Imidodicarbonic acid, 2-[5-bromo-3-[[(4-methylphenyl)sulfonyl]oxy]-2-pyridinyl]-, 1,3-bis(1,1-dimethylethyl) ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 March 2016 to 30 March 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Organization for Economic Co-operation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4, Health Effects. No.423, "Acute Oral Toxicity - Acute Toxic Class Method", 2001.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Commission Regulation (EC) No 440/2008 Part B: Methods for the Determination of Toxicity and
other Health Effects; B1 tris: "Acute Oral Toxicity, Acute Toxic Class Method". Official Journal of the European Union No. L142, May 2008, including the most recent amendments.

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.1100, Acute Oral Toxicity. Office of Prevention, Pesticides and Toxic Items (7101), EPA 712- C-02-190, 2002.

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFF No 8147

Version / remarks:

Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes

Remarks:

Exceotion: Trial formulation preparation (for optimal vehicle selection) had a non-GLP status but was carried out in the quality assured environment of WIL Research Europe's GLP test facility.

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl N-{5-bromo-3-[(4-methylbenzenesulfonyl)oxy]pyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate

EC Number:

810-844-9

Cas Number:

1803573-21-8

Molecular formula:

C22H27BrN2O7S

IUPAC Name:

tert-butyl N-{5-bromo-3-[(4-methylbenzenesulfonyl)oxy]pyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Purity by HPLC, % a/a: 99.7

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han) (outbred, SPF-Quality)

Sex:

female

Details on test animals or test system and environmental conditions:

6.2. Test System
Species
Rat, Wistar strain Crl:WI (Han) (outbred, SPF-Quality). Recognized by international guidelines as the recommended test system (e.g. OECD, EC).
Source: Charles River Deutschland, Sulzfeld, Germany.

Number of animals
6 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.

Age and body weight
Young adult animals (approx. 8-9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.

Identification
Earmark and tail mark

Health inspection
At least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might have affected the study integrity.

6.3. Animal Husbandry
Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).

Water
Free access to tap water.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

Vehicle
Propylene glycol (Merck, Darmstadt, Germany) (specific gravity 1.036)

Rationale
The vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data supplied by the Sponsor. There was no information available regarding the solubility or stability in vehicle.

Preparation
The preparations (w/w) were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.

Method
Oral gavage, using plastic feeding tubes. The test item preparations were stirred on a magnetic stirrer during dosing.

Fasting
Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.

Frequency
Single dosage on Day 1.

Dose
level (volume) 2000 mg/kg (10 mL/kg) body weight.

Doses:

2000 mg/kg (10 mL/kg) body weight on Day 1.

No. of animals per sex per dose:

3 Females.

Details on study design:

6.4. Study Design
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines.
The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

6.6. Observations
Mortality/Viability Twice daily.
Body weights Days 1 (pre-administration), 8 and 15.
Clinical signs At periodic intervals on the day of dosing (Day 1) and once daily
thereafter, until Day 15. The signs were graded according to fixed scales
and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
Necropsy At the end of the observation period, all animals were sacrificed by
oxygen/carbon dioxide procedure and subjected to necropsy.
Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

< 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture, uncoordinated movements and piloerection were noted for three of the animals on Day 1.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Other findings:

No information provided.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of PF-06841215 in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, PF-06841215 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).