Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
other: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2010-08-24 to 2010-11-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Justification for type of information:
Hostapon SG and acylglycinate GCK-12H-T are structurally closely related UVCB substances, which differ predominantly in the counterion (sodium resp. potassium). According to the available experimental studies, both substances exhibit results in a comparable range. Therefore, it can be assumed that the results obtained with Hostapon SG for this specific endpoint also apply to acylglycinate GCK-12H-T.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Stability of Test Item: Stable under storage conditions
Stability of Test Item Dilution: Unknown in PEG 300; excluded from the statement of compliance.
Storage Conditions: At room temperature (range of 20 ± 5 °C, provided by Harlan Laboratories Ltd.), light protected.
Safety Precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.
Description: Colorless solid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Test Animals:
Animals: Rat, RccHan: WIST(SPF)
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM / The Netherlands
Number of Animals per Group: 5 males and 5 females
Total Number of Animals: 5 males and 5 females
Age (when treated): Males: 9 weeks, Females: 11 weeks
Body Weight Range (when treated): 228 g – 253 g (males), 189 g – 207 g (females)
Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked during acclimatization.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: Eight days under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

Environmental Conditions:
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70%, automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accommodation: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding (‘Lignocel’ J. Rettenmaier&Söhne GmbH&CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) during treatment and observation. Paper enrichment, Reference no. 207057, batch no. 67, (Enviro-dri from Lillico, Biotechnology, Surrey / UK) was included.
Diet: Pelleted standard Teklad Rat-Mouse Diet 2914C, irradiated, batch no. 30/10 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) ad libitum. Results of analyses for contaminants are archived at Harlan Laboratories Ltd.
Water: Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at Harlan Laboratories Ltd.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
Preparation of Dose Formulations:
Dose levels are in terms of the test item as supplied by the Sponsor. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The formulation was prepared shortly before the application using a magnetic stirrer, a spatula and an Ultra-Turrax as homogenizers. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Test Item Administration:
One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10% of the total body surface. Only those animals without injury or irritation on the skin were used in the test. On test day 1, the test item was applied evenly on the intact skin with a syringe and covered with a surgical gauze pad (ca. 5 x 5 cm) held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and an elastic adhesive restrainer bandage wrapped around the abdomen.
The application volume was 6 mL/kg.
Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and drapped off with disposable paper towels. Thereafter, the reaction sites were assessed. All animals were re-shaved on test day 8 to facilitate the reading of the local reactions.
Rationale: Dermal administration was used as this is one possible route of human exposure during manufacture, handling and use of the test item.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
The purpose of this study was to assess the acute dermal toxicity of Hostapon SG dried when administered to rats by single semi-occlusive dermal application, followed by an observation period of 14 days. This study should provide a rational basis for risk assessment.

Vehicle:
The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. Therefore, solubility testing was excluded from the statement of compliance. According to the Sponsor, the test item is soluble in water up to a concentration of 25%. Therefore, polyethylene glycol 300 (PEG 300) was used as vehicle and the test item could be dispersed at the technically highest concentration of 33 % (w/w). This was achieved with an Ultra Turrax and resulted in a white liquid, which was considered dermally applicable.
The following information was provided by Harlan Laboratories Ltd.:
Identification: Polyethylene glycol 300 (PEG 300)
Description: Colorless viscous liquid
Lot Number: STBB 3451
Source: Sigma-Aldrich Chemie GmbH, Riedstr. 2, D-89555 / Germany
Stability of the Vehicle: Stable under storage conditions
Expiry Date: 30-Apr-2012
Storage Conditions: At room temperature (range of 20 ± 5 °C), light protected.
Safety Precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.

Observations:
Viability / Mortality: Daily during the acclimatization period. Once before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Clinical Signs: Daily during the acclimatization period. Once before treatment, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities will be recorded.
Local Dermal Signs: Once daily during days 2 (following dressing removal) through day 15 using the numerical scoring system described in Appendix I.
Body Weights: On test days 1 (prior to administration), 8 and 15.

Pathology:
Necropsy: All animals were sacrificed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. An external examination and opening of the abdominal and thoracic cavities for examinations of major organs was performed. The appearance of any macroscopic abnormalities was recorded. No organs or tissues were retained.

Data Compilation:
Viability/mortality was recorded on data sheets.
Body weights were recorded on-line with the ToxControl Computer System.
Clinical signs, local dermal signs, mortality data and macroscopic findings were compiled into the ToxControl Computer System during recording.
The ToxControl Computer System has been licenced for Harlan Laboratories Ltd. and validated with respect to data collection, storage and retrievability.
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No intercurrent deaths occurred during the course of the study.
Clinical signs:
No clinical signs were recorded throughout the entire observation period.
Body weight:
One animal (No. 8) lost body weight (-1.0%) during the first week after test item administration. However, the animal regained weight until the end of the observation period. Otherwise, the body weight of the animals was within the range commonly recorded for animals of this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.

Any other information on results incl. tables

Local dermal signs:

Very slight to slight erythema was observed on test day 2 (1 male) or from test day 2 to test day 4 (1 female) or test day 6 (1 male). Very slight to slight oedema and slightly maculated crusts were observed in one female (No. 10) from test day 2 to 3 or from test day 7 to 15, the end of the observation period. Slight desquamation was noted in one male and three females during test day 3 to test day 7 or 11 and in one male from test day 8 to test day 12. Slight to moderate desquamation was noted in one female from test day 3 to test day 14. The test item caused white to yellow discoloration of the treated skin in two males and one female on test day 2.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information
Conclusions:
The median lethal dose of Hostapon SG dried after single dermal administration to rats of both sexes, observed over a period of 14 days, is:
LD50 (rat): greater than 2000 mg/kg body weight
Executive summary:

The acute dermal toxicity of `Hostapon SG dried` was investigated in an OECD 402 study in accordance with the principles of GLP. Five male and five female Wistar rats were treated with the test substance at 2000 mg/kg by dermal application. The test item was formulated in polyethylene glycol 300 as vehicle. The application period was 24 hours. Following a 14 day observation period all animals were necropsied and examined macroscopically. No intercurrent deaths occurred and no clinical signs were recorded throughout the entire observation period. The only substance related effects consisted of very slight to slight dermal irritation reactions in form of erythema and/or oedema in one male and two females during the observation period. No macroscopic findings were observed at necropsy. Based on the study results the median lethal dose (LD50) of Hostapon SG dried after single dermal administration to rats of both sexes was greater than 2000 mg/kg body weight.