Tetraisopropyl methylenebisphosphonate

Endpoint summary

Description of key information

The LD50 by oral route was determined to be greater than 500 mg/kg
The LD50 by dermal route was determined to be greater than 1000 mg/kg. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

From 1989-12-27 to 1990-02-09

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No data for individual animals available in the report

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 1500.3(c)(2)( i).

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace animals
- Weight at study initiation: 232 - 270 g
- Fasting period before study: Yes
- Housing: The animals were housed 5 / cage in suspended wire mesh cages. Bedding was placed beneath the cages and changed twice / week
- Diet (e.g. ad libitum): Fresh Purina Rat Chow (Diet #5012) ad libitum
- Water (e.g. ad libitum): Freeely available at all times
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Temperature: Controlled temperature but no data on values
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hours light / dark Cycle

IN-LIFE DATES: From 1990-01-05 To 1990-01-19

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test article was used as received and the dose was based on the sample weight, as calculated from the specific gravity. The test article was administred orally, one time, by syringe and dosing needle at 500 mg/kg of body weight.

Doses:

500 mg/kg

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: Animals were observed 3-4 hours post dose and once daily thereafter for 14 days for mortality, toxicity and pharmacological effects.
- Frequency weighing: Pretest
- Necropsy of survivors performed: no

Sex:

male

Dose descriptor:

LD50

Effect level:

> 500 mg/kg bw

Based on:

test mat.

Mortality:

No mortality at 500 mg/kg

Clinical signs:

other: Soiling of the anogenital area was noted in one animal on day 1. At all other times, all animals appeared normal.

Gross pathology:

No gross pathology performed at the end of the study

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 is greater than 500 mg/kg of body weight.

Executive summary:

The Acute Oral Toxicity of the TIPMDP was evaluated in a GLP study following the standards set forth by FHSA, 16 CFR 1500.3 (C) (2) (i). Ten healthy male Wistar Albino rats were dosed orally with the test substance at 500 mg/kg of body weight. Body weights were recorded pretest. Mortality and systemic observations were recorded 3 -4 hours post dose and daily thereafter for 14 days. All animals survived the 500 mg/kg oral dose in generally good health. The LD50 is greater than 500 mg/kg of body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

LD50 > 500 mg/kg

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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:

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 FHSA standards set forth in 16 CFR 1500.40.

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 2.1 to 2.7 kg
- Fasting period before study: No data
- Housing: The animals were housed 1/cage in suspended wire mesh 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) was provided daily
- Water (e.g. ad libitum): Water was available ad libitum.
- Acclimation period: at least one week

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

IN-LIFE DATES: From 1993-08-03 to 1993-08-27

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Test site
Prior to application of the test article, the abdomen and sides of each animal were clipped free of hair. The prepared site was approximately 10% of the body surface. The clipped site in 1/2 of the animals were abraded with a bent tip needle. Six or seven abrasions about 2-3 cm apart, extending the length of the exposure site, were made. Abrasions were sufficiently deep to penetrate the stratum corneum, but not deep enough to produre bleeding.

Treatment
The test article was used as received and the dose was based on the sample weight as calculated from the specific gravity. The test article was applied to the prepared dermal site, one time, by a syringe type applicator at 1000 mg/kg of body weight. The test article was covered with a gauze patch and gentle pressure was applied to the gauze to aid the distribution of the test article over the prepared site. The torso was wrapped with plastic which was secured with tape. At 24h, the patches were removed and the site was wiped.

REMOVAL OF TEST SUBSTANCE
- the sites were wiped
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg

Duration of exposure:

24 h

Doses:

1000 mg/kg

No. of animals per sex per dose:

10 (5 Males and 5 females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
+The test sites were scored (Draize scale) for dermal irritation at 24h post dose and on day 7 and 14. additional signs were described.
+ The animals were observed daily for 14 days for mortality, toxicity and pharmacologicals effects.
+ Body weight were recorded pretest and at termination
+ No examination for gross pathology was performed

Statistics:

An estimate of the LD50 was made based on mortality occuring during the study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

test mat.

Mortality:

No

Clinical signs:

other: Instances of diarrhea, few feces and soiling of the anogenital area were noted in females. All males appeared normal during the 14 day observation period.

Gross pathology:

Not performed

Body weights, Dose volume and dermal reactions

N°	Sex	Dose(mL)	Abraded	Weight (Kg)		Day 1		Day 7		Day 14		% rem
				D0	D14	R	E	R	E	R	E
C7722	M	2.2	Yes	2.4	2.7	0	0	0	0	0	0	70
C7723	M	2.5	No	2.7	3.2	0	0	0	0	0	0	70
C7724	M	2.1	Yes	2.3	2.5	0	0	0	0	0	0	70
C7725	M	2.4	No	2.6	2.7	1	0	0	0	0	0	70
C7726	M	2.2	Yes	2.4	2.8	1	0	0	0	0	0	70
C7759	F	2.3	No	2.5	2.1**	1	0	0	0	0	0	70
C7760	F	2.2	Yes	2.4	2.2**	0	0	0	0	0	0	70
C7761	F	2.3	No	2.5	2.6	2	0	0	0	0	0	70
C7762	F	2.0	Yes	2.1	2.4	0	0	0	0	0	0	70
C7764	F	2.3	No	2.5	2.7	1	0	0	0	0	0	70

Code: R erythema (redness), E edema, ab abraded, ** body weight verified, % Remaining a visual estimate of the amount of material remaining on the skin, gauze and occlusive binding at 24 hours, after the occlusive binding was removed.

 

 

PHYSICAL SIGNS:

Instances of diarrhea, few feces and soiling of the anogenital area were noted in females. All males appeared normal during the 14 day observation period.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 is greater than 1000 mg/kg of body weight.

Executive summary:

The Acute Dermal Toxicity of the TIPMDP was evaluated in a GLP study following the standards set forth by FHSA, 16 CFR 1500.40. Ten healthy New Zealand Albino rabbits (5 males and 5 females) were dosed dermally with the test substance at 1000 mg/kg of body weight. The test substance was kept in contact with the skin for 24 hours. The animals were observed daily for 14 days for mortality, toxicity and pharmacological effects. Skin reactions were scored on days 1, 7 and 14. Body weights were recorded pretest and at termination.

All animals survived the 1000 mg/kg dermal application. Instances of diarrhea, few feces and soiling of the anogenital area were noted during the observation period. Body weight changes were normal in 8/10 animals. Two females lost weight during the study. Dermal Reactions, absent to well defined on day 1, were absent on days 7 and 14. The LD50 is greater than 1000 mg/kg of body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

LD50 > 1000 mg/kg

Additional information

Oral

The assessment of acute oral toxity with TIPMDP was realised according to the standards set forth by FHSA, 16 CFR 1500. 3(c)(2)( i). The test article was administered by single oral gavage at 500 mg/kg bw to 10 male rats. Animals were subjected to daily observations for 14 days. At 500 mg/kg, soiling of the anogenital area was noted in one animal on day 1. At all other times, all animals appeared normal. Based on these observations, the LD50 value of TIPMDP was established to be greater than 500 mg/kg

Dermal

Two reliable studies are available for acute dermal toxicity (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. The assessment of acute dermal toxity with TIPMDP was realised according to the standards set forth by FHSA standards set forth in 16 CFR 1500.40. Animals were subjected to daily observations for 14 days. At 1000 mg/kg, no death occured. Based on these observations, the LD50 value of TIPMDP was established to be > 1000 mg/kg

Justification for classification or non-classification

Based on the acute oral study, in which an LD50 of > 500 mg/kg was observed, TIPMDP is classified as harmful by ingestion (H302) according to the CLP 1272/2008 criteria

Based on the acute dermal studies, in which an LD50 of > 1000 mg/kg was observed, TIPMDP is classified as harmful in contact with skin (H312) according to the CLP 1272/2008 criteria.