2-Hydroxyethylmethacrylate, reaction products with proyleneoxide and Phthalic anhydride

Acute Toxicity: inhalation

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Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Test material form:

liquid

Details on test material:

- Purity: 100%

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, North Carolina, U.S.A.
- Age at study initiation: 9 weeks
- Weight at study initiation: 339-389 gms for males and 222-227 gms for females.
- Housing: Except during exposure, animals were housed individually in solid bottom caging with bedding and enrichment
- Diet: ad libitum (except during exposure)
- Water: ad libitum
- Acclimation period: At least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-26ºC (68-79ºF)
- Humidity: 30-70%
- Air changes (per hr): Not reported
- Photoperiod: 12-hour light/dark cycle

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 3 - <= 3.1 µm

Geometric standard deviation (GSD):

>= 2.2 - <= 2.3

Remark on MMAD/GSD:

The mass median aerodynamic diameter and geometric standard deviation, MMAD (GSD), was determined twice for the atmosphere and measured 3.0 μm (2.3) and 3.1 μm (2.2).

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass (cylindrical)
- Exposure chamber volume: 34 L
- Method of holding animals in test chamber: During exposure, animals were individually restrained in perforated stainless steel cylinders with conical nose pieces. The restrainers were inserted into a polymethylmethacrylate faceplate attached to the exposure chamber so that the nose of each animal extended into the exposure chamber. The day before the exposure, animals were placed in restrainers once for approximately 15 minutes to acclimate the animals to the restrainers.
- System of generating particulates/aerosols: The chamber atmosphere was generated by aerosolization of the test substance in air with a Spraying Systems Company® nebulizer. The test substance was metered into the nebulizer with a Harvard programmable model PHD 4400 high pressure syringe drive. High-pressure air, metered into the nebulizer by a Brooks model 5850E mass flow controller, carried the resulting atmosphere into the exposure chamber. Chamber concentrations of test substance were controlled by varying the test substance feed rate to the nebulizer. The test atmosphere was exhausted through a dry-ice cold trap followed by an MSA filter cartridge prior to discharge into the fume hood.
- Method of particle size determination: Samples to determine aerosol size distribution (mass median aerodynamic diameter, geometric standard deviation, and percent aerosols less than 1, 3, and 10 μm diameter) were taken twice during the exposure with a Sierra® series 210 cyclone preseparator/cascade impactor and Sierra® series 110 constant flow air sampler.
- Environmental monitoring: Chamber temperature was targeted at 20-24°C, monitored continually with a VWR NIST traceable digital thermometer, and recorded approximately every 30 minutes during the exposure. Chamber relative humidity was targeted at 30-70%, measured with a VWR traceable digital hygrometer, and recorded 3 times during the exposure. Chamber airflow was set at the beginning of the exposure to achieve at least 10 air changes per hour, monitored continually with a Brooks model 5850E mass flow controller, and recorded approximately every 30 minutes during the exposure. Chamber oxygen concentration was targeted to be at least 19%, measured with a Teledyne Analytical Instruments model GB300 oxygen analyzer, and recorded 3 times during the exposure.

Test Substance Sampling and Analysis: During the exposure, the atmospheric concentration of the test substance was determined by gravimetric analysis at approximately 30-minute intervals in the test chamber. Known volumes of chamber atmosphere were drawn from the sampling port through a 25 mm filter cassette containing a pre-weighed glass fiber (Type A/E) filter. The filters were weighed on a Cahn model C-30 Microbalance®. The filter weights were automatically transferred to the Camile Inhalation Toxicology Automated Data System (CITADS), which calculated the chamber concentrations based on the difference between pre- and post-sampling filter weights divided by the volume of chamber atmosphere sampled. Start- and stop-times for each gravimetric sample were controlled and recorded by CITADS. Upon completion of the exposures, CITADS sample results were transferred to the Camile Inhalation Reporting and Analysis System (CIRAS), which collated sample calculations.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

1.1 mg/L (maximum practically-attainable total atmospheric concentration)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Mortality, clinical signs and body weights were observed on Day 1, 2, 4, 8, and 15.
- Necropsy of survivors performed: Yes.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.1 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Highest feasible airborne concentration of test substance that could be achieved

Mortality:

All animals survived the 4-hour exposure to 1.1 mg/L test substance and the subsequent 14-day recovery period.

Clinical signs:

other: During the 1.1 mg/L exposure (test day 1), all animals displayed normal startle response and no abnormalities were observed. All animals had clear discharge from both eyes, and test substance and red stains on their faces during clinical observation after

Body weight:

Three (of 5) male and 2 (of 5) female rats lost up to 3.8% of their initial body weight on test day 2. All rats gained weight and had no abnormalities detected during the rest of the 14-day recovery period.

Gross pathology:

No gross lesions were present in the rats at necropsy.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

4h LC50 (Male/Female): > 1.1 mg/L (maximum practically-attainable total atmospheric concentration)

Executive summary:

The objective of this study was to evaluate the acute inhalation toxicity of test substance when administered as an aerosol for a single, 4-hour, nose-only exposure to one group of 5 male and 5 female (nulliparous and non-pregnant) Crl:CD(SD) rats. Test substance used for this study was a clear, yellowish liquid with a purity of 100% by analysis. The test atmosphere was generated by aerosolization of test substance in air using a nebulizer and the airborne concentration of test substance was determined by gravimetric analysis. During a 14-day recovery period, all animals were weighed and observed for mortality and clinical signs of toxicity. A gross pathological examination was performed on all animals at the scheduled necropsy.

During the exposure, rats were exposed to a maximum practically-attainable total atmospheric concentration of 1.1 ± 0.12 mg/L test substance (mean ± standard deviation). The mass median aerodynamic diameter and geometric standard deviation, MMAD (GSD), was determined twice for the atmosphere and measured 3.0 μm (2.3) and 3.1 μm (2.2).

All animals survived the 4-hour exposure to 1.1 mg/L test substance and the subsequent 14-day recovery period.

All animals displayed normal startle response during the exposure (test day 1), and no test substance-related clinical signs of toxicity were observed after animals were removed from exposure chamber. 3 (of 5) male and 2 (of 5) female rats lost up to 3.8% of their initial body weight on test day 2. All rats gained weight and had no abnormalities detected during the rest of the 14-day recovery period.

No gross lesions were present in the rats at necropsy.

While an exposure atmosphere of ≥ 5 mg/L could not be obtained due to the high viscosity of the test substance, 1.1 mg/L test substance was the highest feasible airborne concentration of test substance that could be achieved.

Under the conditions of this study, the 4-hour inhalation median lethal concentration (LC50) for test substance in male and female rats was greater than 1.1 mg/L, the maximum practically-attainable atmospheric concentration.