Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
03 Feb 2017 - 21 Feb 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 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to
Guideline:
other: EC No 440/2008 Part B. Acute Toxicity (Dermal)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
other: Appendix to Director General Notification, No. 12-Nousan-8147. JMAFF
Version / remarks:
November 2000
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
white to brownish
Details on test material:
Batch 151222

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han); Outbred, SPF-Quality
Sex:
male/female
Details on test animals and environmental conditions:
Test animals
Source:
Charles River France, L’Arbresle, France
Number of Animals:
5 males and 5 females (females were nulliparous and non-pregnant).
Age at the Initiation of Dosing:
Young adult animals (approximately 10 weeks old) were selected.
Weight at the Initiation of Dosing:
276 to 313 g (males) and 189 to 198 g (females).

Animal Identification
At study assignment, each animal was identified using a 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.

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°C to 24°C with a relative target humidity of 40% to 70% were maintained. A 12‑hour light/12‑hour dark cycle was maintained, except when interrupted for designated procedures. 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.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
propylene glycol
Remarks:
Trial preparations were performed at the Test Facility to select the suitable vehicle and to establish a suitable formulation procedure.
Details on dermal exposure:
Administration of Test item
A single dose of test item was administered to the appropriate animals by dermal application on Day 1. One day before dosing, an area of approximately 5x7 cm on the back of the animals was clipped. The test item was applied in an area of approximately 10% of the total body surface, i.e. approximately 25 cm² for males and 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only. The application period was 24 hours, after which the dressing was removed and the skin cleaned of residual test item using water or an appropriate vehicle.
The dose level was 2000 mg/kg body weight.
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 will be used for each dose.
The dosing formulations were stirred continuously during dose administration.
Justification of Route and Dose Levels
The dermal route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item. The dose level was based on the OECD test guidelines.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Mortality/Moribundity Checks
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, once in the morning and once in the afternoon. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.

Clinical 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), particular attention being paid to the animals during and for the first hour after dosing.
Animals were weighed individually on Day 1 (predose), 8 and 15.

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

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortality occurred
Clinical signs:
Chromodacryorrhoea (snout) was noted in the majority of animals on Days 1 and/or 2. Additionally, rales were noted for two female animals on Day 1 only.
Alopecia of the forelegs was noted for one female animal throughout the entire observation period, this effect was considered not indicative of toxicity.
General erythema, maculate erythema, scales and/or scabs were seen in the treated skin-area of the animals during the observation period. These local effects were considered not to have affected the conclusion of the study.
Body weight:
The mean 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:
Based on these results, CH02906 does not have to be classified and has no obligatory labelling requirement for acute dermal 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 CH02906, when given by a single dermal dose.

Assessment of Acute Dermal Toxicity with CH02906 in the Rat.

The study was carried out based on the guidelines described in:

·     OECD No. 402 (1987) "Acute Dermal Toxicity"

·     EC No 440/2008, B: "Acute Toxicity (Dermal)"

·     EPA, OPPTS 870.1200 (1998), "Acute Dermal Toxicity"

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

CH02906 was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

 

No mortality occurred.

Chromodacryorrhoea[KV1] (snout) was noted in the majority of animals on Days 1 and/or 2. Additionally, rales were noted for two female animals on Day 1 only.

General erythema, maculate erythema, scales and/or scabswere seen in the treated skin-area of the animals during the observation period. These local effects were considered not to have affected the conclusion of the study.

The mean body weight gain during the observation period was within the range expected for rats used in this type of study.

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

 

The dermal LD50 value of CH02906 in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, CH02906 does not have to be classified and has no obligatory labelling requirement for acute dermal 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).

 [KV1]Chromodacryorrhea?