1,2,3,4-Butanetetracarboxylic acid, tetramethyl ester, reaction products with 1,2,2,6,6-pentamethyl-4-piperidinol and β,β,β',β'-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol

Endpoint summary

Description of key information

The acute median lethal oral dose (LD50) to rats was demonstrated to be between 300 and 2000mg/kg body weight. According to the CLP criteria LA-63P is classified as category 4 for Acute Oral Toxcitiy- H302 Harmful if swallowed.

The acute dermal median dose (LD50) to rats was demonstrated to be greater than 2000mg/kg body weight. According to the CLP criteria this dose does not meet the criteria for classification therefore LA-63P is unclssified for Acute dermal toxicity.

The inhalation study was waived therefore this endpoint is determined to be non hazardous.

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:

16 January 2014 - 25 February 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Qualifier:

according to guideline

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. QA statement)

Test type:

acute toxic class method

Limit test:

yes

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

Species:

rat

Strain:

other: Crl:CD (SD)

Sex:

female

Details on test animals or test system 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

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.

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.

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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:

21 Dec 2016 - 04 Jan 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 112Z5
- Purity: 100%
- Physical state/ Appearance: white powder
- Expiration date: 30 Jun 2017
- Storage condition of test material: room temperature in the dark

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: at least 200g
- Housing: suspended solid floor polypropelene cages furnished with woodflakes
- Diet: ad libitum:
- Water (e.g. ad libitum):
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/ 12

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks
- % coverage: 10% of the total body surface area
- Type of wrap if used: self adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): skin wipe with cotton wool moistened with arachis oil BP
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg

Duration of exposure:

24h

Doses:

2000mg/kg

No. of animals per sex per dose:

5 males at 2000mg/kg
5 females at 2000mg/kg

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14days
- Frequency of observations: 30min, 1h, 2h and 4h after dosing and subsequently once daily for 14 days.


- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
- all animals showed expected gains in body weights

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No deaths

Clinical signs:

There were no signs of systematic toxicity during the observation period

Body weight:

All animals showed expected gains in weight

Gross pathology:

No abnormalities were noted during necropsy.

Other findings:

Very slight erythema was noted at the test sites of alll animals.
Very slight edema was also noted at the test of all males and four females.
No abnormalities were noted at necropsy

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal median lethal dose (LD50) of the test itiem in the Wistar strain rat was found to be greater than 2000mg/kg body weight

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

The acute median lethal oral dose (LD50) to rats was demonstrated to be between 300 and 2000mg/kg body weight. According to the CLP criteria LA-63P is classified as category 4 for Acute Oral Toxcitiy- H302 Harmful if swallowed. The LD50 values was estimated in accordance with test procedure outlined in the EEC Methods for the determination of toxicity and other health effects. Commission Regulation No. 440/2008, Part B, Method B.1 tris. Acute Oral Toxicity: Acute Toxic Class Method. 30 May 2008.

The acute dermal median dose (LD50) to rats was demonstrated to be greater than 2000mg/kg body weight. According to the CLP criteria this dose does not meet the criteria for classification therefore LA-63P is unclssified for Acute dermal toxicity.

The inhalation study was waived therefore this endpoint is determined to be non hazardous. The study was not conducted because exposure to humans is via inhalation is not likely taking into acount the vapour pressure, particle size and use of the substance. Vapour pressure is 4 x10-9Kpa at 25°C which confirm low volatility. Percentage of test item with a respirable particle size <5.5 µm is 1.34% however aerosol formation is not likely as the substance is completly enclosed during use. Therfore based on the information above the substance is not classified as hazardous by the inhalation route.