(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid;hydrate

Eye irritation

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1994

Materials and methods

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

Test material

Test material information

Constituent 1

Reference substance name:

sodium;(4-amino-1-hydroxy-1-phosphonobutyl)-hydroxyphosphinate

Cas Number:

121268-17-5

Molecular formula:

C4H12NaNO7P2 · 3 H2O

IUPAC Name:

sodium;(4-amino-1-hydroxy-1-phosphonobutyl)-hydroxyphosphinate

Test material form:

solid

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

Test animals / tissue source

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

Test system

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

Results and discussion

In vivo

Results

Results 1

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

Results 2

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

Results 3

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

Results 4

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

Results 5

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.

Applicant's summary and conclusion

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.