Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 Aug 2017 to 08 Oct 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Temporary deviations from the maximum level of mean daily target humidity occurred. This study plan deviation did not affect the integrity of the study because laboratory historical data do not indicate an effect of these deviations.
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Temporary deviations from the maximum level of mean daily target humidity occurred. This study plan deviation did not affect the integrity of the study because laboratory historical data do not indicate an effect of these deviations.
Qualifier:
according to
Guideline:
other: EC No 440/2008, part B: "Acute Oral Toxicity, Acute Toxic Class Method"
Qualifier:
according to
Guideline:
other: JMAFF Guidelines (2000), including the most recent revisions.
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
Details on test material:
Lot number: 2000850599
Analysis date: 19 August 2016
Specific details on test material used for the study:
Identification: Tri-o-tolylphosphine
Appearance: Off-white crystalline powder (determined by Charles River Den Bosch)
Batch: B64002 (Pfizer Lot no. 2000850599)
Purity/Composition: See Certificate of Analysis
Test item storage: At room temperature
Stable under storage conditions until: Unknown
Test Facility test item number: 208378/A
Purity/Composition correction factor: No correction factor required
Stability at higher temperatures: Not available


Test animals

Species:
rat
Strain:
other: Crl: WI(Han)
Sex:
female
Details on test animals and environmental conditions:
Species: Rat
Strain: Crl: WI(Han)
Condition: Outbred, SPF-Quality
Source: Charles River Deutschland, Sulzfeld, Germany
Number of Animals: 6 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age at the Initiation of Dosing: Young adult animals (approximately 8-9 weeks old) were selected.
Weight at the Initiation of Dosing: 132 to 171 g.
Justification for Test System and Number of Animals
The Wistar Han rat was chosen as the animal model for this study as recognized by international guidelines as a recommended test system. The test method and number of animals were based on the test guidelines.
This type of study plan was reviewed and agreed by the Laboratory Animal Welfare Officer and the Ethical Committee of Charles River Den Bosch as required by the Dutch Act on Animal Experimentation (February 1997).
Animal Identification: At study assignment, each animal was identified using an ear mark and tail mark with indelible ink.
Environmental Acclimation: The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.
Selection, Assignment, Replacement, and Disposition of Animals: Animals were assigned to the study at the discretion of the coordinating biotechnician according to body weights, with all animals within ± 20% of the sex mean. Animals in poor health or at extremes of body weight range were not assigned to the study. Before the initiation of dosing, a health inspection was performed and any assigned animal
considered unsuitable for use in the study were replaced by alternate animals obtained from the same shipment and maintained under the same environmental conditions. The disposition of all animals was documented in the study records.
Housing: On arrival and following assignment to the study, animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. These housing conditions were maintained unless deemed inappropriate by the Study
Director and/or Clinical Veterinarian. The room(s) in which the animals were kept were documented in the study records. Animals were separated during designated procedures/activities. Each cage was clearly labeled.
Environmental Conditions: Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 21 to 22°C with an actual daily mean relative humidity of 46 to 72% (Temporary deviations from the maximum level of mean daily target humidity occurred. This study plan deviation did not affect the integrity of the study because laboratory
historical data do not indicate an effect of these deviations. ). A 12-hour light/12-hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
Food: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility. It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
Water: Municipal tap-water was freely available to each animal via water bottles. Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility. It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.
Animal Enrichment: For psychological/environmental enrichment, animals were provided with paper (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom), except when interrupted by study procedures/activities.
Veterinary Care: Veterinary care was available throughout the course of the study; however, no examinations or treatments were required.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE: Propylene glycol
- Concentration in vehicle: 2000 mg/kg- concentration of test substance used for dosing
- Amount of vehicle (if gavage): A dose volume of 10 mL/kg body weight was used for each dose.
- Justification for choice of vehicle: Trial preparations were performed at the Test Facility to select the suitable vehicle and to establish a suitable formulation procedure. Trial preparation formulations were not used for dosing and were discarded after the assessment is complete. These trial preparations have a non-GLP status and were carried out in the quality assured environment of the Test Facility.

MAXIMUM DOSE VOLUME APPLIED: A dose volume of 10 mL/kg body weight was used for each dose.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The dose levels were based on the OECD test guidelines and were selected from the series 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3f/dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days.Animals were weighed individually on Day 1(predose), 8 and 15. A fasted weight was recorded on the day of dosing.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy- macroscopic abnormalities 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
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture and piloerection were noted for all animals between Days 1 and 6. Uncoordinated movements were noted for three animals between Days 1 and/or 2.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of Tri-o-tolylphosphine 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, Tri-o-tolylphosphine 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).
Executive summary:

The objective of this study was to determine the potential toxicity of Tri-o-tolylphosphine,when given by oral  gavage  at a single dose to rats of a single sex at one or more defined doses

to evaluate the potential reversibility of any findings.

The study was carried out in compliance with the guidelines described in:

• OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method"

• EC No 440/2008, part B: "Acute Oral Toxicity, Acute Toxic Class Method"

• EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity"

• JMAFF Guidelines (2000), including the most recent revisions.

Tri-o-tolylphosphine was administered by oral  gavage  to two consecutive groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations

and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Hunched posture and piloerection were noted for all animals between Days 1 and 6. Uncoordinated movements were noted for three animals between Days 1 and/or 2. The body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post  mortem  examination of the animals. The oral LD50 value of Tri-o-tolylphosphine 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, Tri-o-tolylphosphine 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).