Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06 October 1980 - 06 April 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-GLP, no reporting/interpretation of results, missing data (clinical signs, histopathology findings reported with extremely low detail). Suspected pneumonitis and parasitic infestation of some animals. However the raw data given enable to set local and systemic NOAELs (set by RSS/CSR author) for risk assessment of dermal exposures.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Version / remarks:
mentioned as Federal Register, 43 n° 163
Principles of method if other than guideline:
following deviations to OECD 410: only 2 doses (+ control), only 3 rabbits/dose/sex with intact skin, no reporting of conclusions, no data on clinical signs, ornithine decarboxylase not measured, clotting potential only reported semi-quantitatively, insufficient top-dose (below 1000 mg/kg/day and did not cause toxic effects)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
other: Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Breeder: H.A.R.E. Rabbits for Research, P.O. Box "X", Hewitt, New Jersey 07421
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 2.0 - 2.6 kg
- Housing: the rabbits were housed individually or two to a cage in galvanized steel cages with suspended grid flooring
- Diet (e.g. ad libitum): Charles River Rabbit Chow
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 7 days.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: dorsal trunk, clipped and shaved
- % coverage: 10% of body surface
- Type of wrap if used: gauze patch + surgical hypoallergenic adhesive tape + impervious Saran wrap + elastic bandage
- Time intervals for shavings or clippings: "as necessary" (no details)
NB: skin abrasion was carried out on some animals, animals excluded for this RSS, but showing similar results

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with corn oil
- Time after start of exposure: 6h each day

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 and 500 mg/kg/day, no other detail, see calculations at end of RSS by RSS/CSR author

VEHICLE
- none

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, collar during non-exposure times
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
21 days
Frequency of treatment:
Application of the test material on five days per week for three consecutive weeks. 15 treatments.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
500 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6 animals per sex and per dose. 3 with intact skin, 3 with abraded skin.
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale:
The dose-levels were selected so that the highest dose-level would show toxicological or pharmacological effects but would not cause more than 10 percent fatalities.

- Rationale for animal assignment (if not random): random
Positive control:
Not applicable.

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes (cage side or detailed: not indicated)
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily according to Draize scale, one hour after end of treatment

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD CONSUMPTION: yes
- Food consumption for each animal determined : Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD EFFICIENCY: not calculated

WATER CONSUMPTION, OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY, CLINICAL CHEMISTRY: Yes
- Time schedule: at the beginning of the study (before initiation of testing) and at the end of 21-day test period on each animal in the study

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (as required by OECD 410)

ORGANS WEIGHED: Yes (all those required by OECD 410 + many others)

HISTOPATHOLOGY: Yes (all those required by OECD 410 + many others)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
skin only
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Details on results:
No data on clinical signs, only mortality reported. Two deaths occured which were likely not related to the test item (one was due to pneumonitis).

Intercurrent diseases : pneumonia (suspicion of Pasteurella) and liver parasitism (suspicion of coccidiosis), non test-item related

Only dermal effects were noted:
- IN-LIFE : see summary details under section 7.3.1; dose and time-related, delayed erythema and edema in all animals (abraded or not), with occasional skin craking; at both dose-levels
- GROSS NECROPSY: skin changes were minimal to slight and infrequent (occasional erythema, thickening/epithelial hyperplasia/roughening, crusts, dermal inflammation, or hyalinized scar in dermis)
- HISTOPATHOLOGY: not assessable from the poorly detailed data reported (no raw data)

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No relevant systemic effect in the study
Dose descriptor:
conc. level: NOAEC local
Effect level:
0.22 mg/cm² per day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on skin cracking, erythema and edema. Derivation detailed under section "Irritation" of IUCLID.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

For 2EHN applied dermally under semi-occlusion to rabbit skin, 5 days/week for 3 weeks, the systemic NOAEL appeared to be 500 mg/kg/day (highest tested dose; in absence of data of clinical signs, and in view of very limited histopathology data, this is a screening value) and the local NOAEC was derived as 0.22 mg/cm2/day due to erythema, edema and skin cracking appearing in a delayed manner along repeated exposures. NOAEC derivation by RSS/CSR author is explained under section 7.3.1 and in CSR.