Alkyl phosphites

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study conducted to OECD guidelines

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HRP Inc., Denver, PA.
- Age at study initiation: Males 14 weeks, females 15 weeks
- Weight at study initiation: Males 2.24-2.42 kg, Females 2.11-2.47 kg
- Fasting period before study: None stated
- Housing: Single housed in stainless steel wire mesh cages.
- Diet: ad libitum, Agway Certified Diet R.C.A Rabbit.
- Water: ad libitum.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21°C
- Humidity (%): 40 to 60%
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12 hours light (07:00 to 19:00) and 12 hours dark (19:00 to 07:00)

IN-LIFE DATES: From: To:1996-06-11 to 1996-06-25

Administration / exposure

Type of coverage:

occlusive

Vehicle:

peanut oil

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal surface from the shoulder to the lumbar region.
- % coverage: No less than 10%
- Type of wrap if used: gauze patch secured with non irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual material washed off with peanut oil and a paper towel.
- Time after start of exposure: Approximately 24 hours after exposure.

TEST MATERIAL
- A 12.5% concentration of the test material in peanut oil was adminstered at a constant volume of 4 ml/kg to achieve a modified limit dose of 500 mg/kg.

Duration of exposure:

24 hours

Doses:

Range Finding Study: 2000, 1000 and 500 mg/kg of test material in Peanut Oil (50%, 25% and 12.5% concentration respectively) at a constant dose volume of 4 ml/kg.

Experimental Study: 500 mg/kg. Test material was diluted with peanut oil to a concentration of 12.5%

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were examined for viability twice daily Monday through Friday, and once daily on weekends. Clinical observations were made at 1, 2, 4 and 6 hours and then once daily for the duration of the 14 days. Body weights were recorded on Day 0, 7 and 14.
- Necropsy of survivors performed: Yes. A gross necropsy was performed on all animals. The necropsy examination included examination of the external surface of the body, and the cranial, thoracic, and abdominal cavities and their contents. Gross abnormalities were preserved in 10% neutral buffered formalin.

Statistics:

Statistical analysis included means and standard deviations of body weights and body weight change by group and sex.

Results and discussion

Preliminary study:

Range Finding Study

There were no overt signs of toxicity observed in the rangefinding animals at any dose level. However, all animals displayed slight weight loss (0.04 to 0.27 kilograms) over the test period (Day 0 -8). There were single occurrences of soft stool, decreased qualitative food consumption, and nasal discharge. Signs of severe dermal irritation (apparent blanching, necrosis, leathery skin, severe erythema, and/or moderate edema) were observed in the 1000 and 2000 mg/kg group animals. Dermal irritation was also observed in the 500 mg/kg dose gropu but to a lesser degree and there was no evidence of corrosivity. Thus a dose level of 500 mg/kg was selected for the definitive study.

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 500 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: Clinical Observations There were no treatment related clinical signs and the majority of animals were free of abnormalities during the entire test period. Clinical observations were limited to two males and two females with nasal discharge on Day 0. Thes

Gross pathology:

Gross Postmortem Observations.

Postmortem finding were limited to dermal abnormalities. All animals were observed with exfoliation, lethary skin, eschar, and or desquamation. These observations were consistent with dermal irritation observed during the inlife phase.

Any other information on results incl. tables

Analytical Chemistry

Satisfactory unifromity of the mixture was observed. Concentration verification analysis indicated the test material concentration was within 1% of the nominal value.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In conclusion, dermal application of the test substance at a dose level of 500 mg/kg did not produce any mortality or overt signs of systemic toxicity under the condidtions of this study. Severe dermal irritation was the most significant finding. Based on these results the dermal LD50 of the test substance is greater than 500 mg/kg in the rabbit.

Executive summary:

This study was conducted in order to evaluate the acute dermal toxicity of the test material in the rabbit when administered topically as a single dose with a 14 day observation period.

The neat test substance produced signs of corrosivity in a previously conducted primary dermal irratation test (Study number 149204 - IUCLID section 7.3.1). Thus, in an effort to decrease severe dermal irratation, the test material was diluted in peanut oil to a concentration of 12.5% and administered at a constant dose volume of 4ml/kg to achive a "modified limit dose" of 500 mg/kg. This level (500 mg/kg) was selected since it was the maximum dose level that was not overtly corrosive during preliminary range-finding studies in rabbits.

The test substance mixture was applied to not less than 10% of the body surface, covered with a gauze patch and secured with non-irratating tape. The gauze patch was secured to the trunk of the animal with an occlusive covering to retard evaporation, to prevent ingestion of the test material, and to keep the substance in contact with the skin. After approximately 24 hours exposure the plastic sleeve and gauze patch were removed. Residual test material was removed where possible using peanut oil and a paper towell without altering exisiting response or the integritiy of the epidermis. Clinical observations were performed 1,2, 4 and 6 hours after dosing and once per day thereafter fora total of 14 days. Dermal responses were evaluated on days 1 (approximately 45 minutes after patch removal), 3, 7, 10, and 14 according to Draize method. Body weights were recorded on the days prior to dosing, on the day of dosing (day 0) and on days 7 and 14.

All animals survived to sheduled study termination on day 14. There were no treatment related clinical signs and the majority of animals were free of abnormalities during the entire test period. Clinical observations were limited to two males and two females with nasal discharge on day 0. These observations were considered incidental and unrelated to the test substance.

Topical application of the test substance elicited moderate/severe to severe erythema and slight to severe edema in all ten animals. The severity of dermal scores gradually decreased as the study progressed.

Blanching was observed in seven animals on days 1 and 3, while necrosis was observed in two animals on day 3 and one animal of day 7. Other supplemental dermal observations included lethery skin, atonia, desquamation, exfoliation, cracking, fissuring and eschar.

All animals gained weight over their initial (Day 0) values. There was a very slight weight lose (< 0.1 kilograms) in four animals during the day 0-7 interval. The slight weight lose was probably related to stress of the dosing procedure and subsequent severe dermal irratation rather than the direct result of toxicity. During the day 7-14 interval, all animals displayed normal weight gain patterns.

Post mortem finding were limited to dermal abnormalities which were consistent with dermal irritation observed during the inlife phase.

In conclusion, dermal application of the test substance at a dose level of 500mg/kg did not produce any mortality or overt signs of sytemic toxicity under the conditions of this study. Severe dermal irratation was the most significant finding. Based on these results the dermal LD50 of the test substance is greater than 500 mg/kg in the rabbit.