[(9-oxo-9H-thioxanthen-2-yl)oxy]acetic acid

Endpoint summary

Description of key information

Study conducted to recognised testing guidelines with GLP certification

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:

21 Nov 2018 to 18 Dec 2018.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines

Version / remarks:

2000

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EC No 440/2008

Version / remarks:

part B

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

Appearance: Yellow powder
Purity/Composition: 98.25%, assumed 100% for testing
Test item storage: At room temperature protected from light desiccated

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system 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 9-11 weeks old) were selected.
Weight at the Initiation of Dosing: 155 to 207 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.

The study plan was reviewed and agreed by the Animal Welfare Body of Charles River Laboratories Den Bosch B.V. within the framework of Appendix 1 of project license AVD2360020172866 approved by the Central Authority for Scientific Procedures on Animals (CCD) as required by the Dutch Act on Animal Experimentation (December 2014).

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.

Husbandry:
Housing:
On arrival and following assignment to the study, animals were group housed (up to 3 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. The room in which the animals were kept was 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 20 to 21°C with an actual daily mean relative humidity of 40 to 53%. 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.

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

Administration of Test item:
A single dose of test item was administered to the appropriate animals by oral gavage on Day 1, using a syringe with a plastic gavage cannula attached.

The dose volume for each animal was based on the body weight measurement prior to dosing. A dose volume of 10 mL/kg body weight was used for each dose.

The dosing formulations were stirred continuously during dose administration.

Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item, except for one animal (see deviations in Appendix 3) as this was a replacement animal based on a misdosing. Water was available.

Justification of Route and Dose Levels:
The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item.

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 body weight

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. 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. The first group was treated at a dose level of 2000 mg/kg. Based on the results, one additional group was dosed at 2000 mg/kg.

In-life Procedures, Observations, and Measurements:
Mortality/Moribundity Checks:
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.

Clinical Observations:
Postdose Observations:
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.

All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.

Body Weights:
Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing.

Terminal Procedures:
All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation
period. All animals assigned to the study were subjected to necropsy and descriptions of all
internal macroscopic abnormalities were recorded.

Statistics:

The study met the acceptability criteria prescribed by the study plan and was considered valid.

Preliminary study:

See appendix 1

Key result

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, piloerection and/or hypersensitivity to touch were noted for the majority of animals between Days 1 and 3.

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of CMTX 2-carboxymethyloxy-thioxanthone in Wistar Han 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, CMTX 2-carboxymethyloxy-thioxanthone 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 (2017) (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 CMTX 2-carboxymethyloxy-thioxanthone, 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.

Initially, CMTX 2-carboxymethyloxy-thioxanthone was administered by oral gavage to three female Wistar Han rats at 2000 mg/kg body weight. In a stepwise procedure one additional groups of three females were dosed at 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight.

Macroscopic examination was performed after terminal sacrifice (Day 15). Initially, CMTX 2-carboxymethyloxy-thioxanthone was administered by oral gavage to three female Wistar Han rats at 2000 mg/kg body weight. In a stepwise procedure one additional groups of three females were dosed at 2000 mg/kg body weight. All 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, piloerection and/or hypersensitivity to touch were noted for the majority of animals between Days 1 and 3.

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.

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

The oral LD50 value of CMTX 2-carboxymethyloxy-thioxanthone in Wistar Han 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, CMTX 2-carboxymethyloxy-thioxanthone 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

LD50 > 2000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available