Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: In compliance with GLP; according to the OECD guideline 402 (1987)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. certificate)
Remarks:
Assessment on 21-25 March 2011, signed 19 May 2011
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report):MK-0954 Free Acid
- Molecular formula (if other than submission substance):C22H23ClN6O
- Molecular weight (if other than submission substance):422.91
- Physical state: solid
- Analytical purity:
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date:
- Lot/batch No.: Substance 204024/A
- Expiration date of the lot/batch: 24 April 2013 (1 year after receipt of the substance)
- Stability under test conditions:
- Storage condition of test material: At room temperature in the dark
- Other:
ph: 5.8-5-6 (determined at Notox)
hygroscopic: No

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany; Crl:WI (Han) (outbred, SPF-Quality)
- Age at study initiation: Young adult animals(aprox 10 weeks old)
- Weight at study initiation: +/- 20% of the sex mean
- Fasting period before study: no
- Housing:Individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum):Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): free access to tap water
- Acclimation period: at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70 %
- Air changes (per hr): approx 15 room air changes /hour
- Photoperiod (hrs dark / hrs light): 12 hoursdark/12 hours light cycle

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% Aqueous carboxymethyl cellulose (Carmellosum natricum middelvisceus, BUFA, IJsselstein, The Netherlands; water: Elix, Millipore S.A.S., Molsheim, France).
Details on dermal exposure:
TEST SITE
- Area of exposure:One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped
- % coverage: in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- Type of wrap if used:The formulation 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.*. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).


REMOVAL OF TEST SUBSTANCE
- Washing (if done):dressings were removed and the skin cleaned of residual test substance using tap water.
- Time after start of exposure:24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution): 2000 mg/kg (10 mL/kg) body weight
- Constant volume or concentration used: yes
- For solids, paste formed:no

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):1% Aqueous carboxymethyl cellulose (Carmellosum natricum middelvisceus, BUFA, IJsselstein, The Netherlands; water: Elix, Millipore S.A.S., Molsheim, France).
- Lot/batch no. (if required): not indicated
- Purity:The formulation (w/w) was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. No correction was made for purity of the test substance
Duration of exposure:
24 hours
Doses:
2000 mg/kg (10 mL/kg) body weight
No. of animals per sex per dose:
5 mals/5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 day
- Frequency of observations and weighing:
At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
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 of survivors performed: yes, sacrificed by oxygen/carbon dioxide procedure
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Descriptions of all internal macroscopic abnormalities were recorded.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occurred.
Mortality:
no mortality occured
Clinical signs:
Chromodacryorrhoea was noted in one male and one female on Day 1.
Scales and/or focal erythema were seen in the treated skin-area of two animals during the observation period.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
The dermal LD50 value of MK-0954 Free Acid in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, MK-0954 Free Acid 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 (2011) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures
Executive summary:

MK-0954 Free Acid was administered to five Wistar rats of each sex by a single dermal application at 2000mg/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 was noted in one male and one female on Day 1. Scales and/or focal erythema was were seen in the treated skin-area of two animals during the observation period.

 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 MK-0954 Free Acid in Wistar rats was established to exceed 2000 mg/kg body weight.