Propanoic acid, 2-[4-[4,6-bis([1,1'-biphenyl]-4-yl)-1,3,5-triazin-2-yl]-3-hydroxyphenoxy]-, isooctyl ester

Endpoint summary

Description of key information

Acute toxicity was assessed by oral and dermal administration of the test item to male and female rats at concentrations of 2000 mg/kg bw (OECD guideline 423 and 402, GLP). All animals survived until scheduled necropsy. Clinical and histo/pathological examination did not reveal any treatment related findings. Dermal application caused slight, transient skin irritation which resilved within post observation period. LD50 after oral and dermal administration is considered to be higher than 2000 mg/kg bw.

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:

25-Oct-2002 to 13-Nov-2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study (OECD test guideline 423)

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adoted on 22th March 1996

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Crl;CD BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd., Manston Road, Margate, Kent, England
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 95-123 g
- Fasting period before study: overnight prior to dosing until 4 hours after dosing
- Housing:
Rats were allocated without conscious bias to cages within the treatment groups. They were housed in groups of three rats of the same sex in metal cages with wire mesh floors
- Diet:
A standard laboratory rodent diet (Special Diet Services RMl(E) SQC expanded pellet) was provided ad libitum. Access to food only was prevented overnight prior to and approximately 4 hours after dosing.
- Water: drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Humidity: 40-70%
- Photoperiod: 12 hours dark/ 12 hours light

IN-LIFE DATES: From: 24-Oct-2002 to: 11-Nov-2002

Route of administration:

oral: gavage

Vehicle:

other: 1 % (w/v) aqueous methylcellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle: 1% (w/v) in water at a dose volume of 10 mL/kg bodyweight

Doses:

One single dose of 2000 mg/kg bw

No. of animals per sex per dose:

6 animals (3 males and 3 females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days. The day of dosing was designated Day 1.
- Frequency of observations and weighing:
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation. All animals were observed for 14 days after dosing. The bodyweight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: yes. All animals were subjected to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.

Statistics:

Individual weekly bodyweight changes and group mean bodyweights were calculated.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single oral gavage dose to a group of six rats (three males and three females) at a dose level of 2000 mg/kg.

Clinical signs:

Clinical signs of reaction to treatment were confined to piloerection observed in all females on Day 2, resolving completely by Day 3. No clinical signs were observed in the males during the study.

Body weight:

All animals were considered to have achieved satisfactory bodyweight gains throughout the study.

Gross pathology:

No abnormalities were revealed at the macroscopic examination.

Other findings:

No other findings were noted.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute lethal oral dose of the test substance to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Executive summary:

A GLP-compliant acute oral toxicity study according to OECD TG 423 was performed to determine the acute lethal dose of the test substance after oral administration. A group of three fasted male and female rats respectively received a single oral gavage dose of the test substance, formulated in 1 % w/v aqueous methylcellulose, at a dose level of 2000 mg/kg bodyweight. All animals were killed as scheduled and examined macroscopically on Day 15, the end of the observation period. There were no deaths throughout the duration of the study. Clinical signs of reaction to treatment were confined to piloerection observed in all females on Day 2, resolving completely by Day 3. No clinical signs were observed in the males during the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were revealed at the macroscopic examination at study termination on Day 15. As result, the acute lethal oral dose of the test substance was demonstrated to be greater than 2000 mg/kg bodyweight in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimsch 1, according OECD guideline 423 and GLP

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:

25-Oct-2002 to 13-Nov-2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline test, GLP compliance

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted on 24th February 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl;CD BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd., Manston Road, Margate, Kent, England
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 223-253 g
- Housing:
The rats were allocated without conscious bias to cages within the treatment group. They were housed individually in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel) until Day 11 when they were retumed to group housing. The cages were fitted with grid floors to ensure rapid removal of waste material to undertrays. The cages were suspended in mobile stainless steel racks.
- Diet: A standard laboratory rodent diet (Special Diet Services RMl(E) SQC expanded pellet) was provided ad libitum.
- Water: drinking water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Humidity: 40-70%
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

IN-LIFE DATES: not indicated

Type of coverage:

occlusive

Vehicle:

other: 1 % (w/v) aqueous methylcellulose

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 50 mm x 50 mm
- % coverage: approximately 10% of the total body surface area
- Type of wrap if used: porous gauze held in place with a non-irritating dressing, further covered by a waterproof dressing encircled firmly around the trunk of the animal (occlusive coverage)

REMOVAL OF TEST SUBSTANCE
- Washing: with warm water (30 - 40°C). The treated area was then blotted dry with absorbent paper.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Concentration: 55.56% w/v in 1% w/v aqueous methylcellulose and administered
- Constant volume or concentration used: yes; at a dose volume of 3.60 mL/kg

VEHICLE
- Amount(s) applied : 1 mL/100 mL
- Concentration: 1% w/v aqueous methylcellulose

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

10 animals, 5 males and 5 females

Control animals:

yes

Details on study design:

- Duration of observation period following administration:
14 days after dosing. Dosing day = day 1
- Frequency of observations and weighing:
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation. The bodyweight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: yes; all animals were subjected to a macroscopic examination which consisted of opening the thoracic and abdominal cavities. The macroscopic appearance of all tissues was recorded.

Statistics:

Group mean bodyweights were calculated

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single dermal application of the test item to a group of ten rats (five males and five females) at a dose level of 2000 mg/kg bodyweight.

Clinical signs:

Clinical signs were confined to a swollen right forepaw in one male. This was due to the animal trapping its front right forepaw in the divider between cages on Day 10 and was therefore not attributable to treatment. No clinical signs were seen in the remaining four males and five females for the duration of the study.

Body weight:

All animals were considered to have achieved satisfactory bodyweight gains throughout the study.

Gross pathology:

Macroscopic examination at study termination revealed congestion (characterised by darkened tissue/organs) of the liver in one male and white swellings on the kidneys in another male. No abnormalities were revealed in the remaining animals.

Other findings:

- Other observations:
Very slight to well-defined dermal irritation (Grade 1 or 2 erythema and/or Grade 1 or 2 oedema) was observed in three males and two females following removal of the dressings, resolving completely by Day 9. No dermal irritation was noted in the remaining five animals throughout the study. In addition, chemical burn (one male and one female), loss of elasticity (two females), skin damage at bandage removal (two males), yellow test substance staining (which did not impair assessment of erythema) (all animals), dose residue (which did not impair assessment of erythema) (all animals), spots and/or scabbing (over the majority of the treatment site)(one male) and spots and/or scabbing (confined to a small area of the dose site) (one male and two females) were noted from removal of the dressings, resolving completely by Day 11.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute lethal dermal dose of the test substance to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Executive summary:

A GLP-compliant acute dermal toxicity study according to OECD TG 402 was performed to determine the acute lethal dose of the test substance after dermal administration. A group of ten rats (five males and five females) received a single topical application of the test substance, formulated at a maximum practical concentration in 1% w/v aqueous methylcellulose, at dose level of 2000 mg/kg bodyweight, for a duration of 24 hours. All animals were killed and examined macroscopically on Day 15, the end of the observation period. Very slight to well-defined irritation (Grade 1 or 2 erythema and/or Grade 1 or 2 oedema) was observed in five animals following removal of the dressings, resolving completely by Day 9. No dermal irritation was noted in the remaining five animals throughout the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination at study termination on Day 15 revealed congestion (characterised by darkened tissue/organs) of the liver in one male and white swellings on the kidneys in another male. These findings are of single character and are not considered to be treatment related. No abnormalities were revealed in the remaining animals. As result, the acute lethal dermal dose of the test substance was demonstrated to be greater than 2000 mg/kg bodyweight in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimsch 1, according OECD guideline 402 and GLP

Additional information

Procedure and observations

A group of three fasted female rats received a single oral gavage dose of the test substance, formulated in 1 % w/v aqueous methylcellulose, at a dose level of 2000 mg/kg bodyweight. As results at this dosage indicated the acute lethal oral dose of the test material to be greater than 2000 mg/kg bodyweight, in compliance with the study guidelines, a group of three fasted males was similarly dosed at 2000 mg/kg to confirm results at this dosage and complete the study. All animals were killed as scheduled and examined macroscopically on Day 15, the end of the observation period. There were no deaths throughout the duration of the study. Clinical signs of reaction to treatment were confined to piloerection observed in all females on Day 2, resolving completely by Day 3. No clinical signs were observed in the males during the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were revealed at the macroscopic examination at study termination on Day 15.

 

A group of ten rats (five males and five females) received a single topical application of the test substance, formulated at a maximum practical concentration in 1% w/v aqueous methylcellulose, at dose level of 2000 mg/kg bodyweight, for a duration of 24 hours. All animals were killed and examined macroscopically on Day 15, the end ofthe observation period. Very slight to well-defined irritation (Grade 1 or 2 erythema and/or Grade 1 or 2 oedema) was observed in five animals following removal of the dressings, resolving completely by Day 9. No dermal irritation was noted in the remaining five animals throughout the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination at study termination on Day 15 revealed congestion (characterised by darkened tissue/organs) of the liver in one male and white swellings on the kidneys in another male. These findings are of single character and are not considered to be treatment related. No abnormalities were revealed in the remaining animals.

 

Conclusion

The acute lethal oral dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No mortality occurred at the limit dose of 2000 mg/kg bw. As a result, the substance is not considered to be classified for acute oral or dermal toxicity under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.