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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
9/19/2001-10/16/2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
other: Japan 59 NohSan Notification No. 4200, Acute Dermal Toxicity Study
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(3-oxazolidinyl)ethyl methacrylate
EC Number:
256-260-2
EC Name:
2-(3-oxazolidinyl)ethyl methacrylate
Cas Number:
46235-93-2
Molecular formula:
C9H15NO3
IUPAC Name:
2-(1,3-oxazolidin-3-yl)ethyl 2-methylprop-2-enoate
Test material form:
liquid
Remarks:
yellow

Test animals

Species:
rat
Strain:
other: Crl: CD BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Adult male and female Crl:CD®BR rats were obtained from Charles River Laboratories, Raleigh, NC. Upon arrival, all animals were examined for physical abnormalities and quarantined/acclimated for approximately one week. The animals were individually housed in suspended stainless steel cages (18x34x20 cm) with wire mesh fronts and bottoms. Cages were suspended above absorbent-paper pan liners, which were changed 3 times a week. Throughout the test period, all rats had free access to water (via automatic watering) purified by reverse osmosis and PMI Certified Rodent Diet 5002(C) (Purina Mills Inc., Richmond, IN). The animal room was environmentally controlled with controls set to maintain a temperature of approximately 23 °C and a relative humidity range of 30-70%. The temperature and relative humidity were monitored 24 hrs a day. During the study, the average daily temperature was approximately 22°C and average daily relative humidity ranged from 44 to 54%. Any excursions beyond these ranges were minimal and did not affect the integrity of the study. Temperature and relative humidity remained in compliance with acceptable ranges defined in the "Guide for the Care and Use of Laboratory Animals" ISBN No. 0-309-05377-3, Revised 1996. The light cycle was automatically controlled, 12 hrs on and 12 hrs off.

On the day prior to treatment, rats were selected from a healthy stock population, assigned to the study group using a computer-generated sequence of random numbers and identified by uniquely numbered ear tags. At the time they were dosed, the males were approximately 8 weeks old and the females were approximately 9 weeks old. The body weights ranged from 236 to 274 g for males and from 204 to 244 g for females.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Approximately 24 hrs prior to the application of the test substance, the hair around the entire trunk between the flank and shoulders was shaved closely with electric clippers. The test substance, undiluted, was applied topically to the shaved intact skin (target of 10% body surface area) of five male and five female rats at 2000, 1200 or 400 mg/kg body weight. Dose was calculated on an "as is" basis; no adjustment was made for percent active ingredient. The entire trunk of each animal was wrapped in a polyethylene sheet covered with Elastoplast® (Beiersdorf, Inc., Norwalk, CT) and PEG®(Becton-Dickinson Co., Franklin Lakes, NJ) elastic bandages and secured in place with adhesive tape.

The test substance remained in contact on the skin of each animal for 24 hrs. Each cuff was removed after the 24-hr exposure period, and the application site was wiped with paper towels saturated with tap water. The application site was blotted dry with paper towels, and the approximate dimensions of the contact area of the test substance were determined.

Each animal was fitted with a cardboard collar to prevent preening of the application site. The collar was worn throughout the 14-day observation period.

After dermal application, the test substance covered an area approximately 6 cm x 6 cm.
Duration of exposure:
24
Doses:
400, 1200, 2000 mg/kg
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
All animals were observed for signs of ill health, or reaction to treatment at approximately 1, 2 and 4 hrs after dosing and once daily thereafter for 14 days. Body weights were recorded on day 0 (prior to dosing) and on days 7 and 14.

Decedents were necropsied as they were found. Surviving rats were euthanized on day 14 and necropsied. Necropsy consisted of a gross examination of organs in situ.
Statistics:
The mortality incidences of males and females were compared across doses with a categorical data modeling procedure using SAS CATMOD (SAS Institute Inc. SAS User's Guide: Statistics, Version 6 Edition, p 405-517. Cary, NC: SAS Institute Inc., 1990). The criterion of statistical significance was 0.05. Since the results did not indicate a significant difference between the mortality responses across dose groups for males and females, the LDso was calculated on the pooled (male and female combined data) mortality incidences at each dose.

The LD50, 95% confidence limits; and slope were calculated from the logarithm of the doses and the incidences of mortality using a SAS PR OBIT procedure (SAS Institute Inc. SAS User's Guide: Statistics, Version 6 Edition, p 1324-1350. Cary, NC: SAS Institute Inc., 1990) based on the method of D.J. Finney (Probit Analysis, Third Edition, London: Cambridge University Press, 1971 ).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 641 mg/kg bw
Based on:
test mat.
95% CL:
ca. 1 115 - ca. 3 663
Mortality:
Three males and 4 females at 2000 mg/kg and 2 females at 1200 mg/kg died by day 2. No deaths occurred in either sex at 400 mg/kg.
Clinical signs:
Scant or no feces was observed in both sexes at 2000 mg/kg on days 1 and 2. Ataxia and passiveness were seen in both sexes at 2000 mg/kg and in one female at 1200 mg/kg on day 1. There were no clinical signs of systemic toxicity noted in either sex at 400 or in males at 1200 mg/kg.

Periodically during the study, the fur surrounding the eyes and muzzle of several animals was observed to be red stained; these effects were judged to be caused by the occluded testing methodology and by the use of collars.

Skin effects, (i.e., edema,. erythema, pocketing edema, eschar, blanching, dark areas, scabs, sloughing and desiccation), were observed in both sexes at all levels beginning on day 1 and continued through the day 14 observation period.
Body weight:
Body weight gain over the 14-day observation period was decreased (10- 71 %) in both sexes at all levels when compared to historical control data.
However, all surviving animals gained weight by the end of the observation period.
Gross pathology:
Necropsy of the decedents in both sexes at 2000 mg/kg revealed carcass autolysis and gastrointestinal changes which included stomach: contains black material, glandular portion reddened, and intestine: reddened or blackened. Two females at 1200 mg/kg revealed carcass autolysis only. Necropsy of survivors revealed no gross observations.
Other findings:
The acute dermal LD50 in male and female rats is 1641 mg/kg with 95% confidence limits of 1115 to 3 663. The log probit slope of the dose-mortality data (probit incidence versus log dose) was 4.89 in this study.

Any other information on results incl. tables

Table 1: Male Mortality

 Dose (mg/kg bw)  Died  Comments
 400  0/5  
 1200  0/5  
 2000  3/5

 All died on day 1.

Table 2: Female Mortality

 Dose (mg/kg bw)  Died  Comments
 400  0/5  
 1200  2/5  Animals died on days 1 and 2.
 2000  4/5  Animals died on days 1 (n=3) and 2 (n=1).

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute dermal toxicity of OXEMA was assessed in Crl:CD®BR rats. The test substance was applied to the shaved intact skin of five male and five female rats at 2000, 1200 or 400 mg/kg body weight. The application sites were occluded for 24 hrs. After the 24-hr exposure, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels.

Three males and four females died at 2000 mg/kg and two females died at 1200 mg/kg. Scant or no feces was noted in both sexes on days 1 and 2. Ataxia and passiveness were seen in both sexes at 2000 mg/kg and in one female at 1200 mg/kg on day 1. There were no clinical signs of systemic toxicity noted in either sex at 400 or in males at 1200 mg/kg. Signs of skin irritation (i.e., edema, erythema, pocketing edema, eschar, blanching, dark areas, scabs, sloughing and desiccation) were observed in both sexes at all levels beginning on day 1 and continued through the day 14 observation period. Body weight gain over the 14-day observation period was decreased (10-71 %) in both sexes at all levels when compared to historical control data. Necropsy of the decedents in both sexes at 2000 mg/kg revealed gastrointestinal changes. Necropsy of decedents at 1200 mg/kg showed no treatment-related changes. Necropsy of survivors revealed no gross observations. The acute dermal LD50 in male and female rats for OXEMA is 1641 mg/kg with 95% confidence limits of 1115 to 3663.
Executive summary:

The acute dermal toxicity of OXEMA was assessed in Crl:CD®BR rats. The test substance was applied to the shaved intact skin of five male and five female rats at 2000, 1200 or 400 mg/kg body weight. The application sites were occluded for 24 hrs. After the 24-hr exposure, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels.

Three males and four females died at 2000 mg/kg and two females died at 1200 mg/kg. Scant or no feces was noted in both sexes on days 1 and 2. Ataxia and passiveness were seen in both sexes at 2000 mg/kg and in one female at 1200 mg/kg on day 1. There were no clinical signs of systemic toxicity noted in either sex at 400 or in males at 1200 mg/kg. Signs of skin irritation (i.e., edema, erythema, pocketing edema, eschar, blanching, dark areas, scabs, sloughing and desiccation) were observed in both sexes at all levels beginning on day 1 and continued through the day 14 observation period. Body weight gain over the 14-day observation period was decreased (10-71 %) in both sexes at all levels when compared to historical control data. Necropsy of the decedents in both sexes at 2000 mg/kg revealed gastrointestinal changes. Necropsy of decedents at 1200 mg/kg showed no treatment-related changes. Necropsy of survivors revealed no gross observations. The acute dermal LD50 in male and female rats for OXEMA is 1641 mg/kg with 95% confidence limits of 1115 to 3663.

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