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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:
adopted May 12, 1981
Qualifier:
according to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Version / remarks:
Revised Edition November 1984
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-Ethylhexyl (R)-2-(2-methyl-4chlorophenoxy)propionate
EC Number:
630-324-3
Cas Number:
861229-15-4
Molecular formula:
C18H27ClO3
IUPAC Name:
2-Ethylhexyl (R)-2-(2-methyl-4chlorophenoxy)propionate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- batch No.of test material: 5007
- sample No.:1505E
- Expiration date of the lot/batch: March 1993

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: 4°C in the dark




Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach/Riss
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 299 (284-323) g for males and 264 (246 -276) g for females
- Housing: housed singly in type DK III stainless steel wire cages
- Diet: ad libitum, ground Kliba maintenance diet rat/mouse/hamster, 343 meal
- Water: ad libitum
- Acclimation period: 9 days

DETAILS OF FOOD AND WATER QUALITY: The food and water used was assayed for chemical and microbiological contaminants.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12hours/12 hours

IN-LIFE DATES: From: To: July 19, 1993 to August 26, 1993

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 50cm2, dorsal and dorsolateral parts of the trunk
- % coverage: 10%
- Type of wrap: 4 layers of absorbent gauze and an elastic dressing
- Time intervals for shavings or clipplings: at least twice once a week

REMOVAL OF TEST SUBSTANCE
- Washing: with lukewarm water
- Time after start of exposure: 6 hours

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test item in olive oil DAB 10 over 26 hours was confirmed by analysis. In addition, analysis was performed to verify the correctness of the concentrations of the test substance preparations. The content of the active ingredient was determined by combining the results of Chiral HPLC analysis and packed column GC analysis. The analysis of the test substance preparations in olive oil were determined by Reversed Phase HPLC (stability analysis in olive oil) and by HPLC with UV-Detection (concentration control analysis).
Duration of treatment / exposure:
4 weeks (21 applications)
Frequency of treatment:
5 x 6h/week
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Control animals:
other: yes, solvent control: olive oil DAB 10
Details on study design:
Mecoprop-P 2-EHE was applied 5 days per week for 6 hours to the clipped intact dorsal skin (at least 10 % of the body surface area) of Wistar rats over a period of 4 weeks (21 applications) using a semi occlusive dressing.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day, before and after exposure
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day on weekdays and once on weekends
DERMAL IRRITATION: Yes
- Time schedule for examinations: recorded daily, about 30 min after removal of the dressing
BODY WEIGHT: Yes
- Time schedule for examinations: once every week
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day
HAEMATOLOGY: Yes
- Time schedule for collection of blood: taken in the morning
- Anesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters: leucocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, clotting analysis
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: taken in the morning
- Animals fasted: Yes
- How many animals:5 animals per test group and sex (same as for hematology)
- Parameters checked: Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-gamma-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, and magnesium
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Statistics:
For body weight non-parametric one-way analysis was performed using the Kruskal-Wallis test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was carried out. This comparison was performed via the Mann-Withney U-test for hypothesis of equal medians. Both tests were performed two-sided. For all parameters, except the differential blood counts, a non-parametric one-way analysis was performed using the Kruskal-Wallis test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was carried out. This comparison was performed via the MANN-WITHNEY U-test for the hypothesis of equal medians. Both tests were performed two-sided.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Incidence and types of clinical signs were not adversely affected by treatment.
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight gain in test animals was comparable with that seen in controls.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were some statistically significant inter-group differences in the results of the clinical pathology testing. These deviations are marginal, sporadic or incidental, inconsistent, when compared with the other sex, or lack dosage-relationship. Accordingly, these findings are considered to be of ne toxicological significance.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No substance-related findings

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

The stability of the test substance in olive oil DAB 10 over a time interval of 26 hours was verified by analysis. The concentration control analysis yielded 96.5% and 100% of the nominal content for the 1.5g/100 mL and 15g/100 mL samples, respectively.

Applicant's summary and conclusion

Conclusions:
The NOAEL of MCPP-P 2-EHE for male and female rats after repeated dermal application for 4 weeks is 1000 mg/kg bw/day for systemic and local effects, the highest dose level investigated.
Executive summary:

An OECD TG 410 study under GLP conditions was performed to assess the dermal toxicity after repeated application of MCPP-P 2-EHE on rat skin over a period of 4 weeks. The unchanged test item was applied on clipped skin in concentrations of 1000, 150 or 15 mg/kg bw/day to 5 male and 5 female rats per dose. The frequency of treatment was 5 days per week for 6 hours. The test substance did not produce local irritation. No substance-related change in hematology and clinical chemistry was observed. In the clinical examinations, no substance-induced changes could be observed in all test groups. No treatment-related significant difference in absolute or relative weight parameters and no treatment-related gross lesions or microscopic findings were observed. The NOAEL of MCPP-P 2-EHE in this study is 1000 mg/kg bw/day for systemic and local effects for male and female rats.