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Toxicological information

Acute Toxicity: dermal

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetraisopropyl methylenebisphosphonate
EC Number:
216-765-0
EC Name:
Tetraisopropyl methylenebisphosphonate
Cas Number:
1660-95-3
Molecular formula:
C13H30O6P2
IUPAC Name:
tetraisopropyl methylenebis(phosphonate)
Test material form:
other: liquid

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Based on:
test mat.
Mortality:
No
Clinical 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.
Body weight:
See table
Gross pathology:
Not performed

Any other information on results incl. tables

Body weights, Dose volume and dermal reactions

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.

Applicant's summary and conclusion

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.