Reaction mass of (8R)-(11S)-11-[(4-hydroxyphenyl)methyl]-8-alkyl-polyoxo-1-phenyl-polyaza-2-oxadodecane and (8R)-(11R)-11-[(4-hydroxyphenyl)methyl]-8-alkyl-polyoxo-1-phenyl-polyaza-2-oxadodecane

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 July 2009 - 07 August 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted to EC, OECD, US EPA, and Japanese test guidelines, and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

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 Nohsan No 8147, Agricultural Production Bureau, November 24, 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The study report included a current certificate of GLP compliance for the test facility, issued by the MHRA.

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Details on test material:

- Physical state: Off-white solid
- Storage condition of test material: aprox. -20 degrees in the dark.

Test animals

Species:

rat

Strain:

other: CD (Crl: CD 'SD')

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: approximately eight to twelve weeks prior to dosing (day 1).
- Weight at study initiation: In the range 185 to 223 g.
- Fasting period before study: no access to food overnight before dosing.
- Housing: Animals were housed in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding. Cages, food hoppers, water bottles and bedding were changed at appropriate intervals.
- Diet (e.g. ad libitum): The animals were allowed free access to a standard pelleted rodent diet.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes.
- Acclimation period: 5 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C.
- Humidity (%): 40 to 70% relative humidity.
- Air changes (per hr): The animal room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air, which was passed to atmosphere and not re-circulated. Number of changes per hour not specified.
- Photoperiod (hrs dark / hrs light): 12 hours darkness / 12 hours light.


IN-LIFE DATES: From: 09 July 2009 (initial animal allocation) To: 07 August 2009 (date of necropsy).

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% (w/v) Methylcellulose in water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL in vehicle.
- Amount of vehicle (if gavage):10 mL/kg bodyweight.
- Justification for choice of vehicle:
- Lot/batch no. (if required):
- Purity:


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


DOSAGE PREPARATION (if unusual):


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The dose levels for the study were chosen in compliance with the study guidelines. As no previous
toxicological information was available the initial dose level was 300 mg/kg bw.

Doses:

300 mg/kg (Dosed 14 July and 16 July 2009)
2000 mg/kg (Dosed 22 July and 24 July 2009)

No. of animals per sex per dose:

6 (2 groups of three per dose level)

Control animals:

no

Details on study design:

- Duration of observation period following administration: all animals were observed for 14 days after dosing.
- Frequency of observations and weighing: Mortalities were checked twice per day. Clinical signs were observed soon after dosing and at frequent
intervals during day 1. On subsequent days all animals were observed twice per day except day 15 (day of necropsy, observation in the morning only). Bodyweights were recorded on day 1 (prior to dosing) and on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic pathology
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

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths during the study.

Clinical signs:

Clinical signs of reaction to treatment comprised salivation immediately after dosing, resolving by approximately 30 minutes later, seen in one female (A1) dosed at 300 mg/kg. Piloerection was seen in three females (A7, A8 and A9) dosed at 2000 mg/kg. This sign was seen approximately 4 hours
after dosing and had resolved by approximately 6 hours after dosing.

Body weight:

All animals were considered to have achieved satisfactory bodyweight gains throughout the observation period, demonstrating that there was no
effect of treatment upon bodyweight.

Gross pathology:

There were no treatment-related macroscopic changes.
Macroscopic examination at Day 15 of the observation period revealed a small (atrophic) stomach in one female (A4) treated at 300 mg/kg but no
abnormalities were revealed in any other animal at this macroscopic examination.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute median lethal oral dose (LD50) to rats of the test substance was demonstrated to be greater than 2000 mg/kg bodyweight.
On the basis that the acute oral LD50 value is greater than 2000 mg/kg, the substance does not require classification as harmful or toxic by the oral route, according to EC Directive 67/548/EEC.

Executive summary:

An acute oral toxicity study was performed by Huntingdon Life Sciences, UK, to determine the acute oral toxicity of the test substance. The study was conducted to EC, OECD, EPA and Japanese test guidelines, and complied to GLP. Groups of six female rats were dosed by oral gavage at 300 and 2000 mg/kg bodyweight, then observed for 14 days prior to necropsy. No deaths occurred during the study. Clinical signs were observed shortly after dosing, but were seen to resolve quickly. No treatment-related macroscopic pathological signs were observed. The acute median lethal oral dose (LD50) to rats of the test substance was demonstrated to be greater than 2000 mg/kg bodyweight. On the basis that the acute oral LD50 value is greater than 2000 mg/kg, the substance does not require classification as harmful or toxic by the oral route, according to EC Directive 67/548/EEC.