted approximately one hour after dosing. Recovery of these animals, as judged by external appearance and behaviour, was complete by Day 2.
Body weight:
All surviving animals were considered to have achieved satisfactory body weight gains throughout the study.
Gross pathology:
No abnormalities were noted at the macroscopic examination at study termination on Day 15 in any surviving animal dosed at 300 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute median lethal oral dose (LD50) to rats of ADK STAB LA-63P was demonstrated to be between 300 and 2000 mg/kg body weight.
No abnormalities were noted at the macroscopic examination at study termination on Day 15 in any surviving animal dosed at 300 mg/kg.
All surviving animals were considered to have achieved satisfactory body weight gains throughout the study.
Executive summary:

The study was performed to assess the acute oral toxicity of ADK STAB LA-63P a light stabilizer, to the rat. A group of three fasted female rats received a single oral gavage dose of the test substance, formulated in 1% w/v aqueous methyl cellulose, at a dose level of 2000 mg/kg body weight. As results at this dose level indicated the acute median lethal dose to be below 2000 mg/kg

body weight, in compliance with the study guidelines, a further two groups of three fasted females were similarly dosed at 300 mg/kg body weight to complete the study.

Results

Two females dosed at 2000 mg/kg died on Day 2 and a further female was sacrificed on Day 2 due to deteriorating condition. Clinical signs prior to death comprised loose faeces, elevated gait, underactivity, reduced body temperature, unsteady gait, partially closed eyelids, irregular breathing, shallow breathing, blue extremities and piloerection. Loose faeces were seen from approximately 30 minutes after dosing, elevated gait was noted approximately 3 hours after dosing and the remaining signs were seen from Day 2. A loss in body weight was noted for all decedents. Macroscopic examination of decedents revealed congestion

(characterised by darkened tissues/organs) of the subcutaneous tissue, heart and liver, congestion (blood vessels injected) of the brain and lungs, Pallor of the spleen and kidneys, enlarged swollen or thickened stomach and caecum, small (atrophy) spleen, gaseous distension of the stomach and yellow or green fluid contents of the duodenum, large and small intestines and caecum.

Clinical signs of reaction to treatment seen in females dosed at 300 mg/kg comprised of loose faeces, seen in five females. These signs were first noted approximately one hour after dosing. Recovery of these animals, as judged by external appearance and behaviour, was complete by Day 2. All surviving animals were considered to have achieved satisfactory body weight gains

throughout the study. No abnormalities were noted in any surviving animal at the macroscopic examination at study termination on Day 15.

Conclusion

The acute median lethal oral dose (LD50) to rats of ADK STAB LA-63P was demonstrated to be between 300 and 2000 mg/kg body weight.