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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-03-08 to 1983-03-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (e.g. purity of test substance not reported)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
no
GLP compliance:
no
Remarks:
study performed prior to implementation of GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Davidson's Mill Farm; Jamesbury, NJ, U.S.A.
- Age at study initiation: 12 - 14 weeks
- Weight at study initiation: not reported
- Fasting period before study: not reported, fasting prior to collecting of blood samples
- Housing: individually, in hanging wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 22 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): 11.3 h
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: mineral oil
Details on exposure:
TEST SITE
- Area of exposure: back
- % coverage: 30 % of total skin surface
- Type of wrap if used: gauze bandaging and occlusion with impervious plastic (Prime Wrap II (R)), wrapping of total application site with 3-inch wide Dermiform (R) Tape.
- Time intervals for shavings or clippings: not reported
- plastic collars (E-Jay Saf-T Shields, W.A. Butler, Inc. Columbus, Ohio, U.S.A.) were applied 1 week prior to study initiation and remained for the duration of the study

REMOVAL OF TEST SUBSTANCE
- Washing: tepid water and disposable papertowels
- Time after start of exposure: 6 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Concentration: 0, 25, 75 and 250 mg/mL
- Constant volume or concentration used: no
- For solids, paste formed: no, suspension


VEHICLE
- Justification for use and choice of vehicle: most suitable vehicle for generation of suspensions
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Lot/batch no. : not reported
- Purity: not reported


USE OF RESTRAINERS FOR PREVENTING INGESTION: no, plastic collars (E-Jay Saf-T Shields, W.A. Butler, Inc. Columbus, Ohio, U.S.A.) were applied 1 week prior to study initiation and remained for the duration of the study
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
3 weeks
Frequency of treatment:
5 days/week, 6 h/day
Doses / concentrations
Remarks:
Doses / Concentrations:
0,50, 150, 500 mg/kg (m/f)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table 1 were included.
- Presumably further observations were conducted in addition, but they were not reported in detail

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- no differentiation was made between cage side observation and clinical observations
- see table 1 for checked observations


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily
- grading of skin reactions according to Draize score


BODY WEIGHT: Yes
- Time schedule for examinations: at study start and weekly thereafter


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, but individual food consumption was estimated, based on visual examination of food remaining in the feeder dish


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: once on study day 0 and once at study day 20
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 6 per group
- Parameters checked in table 2 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once on study day 0 and once at study day 20
- Animals fasted: Yes
- How many animals: 6 per group
- Parameters checked in table 2 were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 3)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- occasional findings of ocular and nasal discharges in all groups except the high dose group, nasal discharge very prominent in high dose group
- other signs and findings are incidentally and scattered over the dose groups
- dermal irritation:
- no dermal irritation in the control group
- slight dermal irritation in the vehicle test group (slight erythema and slight to no edema) during the last 7 to 10 days of the study
- significant dermal irritation in the three dose groups showing dose-related progression, dermal irritation increased also with duration of the study in these dose groups (sequence: blanching, fissuring, desquamation, eschar (if present) and exfoliation (if present)
dose signs
50 mg/kg bw/day moderate to marked erythema and edema, blanching, fissuring and desquamation, plus 1/3 of the group showed eschar and exfoliation
150 mg/kg bw/day marked erythema and edema, blanching, fissuring and desquamation eschar and exfoliation
500 mg/kg bw/day marked erythema and edema, blanching, fissuring and desquamation eschar and exfoliation

- Mortality: 3 animals died
animal // dose goup // cause of death // test item related
animal 21465 // (150 mg/kg bw/day) // multifocal ulcerative dermatitis and associated debilitating effects // yes
animal 21435 // (vehicle control group) // multifocal renal and pulmonary abscessation // no
animal 21479 // (150 mg/kg bw/day) // severe hepatic necrosis and severe bronchopneumonia // no


BODY WEIGHT AND WEIGHT GAIN
- see table 4
- Body weight losses from study initiation to termination were noted for group 4 males and group 5 males and females
- Body weights of group 5 females were significantly different from both control groups at day 21 of the study
- All noted group mean body weight losses are considered biologically significant and related to the administration of the test article

FOOD CONSUMPTION
- no remarkable changes in the dietary habits of the study animals on the daily visual estimate of food remaining in the dish


HAEMATOLOGY
- No test article related values observed
- statistically significant differences from control group values were considered to be due to normal biological variability

CLINICAL CHEMISTRY
- No test article related values observed
- statistically significant differences from control group values were considered to be due to normal biological variability


URINALYSIS
- not performed

NEUROBEHAVIOUR
- not performed

ORGAN WEIGHTS
- no test article related changes observed
- occasional statistically significant changes either due to low body weights or within normal biological variability

GROSS PATHOLOGY
- no test article related changes observed

HISTOPATHOLOGY: NON-NEOPLASTIC
- all organs except skin:
- generally no test article related changes observed
- additional occasional findings in treated animals were similiar in type and frequency as in the control groups and were therefore considered to be due to normal biological variability
-skin:
- no findings in the untreated control group
- findings in the vehicle control groups included epidermal hyperkeratosis and acanthosis and follicular hyperkeratosis and acanthosis
- numerous test article related microscopic changes in the epidermis, dermis and follicles in treated skin of dosed animals:
- intraepidermal suppuration
- ulceration in the epidermis in groups 4 (mid dose) and 5 (high dose) (more prominent in group 5)
- more pronounced dermal inflammation and follicular acanthosis in dose groups compared to vehicle control
- more pronounced epidermal acanthosis and follicular hyperkeratosis (males only in groups 4 and 5)
- additional microscopic findings were considered not test item related

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- not applicable

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no indications for systemic toxicity
Key result
Dose descriptor:
LOAEL
Remarks:
local effects (irritation)
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: skin corrosion/irritation

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

- Table 4: Average body weights and body weight gains during 3 weeks of treatment

Dose rate

[mg/kg bw/day]

Body Weights (g)

Total Weight Gain

Week ‑1

Week 1

Week 2

Week 3

g

% of control

Male

    0

group 1

 2693 ± 179.7

 2906

 2984

 2968 ± 331.1

 275

 100

    0, vehicle

group 2

 2733 ± 263.3

 2831

 2929

 2972 ± 141.2

 239

 87

   Low (50)

group 3

 2686 ± 229.7

 2723

 2836

 2805 ± 335.9

 119

 43.3

  Mid (150)

group 4

 2672 ± 229.9

 2676

 2721

 2598 ±287.4

 - 74

 - 23

 High (500)

group 5

 2704 ±239.2

 2617

 2590

 2521 ± 305.6

 - 183

 - 67

Female

    0

group 1

 2819 ± 192.9

 2986

 3142

 3076 ±309.0

 257

 100

    0, vehicle

group 2

 2806 ±127.9

 2989

 3102

 3172 ±255.0

 366

 142

   Low (50)

group 3

 2799 ± 170.8

 2809

 2969

 2984 ±263.6

 185

 72.0

  Mid (150)

group 4

 2832 ± 178.9

 2817

 2962

 2935 ±163.2

 103

 40.1

 High (500)

group 5

 2821 ±226.4

 2743

 2778

 2646 ±292.3 1, 4

 175

 - 68.1

1  Significantly different (p 0.05) from the control.

2 Significantly different (p 0.01) from the control.

3  Significantly different (p 0.05) from the vehicle control.

4 Significantly different (p 0.01) from the vehicle control.

Applicant's summary and conclusion

Conclusions:
Under the condition of the present study a LOAEL of 50 mg/kg bw/day could be deduced for local dermal effects. As body weight effects were clearly assigned to reduced food intake due to stress caused by repeated treatment with the corrosive substance and no other indications for systemic toxicity was observed a systemic NOAEL of 500 mg/kg bw/d can be derived.