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Description of key information

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-07-04 to 1988-06-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Principles of method if other than guideline:
- Principle of test: To determine the possible dermal irritation of Aledronate Sodium a bone resorption inhibitor, when applied to skin of rabbits for 24 hours.
- Short description of test conditions: A testto determine the skin irritation caused by application of the neat test substance onto shaved and abraded skin of 3 rabbits.
- Parameters analysed / observed: The rabbits were observed daily for systemtic toxicity and mortality, as well as dermal examinations were scored according to the Draize Method.
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot No.of test material: Sponsor and 004
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, PA
- Age at study initiation: Approximately 26 weeks
- Weight at study initiation: 3.72 - 3.96 kg
- Housing: stainless steal cages
- Diet (e.g. ad libitum): Certified Purina High Fiber Rabbit Diet ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Pre-determined standards
- Humidity (%): Pre-determined standards
- Air changes (per hr): Pre-determined standards
- Photoperiod (hrs dark / hrs light):Pre-determined standards
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg/site
Duration of treatment / exposure:
24 hours
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: Plastic occlusive wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Cleaned with tap water
- Time after start of exposure: 24 hours

OBSERVATION TIME POINTS
1, 2, 3, 4, 5, 6, 7,8,9,10,11,12,13,14 days

SCORING SYSTEM:
- Method of calculation: Draize Modified Scoring System
A Erythema and eschar formation: Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4

B Edema formation:
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-definedby definite raising) 2
Moderate edema (raised approximately 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
14 d
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
14 d
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
14 d
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
14 d
Score:
1
Max. score:
1
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
14 d
Score:
1
Max. score:
1
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
14 d
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of severe irritation
Irritant / corrosive response data:
MK-0217 in 24 hours produced well-defined erythema on 2 intact sites and slight edema on 1 site. One rabbit had no signs on the intact site after 24 hours. The incidence and severity of these signs generally increased and all sites had erythema and edema by Day 3. By Day 8 through Day 14 all intact sites had moderate to severe erythema with slight edema observed on 2 sites and moderate edema observed on the third. Wrinkling of several sites was seen starting Day 7 to Day 0 until Day 12, while scaling was observed from Day 10 to Day 14.

Other effects:
- Other adverse systemic effects: MK-0217 produced no observable systemic toxicity throughout the duration of the study.

AS = Abraded Skin / IS = Intact Skin

 Rabbit # and Sex        Type of Irritation Score 24 Hours 2 Days 3 Days 4 Days 5 Days 6 Days  7 Days 8 Days  9 Days    10 Days 11 Days     12 Days     13 Days     14 Days  
AS IS AS IS AS IS AS IS AS IS AS IS

AS

IS

AS

IS

AS

IS

AS

IS

AS

IS

AS

IS

AS

IS

AS

IS

 Male #1   

 Erythema

 4

 0

 4

 0

 4

 2

 4

 2

 *

 *

 *

 *

 4

 3

 4

 3

 4

 3

 4

 3

 4

 3

 4

 3

 4

 3

 4

 3

 Edema

 1

 0

 1

 0

 2

 0

 2

 1

 *

 *

 *

 *

 2

 1

 2

 1

 2

 1

 2

 1

 2

 1

 2

 1

 2

 1

 2

 1

 Female #1   

 Erythema

 2

 2

 2

 2

 2

 2

 3

 2

 *

 *

 *

 *

 3

 3

 3

 3

 3

 4

 3

 4

 3

 4

 3

 4  3  4  3
 Edema  1  0  2  1  3  1  3  1  *  *  *  *  3  1  3  1  3  1  3  1  3  1  3  1  3  1  3  1
 Female #2     Erythema  4  2  4  2  4  3  4  3  *  *  *  *  4  3  4  3  4  3  4  3  4  3  4  3  4  3  4  3
 Edema  2  2  2  2  2  2  3  2  *  *  *  3  2  3  3  3  3  3  3  3  3  3  3  3  3  3  3

 

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
This study found the neat test substance to be extremely irritating to both the intact and abraded skin of rabbits.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-06-20 to 1988-06-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Principles of method if other than guideline:
- Principle of test: To determine the possible ocular irritation of L-670,452, a bone resorption inhibitor, when applied to one eye each of four rabbits.
- Short description of test conditions:
- Parameters analysed / observed: Eye irritation scores per Draize method
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot No.of test material: PR&D, Rahway, NJ. and #04
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, PA
- Age at study initiation: ~26 weeks
- Weight at study initiation: 3.70-4.07 kg
- Housing: Stainless steel cages
- Diet (e.g. ad libitum): Certified Purina High Fiber Rabbit Chow
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled and set to predetermined standards
- Humidity (%): Controlled and set to predetermined standards
- Air changes (per hr): Controlled and set to predetermined standards
- Photoperiod (hrs dark / hrs light): Controlled and set to predetermined standards
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
100 mg/eye
Duration of treatment / exposure:
The eye was held closed for 20 seconds
Observation period (in vivo):
48 hours
Number of animals or in vitro replicates:
4
Details on study design:
SCORING SYSTEM:
CALE FOR SCORING OCULAR LESIONS (Draize Method)

(1) Cornea
(A) Opacity-degree of density (area most dense taken for reading)
No opacity-------------------------------------------------------------------- 0
Scattered or diffuse area, details of iris clearly visible-------------------- 1
Easily discemible translucent areas, details of iris slightly obscured------- 2
Opalescent areas, no details of iris visible, size of pupil barely discemible 3
Opaque, iris invisible-------------------------------------------------------- 4
(B) Area of comea involved
One quarter (or less) but not zero-------------------------------------------- 1
Greater than one quarter, but less than half---------------------------------- 2
Greater than half, but less than three quarters------------------------------- 3
Greater than three quarters, up to whole area--------------------------------- 4
A X B X 5
Total maximum = 80

(2) Iris
(A) Values
Normal------------------------------------------------------------------------ 0
Folds above normal, congestion, swelling, circumcomeal injection (any or all
of these or combination of any thereof), iris still reacting to light
(sluggish reaction is positive)--------------------------------------------- 1
No reaction to light, hemorrhage, gross destruction (any or all of these)----- 2
A X 5
Total maximum = 10

(3) Conjunctivae
(A) Redness (refers to palpebral and bulbar conjunctivae, excluding comea and iris)
Vessels normal---------------------------------------------------------------- 0
Vessels definitely injected above normal-------------------------------------- 1
More diffuse deeper crimson red, individual vessels not easily discemible---- 2
Diffuse beefy red------------------------------------------------------------- 3
(B) Chemosis
No swelling------------------------------------------------------------------- 0
Any swelling above normal (includes nictitating membrane)--------------------- 1
Obvious swelling with partial eversion of lids-------------------------------- 2
Swelling with lids about half closed------------------------------------------ 3
Swelling with lids about half closed to completely closed--------------------- 4
(C) Discharge
No discharge------------------------------------------------------------------ 0
Any amount different from normal (does not include small amounts observed in
inner canthus of normal animals)-------------------------------------------- 1
Discharge with moistening of the lids and hairs just adjacent to lids--------- 2
Discharge with moistening of the lids and hairs and considerable area around
the eye--------------------------------------------------------------------- 3
Score (A + B + C) x 2
Total maximum = 20
Irritation parameter:
cornea opacity score
Basis:
other: animals 1-4
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
other:
Remarks:
animal euthanised in extremis at 48 hr
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
other: animals 1-4
Time point:
24 h
Score:
1
Max. score:
1
Reversibility:
other: see above
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
other: animals 1-4
Time point:
24/48 h
Score:
4
Max. score:
4
Reversibility:
other: see above
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
other: animals 1-4
Time point:
24/48 h
Score:
3
Max. score:
3
Reversibility:
other: see above
Remarks on result:
positive indication of irritation
Irritation parameter:
other: discharge
Basis:
other: Animals 1-4
Time point:
24/48 h
Score:
3
Max. score:
3
Reversibility:
other: see above
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
L-670,452 produced congestion of the iris, corneal anesthesia, conjnnctival injection, chemosis, and discharge within 15 minutes of treatment. After 2 hours slight corneal opacity was seen in the eyes of two rabbits. By 24 hours each eye had moderate corneal opacity with anesthesia, and severe conjunctival injection, chemosis, and discharge (clear and colorless with some white mucoid material). Chemosis at 24 hours prevented observation of the entire eye. In 48 hours, only severe chemosis and discharge were noted because the eyes were tightly shut and no attempt was made to open them. The discharge showed a red coloration that had not previously been seen.

L-670,452 produced no observable systemic toxicity throughout the duration of the study.
Other effects:
All rabbits survived to the termination of the study.
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
L-670,452 was found to be extremely irritating to the eyes of rabbits.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Based upon the weight of evidence from dermal, ocular and oesophageal irrritancy studies it is concluded that the substance will be a respiratory irritant.

Justification for classification or non-classification

In vivo studies conducted with the source substance, sodium alendronate, resulted in severe irreversible skin irritation (erythema with concommitent scaling) 14 days post dosing ; in conjunction with the pH of the target substance (pH 2.1) this was considered sufficient to classify the substance as Skin corrosive 1C.

Ocular studies conducted in NZW rabbbits resulted in premature termination of the study on humane grounds following extreme chemosis at the 48hr timepoint; the substance is considered to be classified as Severe Eye Damage 1.

Oesophageal irritancy studies conducted in dogs resulted in ulcerative damage following 4 weekly doses of the substance; this has been considered to be a surrogate tissue for the respiratory tract mucosa and classification as a respiratory irritant is justified.