2-Propenoic acid, 2-hydroxyethyl ester, reaction products with O,O-bis(dialkyalkyl) hydrogen phosphorodithioate and dimethyl phosphonate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 December 2019 to 19 December 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

2017

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

1998

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: JMAFF 12-Nousan-8147

Version / remarks:

2000

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

liquid

Details on test material:

- Appearance/physical state: Light yellow liquid
- Storage conditions: Ambient temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

ANIMALS
- Source: Received from Charles River Laboratories on 21 November 2019.
- Number of animals: 10
- Sex: Five males and five females. Females assigned to the test were nulliparous and non-pregnant.
- Age: Young adult (10 weeks)
- Bodyweight: 274 to 327 g (males) and 221 to 246 g (females) at experimental start.

HUSBANDRY
- Housing: The animals were housed in caging which conforms to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Animals were group housed, except on the day of application, at which time they were singly housed until the animals were deemed acceptable, based on observations, to return to group housing. Enrichment (e.g. toy) was placed in each cage and litter was changed at least once per week.
- Animal Room Temperature and Relative Humidity Ranges: 21 to 24 °C and 41 to 56 % respectively.
- Animal Room Air Changes/Hour: 12. Airflow measurements are evaluated regularly and the records are kept on file at Product Safety Labs.
- Photoperiod: 12-hour light/dark cycle.
- Acclimation period: 14 days.
- Food: Food: Envigo Teklad Global 16 % Protein Rodent Diet #2016. The diet was available ad libitum.
- Water: Filtered tap water was supplied ad libitum.
- Contaminants: There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study. Analyses of the food and water are conducted regularly and the records are kept on file at Product Safety Labs.

IDENTIFICATION
- Cage: Each cage was identified with a cage card indicating at least the study number and identification and sex of the animal.
- Animal: A number was allocated to each rat on receipt and a stainless steel ear tag bearing this number was attached to the animal, This number, together with a sequential animal number assigned to study 51951, constituted unique identification. Only the sequential animal number was presented in the report.

PREPARATION AND SELECTION OF ANIMALS
- On the day prior to application, a group of animals was prepared by clipping the dorsal area and the trunk.
- After clipping and prior to application, the animals were examined for health, weighed (initial) and the skin checked for any abnormalities.
- Ten healthy, naïve rats (five males and five females; not previously tested) were selected for test.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

PREPARATION OF TEST SUBSTANCE
- The test substance was applied as received and mixed well prior to use.

DOSE CALCULATIONS
- Individual doses were calculated based on the initial body weights, taking into account the
density (determined by PSL) of the test substance.

APPLICATION OF THE TEST SUBSTANCE
- Test substance (2000 mg/kg bw) was applied evenly over a dose area of approximately 2
inches x 3 inches (approximately 10% of the body surface) and covered with a 2-inch x 3-inch, 4-ply gauze pad.
- The gauze pad and entire trunk of each animal were wrapped with 3-inch Durapore tape to avoid dislocation of the pad and to minimise loss of the test substance.
- The rats were then returned to their designated cages.
- The day of application was considered Day 0 of the study.
- After 24 hours of exposure to the test substance, the pads were removed and the test sites were gently cleansed with a 3 % soap solution followed by tap water and a clean paper towel to remove any residual test substance.

IN-LIFE OBSERVATIONS
- The animals were observed for mortality, signs of gross toxicity. and behavioral changes during
the first several hours after application, after patch removal, and then at least once daily thereafter
for 14 days.
- Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, and coma.

BODY WEIGHTS
- Individual body weights of the animals were recorded prior to test substance application (initial) and again on Days 7 and 14 (terminal).

NECROPSY
- All rats were euthanized via CO2 inhalation at the end of the 14-day observation period.
- Gross necropsies were performed on all animals.
- Tissues and organs of the thoracic and abdominal cavities were examined.

Duration of exposure:

24 hours

Doses:

Single dose of 2000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Statistics:

STATISTICAL ANALYSIS
- Statistical analysis was limited to the calculation of the mean density value for dosing.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- All animals survived test substance administration.

Clinical signs:

- Individual in-life observations are presented in Table 2 (attached).
- Dermal irritation was noted at the dose sites of six animals on Day 1. However, the animals recovered by Day 2, and along with the remaining animals, appeared active and healthy for the remainder of the 14-day observation period.

Body weight:

- Individual body weights and doses are presented in Table 1 (attached).
- All animals gained body weight during the study.

Gross pathology:

- Individual necropsy observations are presented in Table 3 (attached).
- No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the single dose acute dermal LD50 of test item is greater than 2000 mg/kg bw in male and female rats.

Executive summary:

GUIDELINE

The study was conducted in accordance with U.S. EPA Health Effects Test Guidelines, OPPTS 870.1200, OECD Guidelines for the Testing of Chemicals, Test No. 402, JMAFF 12-Nousan-8147 and the Official Journal of the European Union. Methods for the Determination of Toxicity and Other Health Effects, Part B.3 (Acute Toxicity Dermal), Council Regulation (EC) No. 440/2008.

 

METHODS

An acute dermal toxicity test was conducted with rats to determine the potential for test item to produce toxicity from a single topical application. Test substance (2000 mg/kg bw) was applied to the skin of ten healthy rats for 24 hours. The animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days. Body weights were recorded prior to application (initial) and again on Days 7 and 14 (terminal). Necropsies were performed on all animals at terminal sacrifice.

 

RESULTS

All animals survived test substance administration and gained body weight during the study. Dermal irritation was noted at the dose sites of six animals on Day 1. However, the animals recovered by Day 2, and along with the remaining animals, appeared active and healthy for the remainder of the 14-day observation period. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

 

CONCLUSION

Under the conditions of this study, the single dose acute dermal LD50 of test item is greater than 2000 mg/kg bw in male and female rats.