Tetraisopropyl methylenebisphosphonate

Endpoint summary

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:

supporting study

Study period:

from 1989-12-27 to 1990-02-13

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No indication on the purity of the substance

Qualifier:

no guideline followed

Principles of method if other than guideline:

To determine the irritation potential of the test article when applied dermally. This study was designed to comply with the FHSA standards set forth by 16 CFR 1500.41.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals
- Age at study initiation: No data
- Weight at study initiation: 2.0 -2.5 kg
- Housing: The animals were housed 2/cage in suspended wire mesh cages. Bedding was placed beneath the cages and changed twice/week.
- Diet (e.g. ad libitum): Fresh Purina Rabbit Chow (Diet #5321)
- Water (e.g. ad libitum): yes
- Acclimation period: At lest one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controled but no data available
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From 1990-01-02 to 1990-01-05

Type of coverage:

occlusive

Preparation of test site:

other: clipped, abraded on left side and intact on right side

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL /site

Duration of treatment / exposure:

24 hour oclusive exposure

Observation period:

72 hours

Number of animals:

6 (3 males and 3 females)

Details on study design:

TEST SITE
Prior to application of the test article, the back and sides of each animal were clipped free of hair. The left side of each animal was abraded with a bent tip needle. Three abrasions, approximately 2-3 cm apart, extending the length of the exposure site were made. The abrasions were sufficiently deep to penetrate the stratum corneum, but not deep enough to produce bleeding. The right side of each animal remained intact.

EXPERIMENTAL DESIGN
The test article was used as received and dosed by volume, 0.5 ml/site, for a total dose of 1.0 ml/rabbit. The test article was applied to two areas, 1 intact and 1 abraded, on the prepared site, on the back of each of six rabbits.
The treated sites were covered with 2.5 cm square gauze patches which were secured with adhesive tape. The torso was wrapped with plastic which was secured with adhesive tape. The sites were occluded for 24 hours at which time the patches were removed.

TYPE AND FREQUENCY OF OBSERVATIONS
Animals were observed for skin reactions at 24 and 72 hours after application of the test article. Erythema and edema were scored according to the numerical Draize technique. Body weights were recorded pretest. Additional signs were described.
The general health of the animals was monitored at each observation time.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24h and 72h

Score:

1.17

Max. score:

1.17

Reversibility:

no data

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

0.75

Max. score:

1.17

Reversibility:

no data

Remarks on result:

other: Intact skin

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

0.835

Max. score:

1.17

Reversibility:

no data

Remarks on result:

other: Abraded skin

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

0.335

Max. score:

0.67

Reversibility:

no data

Remarks on result:

other: Intact skin

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24h and 72 h

Score:

0.42

Max. score:

0.67

Reversibility:

no data

Remarks on result:

other: Abraded skin

Individual scores

Animal number		C7859	C7860	C7861	C7808	C7813	C7814	Mean Scores
Pretest body weight (kg)		2.4	2.5	2.0	2.3	2.0	2.0
Erythema & eschar formation
Intact Skin	24h	1	1	1	2	1	1	1.17
	72h	0	0	0	1	0	1	0.33
Abraded skin	24h	1	1	1	2	1	1	1.17
	72h	1	0	0	1	0	1	0.50
Edema
Intact skin	24h	2	0	1	0	0	1	0.67
	72h	0	0	0	0	0	0	0
Abraded skin	24h	2	0	1	0	0	1	0.67
	72h	1	0	0	0	0	0	0.17
Sum of mean score								4.68
Primary dermal irritation index = sum of mean score /4								1.17

Interpretation of results:

GHS criteria not met

Conclusions:

The substance was not considered to be irritant.

Executive summary:

The dermal irritation of TIPMDP was tested on 6 New Zealand Albino rabbits in a primary dermal irritation following the standards set forth by FHSA, 16 CFR 1500.3(c)(4). 0.5 ml of the test substance was applied to 1 intact and 1 abraded site on the clipped back for a total dose of 1.0 ml/rabbit. The sites were occluded for 24 hours. The skin reactions were evaluated by the Draize technique at 24 and 72 hours after dosing. Body weights were recorded pretest. The Primary Irritation Index was calculated.

Erythema , slight to well defined at 24 hours, was absent to slight at 72 hours. Edema, absent to well defined at 24 hours, was absent at 72 hours. Abnormal systemic signs of diarrhea and few feces were noted during the observation periods. The substance was not found to be irritating to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

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:

from 1993-03-08 to 1993-09-15

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study was designed to comply with the standards set forth by FHSA 16 CFR 1500.42.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ace Animals
- Age at study initiation: No data
- Weight at study initiation: 2.7 -3.2 kg
- Housing: The animals were housed 1/cage in suspended cages. Bedding was placed beneath the cages and changed at least three times/week.
- Diet (e.g. ad libitum): Fresh Purina Rabbit Chow (Diet #5321)
- Water: ad libitum
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled but no data oe the values
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From 1993-08-10 to 1993-08-24

Vehicle:

unchanged (no vehicle)

Controls:

other: The contralateral eye served as a control.

Amount / concentration applied:

0.1 ml of the test article was placed by syringe or syringe-type applicator into the conjunctival sac which was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together briefly to insure adequate distribution of the test article. One eye of each rabbit was dosed. The contralateral eye served as a control.

Duration of treatment / exposure:

Once

Observation period (in vivo):

The treated eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva on days 1, 2, 3, 7 and 14. Ocular reactions were graded according to the numerical Draize technique. Additional signs were described. Body weights were recorded pretest.
The general health of the animals was monitored at each observation time.

Number of animals or in vitro replicates:

6 females

Details on study design:

The primary eye irritation score for each rabbit was calculated from the weighted Draize scale. The method of calculation is indicated on the attached scale.
The irritation potential was determined by counting the number of rabbits with positive irritation on days 1, 2 or 3. Positive irritation is defined as any score for opacity or iritis, or 2 or more for redness or chemosis. The test article is an irritant if 4 or more rabbits had a positive score at any time period.

Remarks on result:

not measured/tested

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0.97

Max. score:

3

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0.83

Max. score:

1

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Other effects:

There were no abnormal physical signs noted during the observation period.

 

N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7359	Female	A	Cornea	Opacity	0h	2	2	0	0
		B		Area	0	1	1	0	0
		1°) Total (A x B) X5			0	10	10	0	0
		C	Iris		1	1	0	0	0
		2°) Total C x 5			5	5	0	0	0
		D	Conjunctiva	Redness	2	2	1	1	0
		E		Chemosis	2	2	2	1	0
		F		Discharge	2	2	0	0	0
		3°) (D+E+F) x2			12	12	6	4	0
		Totals = 1 + 2 + 3			17	27	16	4	0
		systemic observations			A	A	A	A	A
		Pretest body weight= 2.7 kg
N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7360	Female	A	Cornea	Opacity	0h	2	3	2	0
		B		Area	0	2	1	1	0
		1°) Total (A x B) X5			0	20	15	10	0
		C	Iris		1	1	1	0	0
		2°) Total C x 5			5	5	5	0	0
		D	Conjunctiva	Redness	3	3	2	2	0
		E		Chemosis	3	3	2	2	0
		F		Discharge	2	2	2	1	0
		3°) (D+E+F) x2			16	16	12	10	0
		Totals = 1 + 2 + 3			21	41	32	20	0
		systemic observations			A	A	A	A	A
		Pretest body weight= 3.2 kg
N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7361	Female	A	Cornea	Opacity	2	2	2	0	0
		B		Area	1	1	1	0	0
		1°) Total (A x B) X5			10	10	10	0	0
		C	Iris		1	1	1	0	0
		2°) Total C x 5			5	5	5	0	0
		D	Conjunctiva	Redness	2	2	2	1	0
		E		Chemosis	2	2	2	0	0
		F		Discharge	2	2	2	0	0
		3°) (D+E+F) x2			12	12	12	2	0
		Totals = 1 + 2 + 3			27	27	27	2	0
		systemic observations			A	A	A	A	A
		Pretest body weight= 3.1 kg
N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7362	Female	A	Cornea	Opacity	0h	2	2	3p	0hp
		B		Area	0	1	2	3	0
		1°) Total (A x B) X5			0	10	20	45	0
		C	Iris		0	1	1	1	0
		2°) Total C x 5			0	5	5	5	0
		D	Conjunctiva	Redness	2	2	2	2	1
		E		Chemosis	2	2	2	2	2
		F		Discharge	2	2	2	2	2
		3°) (D+E+F) x2			12	12	12	12	10
		Totals = 1 + 2 + 3			12	27	37	62	10
		systemic observations			A	A	A	A	A
		Pretest body weight= 2.9 kg
N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7363	Female	A	Cornea	Opacity	0	2	2	0	0
		B		Area	0	1	1	0	0
		1°) Total (A x B) X5			0	10	10	0	0
		C	Iris		1	1	1	0	0
		2°) Total C x 5			5	5	5	0	0
		D	Conjunctiva	Redness	2	2	2	0	0
		E		Chemosis	2	2	2	0	0
		F		Discharge	2	2	2	0	0
		3°) (D+E+F) x2			12	12	12	0	0
		Totals = 1 + 2 + 3			17	27	27	0	0
		systemic observations			A	A	A	A	A
		Pretest body weight= 2.9 kg
N° animal	Sex	Item	Tissue	Reading	Day 1	Day 2	Day 3	Day 7	Day 14
C7364	Female	A	Cornea	Opacity	2	2	2	0	0
		B		Area	1	1	1	0	0
		1°) Total (A x B) X5			10	10	10	0	0
		C	Iris		1	1	0	0	0
		2°) Total C x 5			5	5	0	0	0
		D	Conjunctiva	Redness	2	2	2	1	0
		E		Chemosis	2	2	2	1	0
		F		Discharge	2	2	2	0	0
		3°) (D+E+F) x2			12	12	12	4	0
		Totals = 1 + 2 + 3			27	27	22	4	0
		systemic observations			A	A	A	A	A
		Pretest body weight= 2.8 kg

A normal h = lack of normal luster p = panus

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

The test article is an eye irritant but not corrosive

Executive summary:

The eye irritation of TIPMDP was tested on 6 female New Zealand Albino rabbits in an eye irritation study following the standards set forth by FHSA, 16 CFR 1500.42. 0.1 ml of the test substane was placed into the conjunctival sac of one eye of each rabbit. The other eye was use as control eye. The eyes were not washed. The eyes were examined and scored by the Draize technique on days 1, 2, 3, 7 and 14. Body weights were recorded pretest. The primary eye irritation score for each rabbit, each day, was calculated. Corneal opacity and iritis, noted in 6/6 eyes, cleared by day 14. Moderate conjunctival irritation, noted in 6/6 eyes, persisted to day 14 in one eye. There were no abnormal physical signs noted during the observation period. The test substance is an eye irritant but not corrosive.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

One reliable study is available for skin irritation/corrosion. In this study, TIPMDP was found to be not irritating.

Eye irritation

Two reliable studies are available for eye irritation (Moreno 1990 and 1993). The study performed in 1993 was choosen as key study as the batch tested during this study was a higher and a more representative purity. Based on the results of this study, TIPDMP is considered as irritating to eyes. Therefore, the classification "Eye irritation (H319)" is warranted according to Regulation (EC) 1272/2008.

Justification for classification or non-classification

For eye irritation, classification is warranted according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 (Cat. 2; H319). Classification for skin irritation is not needed based on the available data.