Registration Dossier

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:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Brown particles
Details on test material:
- Name of test material (as cited in study report): MON 13900
- Physical state: Brown particles
- Purity: 96.4%
- Lot/batch No.: DAY-8912-1370T
- Vapor pressure: 5 x 10-6 Torr
- Octanol/water partition coefficient: 2.67
- Date received: June 22, 1990

Test animals

Species:
other: Albino rat
Strain:
other: Sprague-Dawley (CD)
Sex:
male/female
Details on test animals and environmental conditions:
Source: Charles River Breeding Laboratory, Portage, MI
Sex and numbers: Males, 32; females, 32
Age at study start: Approx 8 wk
Weight range at study start: Males-90.3-329.9 g; females-178.9-209.1 g
All rats were housed one per cage. Information on the temperature and humidity of the animal room was not provided. However, the study authors stated that animal housing and husbandry were in accordance with the provisions of the “Guide to the Care and Use of Laboratory Animals.” Animals were identified by an individual eartag and a barcoded cage card. The animal room was supplied daily with 12 h of light. The rats were acclimated to laboratory conditions for approx 27 d prior to dosing. Purina Certified Rodent Chow #5002 and tap water were provided ad libitum throughout the predose and dosing periods. Rats were assigned into groups according to weight via computer-generated randomization.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Neat test substance was dermally applied under occlusion to a shaved area (approx 25 cm2) on each animal’s back. The shaved area comprised approximately 10% of the total body surface. The shaved area was covered with a gauze patch and occlusive dressing.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21 d
Frequency of treatment:
6 h/d, 5 d/wk
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 250, and 1000 mg/kg bw/day
Basis:
nominal per unit area
No. of animals per sex per dose:
8/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on a previous range-finding study; the range-finding study reported no observed effect level (NOELs) of 500 mg/kg bw/day for males and 1000 mg/kg bw/day for females. The low observed effect level (LOEL) for males was 750 mg/kg bw/day based on a dose-related increase in the incidence of liver foci; a LOEL was not established for females. Liver foci were observed during the macroscopic pathology examination.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and moribundity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily for clinical signs of toxicity

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Throughout the study period

BODY WEIGHT AND FOOD CONSUMPTION: Yes
- Time schedule for examinations: Once weekly

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
General observations: No mortalities occurred during the study. There were no treatment-related signs of dermal irritation or clinical indications of systemic toxicity. No effects were observed on body weight or food consumption.

Haematology and clinical chemistry: There were no alterations in haematological parameters that were considered toxicologically significant. Blood urea nitrogen (BUN) was slightly, but significantly increased (128% of control mean value) in females from the 1000 mg/kg/day group.

Gross pathology, organ weights and histopathology: No treatment-related changes in gross pathology, organ weights or histopathology were observed

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
haematology
clinical biochemistry
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
haematology
clinical biochemistry

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOEL of MON 13900 for the local effects was > 1,000 mg/kg bw/day for males and females. The NOEL for systemic toxicity was determined to be 250 mg/kg bw/day for females and > 1,000 mg/kg bw /day for males.



Executive summary:

A study was conducted to evaluate the subchronic toxic effects of MON 13900 when administered by the dermal route in Sprague-Dawley rats. The study was performed according to the EPA Guideline OPP 82-2 in compliance with GLP.

 

The test substance was administered dermally to three groups of rats at dose levels of 25, 250 and 1,000 mg/kg bw/day. No mortalities occurred during the study. There were no treatment-related signs of dermal irritation or clinical indications of systemic toxicity. No effects were observed on body weight or food consumption. There were no alterations in haematological parameters that were considered toxicologically significant. Blood urea nitrogen (BUN) was slightly, but significantly increased (128% of control mean value) in females from the 1,000 mg/kg bw/day group. No treatment-related changes in gross pathology, organ weights or histopathology were observed.

 

Under the test conditions, the NOEL of the test substance for the local effects was > 1,000 mg/kg bw/day for males and females. The NOEL for systemic toxicity was determined to be 250 mg/kg bw/day for females and > 1,000 mg/kg bw /day for males.