4,4'-Isopropylidenediphenol, polymer with 1-chloro-2,3-epoxypropane, propane-1,2-diol acrylate and succinic anhydride

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 29 October, 2002 to 16 November, 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

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:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

other: Limit test

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-Isopropylidenediphenol, polymer with 1-chloro-2,3-epoxypropane, propane-1,2-diol acrylate and succinic anhydride

EC Number:

500-240-0

EC Name:

4,4'-Isopropylidenediphenol, polymer with 1-chloro-2,3-epoxypropane, propane-1,2-diol acrylate and succinic anhydride

Cas Number:

68958-77-0

Molecular formula:

UVCB, major component represented by di-functionalised BADGE (HPA-SA-BADGE-SA-HPA): C41H52O16 Other constituents present at >10%: Mono-functionalised BADGE (BADGE-SA-HPA): C35H44O14 Dimers (HPA-SA-BADGE-SA-BADGE-SA-HPA): C66H82O24

IUPAC Name:

2-Propenoic acid, monoester with 1,2-propanediol, polymer with 2-(chloromethyl)oxirane, dihydro-2,5-furandione and 4,4'-(1-methylethylidene)bis[phenol]

Test material form:

liquid: viscous

Test animals

Species:

rat

Strain:

other: Sprague-Dawley Crl:CD® (SD) IGS BR strain rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats were supplied by Charles River (UK) Ltd, Margate, Kent. On receipt the animals were randomly allocated to cages. After an acclimatization period of at least 5 d the animals were given a number unique within the study by ear punching and a number written on a colour coded cage card. At the start of the study the animals were approx 8 to 12 wk old. All male animals exceeded the weight range specified in the protocol (200 g – 350 g) with actual male bw in the range 357 g -380 g but this was considered not to affect the purpose or integrity of the study. The females were nulliparous and non-pregnant and within the required weight range. The animals were housed in groups of 5 by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd., Cheshire, UK) and provided with environmental enrichment items: wooden chew blocks (B & K Universal Ltd, Hull, UK) and cardboard "fun tunnels" (Datesand Ltd., Cheshire, UK). With the exception of the exposure period, free access to mains drinking water and food (EU Rodent Diet 5LF2, IPS Limited, Wellingborough, Northants, UK) was allowed throughout the study. The diet, drinking water, bedding and chew blocks are routinely analysed and are considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. The environmental controls were set to achieve values of 21 ± 2°C and 55 ± 15% relative humidity. The rate of air exchange was at least 15 changes/h and the lighting was controlled to give 12 h continuous light and 12 h darkness. The animals were retained in this accommodation at all times except during the exposure period.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: acetone

Details on inhalation exposure:

The test substance formulation was aerosolised using a glass concentric jet nebuliser (Radleys, Saffron Walden, Essex, UK) located at the top of the exposure chamber. The nebuliser was connected to a glass syringe attached to an infusion pump, which provided a continuous supply of test substance formulation under pressure, and to a metered compressed air supply. Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the nebuliser dust feed SAG 410. The cylindrical exposure chamber had a volume of approximately 30 L (dimensions: 28 cm diameter x 50 cm high). The concentration within the exposure chamber was controlled by adjusting the rate of the infusion pump. The extract from the exposure chamber passed through a 'scrubber' trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure. Homogeneity of the test atmosphere within the chamber was not specifically determined during this study. Chambers of the same design (ADG Developments Ltd, Hitchin, Herts, UK) have been fully validated and shown to produce evenly distributed atmospheres in the animals' breathing zone with a wide variety of test substances (Green J D et ai, 1984). Prior to the start of the study, test substance atmospheres were generated within the exposure chamber. During this characterisation period air flow settings, test substance formulation input rates and formulation details were varied to achieve the required atmospheric concentrations.

Analytical verification of test atmosphere concentrations:

no

Remarks:

However, chambers of the same design (ADG Developments Ltd, Hitchin, Herts, UK) have been fully validated and shown to produce evenly distributed atmospheres in the animals' breathing zone with a wide variety of test substances (Green J D et al, 1984).

Duration of exposure:

4 h

Concentrations:

The rats were exposed to an aerosol atmosphere of a formulation of the test substance (60% test subsatnce : 40% acetone w:w).

No. of animals per sex per dose:

5/sex

Control animals:

no

Details on study design:

Sighting Exposure: During characterisation, a group of two rats (one male, one female) was exposed to an atmosphere of the test substance formulation at an approx concentration of 2 mg/L for approx 4 h. No significant effects were noted for the animals.

Exposure procedure: Each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber 'O' ring. Only the nose of each animal was exposed to the test atmosphere. Following an appropriate equilibration period a single group of ten rats (five males and five females) was exposed to an atmosphere of the test material, generated from the formulation, for a period of 4 h. Based on the results of the sighting exposure, a target concentration of 5 mg/L was used for the exposure. As no deaths occurred and the mean achieved concentration was 98% of target, no further levels were required.

Exposure chamber temperature and relative humidity: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter (Hanna Instruments Ltd, Beds., UK) located in a vacant port in the animals' breathing zone of the chamber and recorded every 30 min throughout the 4 h exposure period.

Exposure Chamber Oxygen Concentration: Oxygen levels within the exposure chamber were measured by an electronic oxygen analyser (Servomex (UK) Ltd, Crowborough, East Sussex) located in a sampling port in the animals breathing zone during each exposure period. The test atmosphere was generated to contain at least 19% oxygen.

Exposure Chamber Atmosphere Concentration: The actual chamber concentration was measured at regular intervals during the exposure period. The gravimetric method used employed glass fibre filters (Gelman type A/E 25 mm) placed in a filter holder. The holder was temporarily sealed in a vacant port in the exposure chamber in the animals breathing zone and a suitable, known volume of exposure chamber air was drawn through the filter using a vacuum pump. Each filter was weighed before and after sampling in order to calculate the weight of collected test substance. The difference in the two weights, divided by the volume of atmosphere sampled, gave the actual chamber concentration (assuming total volatilisation of the acetone component). The nominal chamber concentration was calculated by dividing the mass of test substance used by the total volume of air passed through the chamber.

Particle size distribution: The particle size of the generated atmosphere inside the exposure chamber was determined three times during the exposure period using a Marple Personal Cascade Impactor (Schaefer Instruments Ltd, Oxon., UK). This device consisted of six impactor stages (9.8, 6.0, 3.5, 1.55, 0.93 and 0.52 µm cut points) with stainless steel collection substrates and a back up glass fibre filter, housed in an aluminium sampler. The sampler was temporarily sealed in a sampling port in the animals' breathing zone and a suitable, known volume of exposure chamber air was drawn through it using a vacuum pump. The collection substrates and backup filter were weighed before and after sampling and the weight of test substance, collected at each stage, calculated by difference. The mean amount for each stage was used to determine the cumulative amount below each cut–off poin size. In this way, the proportion (%) of aerosol less than 9.8, 6.0, 3.5, 1.55, 0.93 and 0.52 µm was calculated. The resulting values were converted to probits and plotted against log10 cut-point size. From this plot, the Mass Median Aerodynamic Diameter (MMAD) was determined (as the 50% point) and the geometric standard deviation was calculated. In addition the proportion (%) of aerosol less than 4 µm (considered to be the respirable portion) was determined. All particle size distribution calculations were performed using a purpose designed computer programme (Chrom Series Data Server and Reg 2000 Graph Plotter).

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

4 900 other: mg/m3 (mean achieved atmosphere concentration)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No

Clinical signs:

other: Common abnormalities noted during the study included increased respiratory rate, noisy respiration, hunched posture, pilo-erection and wet fur and there were instances of laboured respiration, ptosis and red/brown staining around the eyes or snout. All an

Body weight:

Normal bodyweight development was noted during the study. Several females showed reduced bodyweight gain during Week 1 or 2 of the study but such variations are not uncommon in female rats of this strain or age and are considered not to be significant.

Gross pathology:

No macroscopic abnormalities were detected at necropsy.

Any other information on results incl. tables

The mean atmosphere concentration of test substance was as follows:

Atmospheric concentration
Mean achieved (mg/L)	Standard deviation	Nominal (mg/L)
4.9	0.47	21.1

 

The characteristics of the achieved atmosphere were as follows:

Mean achieved atmosphere concentration (mg/L)	Mean mass median aerodynamic diameter (µm)	Inhalable fraction (% <4µm)	Geometric standard deviation
4.9	1.17	97.9	1.83

Applicant's summary and conclusion

Interpretation of results:

other: Category 4

Conclusions:

Under the conditions of the study, the 4h LC50 of the substance in rat was considered to be greater 4900 mg/m3.

Executive summary:

A study was performed to assess the acute inhalation toxicity of the test substance according to the OECD Guidelines 403 and EU Method B2, in compliance with GLP. A group of 10 Sprague-Dawley Crl:CD® (SD) IGS BR strain rats (fine males and five females) was exposed to an aerosol atmosphere of a formulation of the test substance (60% test substance: 40% acetone w:w) for 4 h using a nose only exposure system, followed by a 14 d observation period. No deaths occurred in a group of 10 rats exposed to a mean achieved atmosphere concentration of 4,900 mg/m3. Under the conditions of the study, the 4h LC50 of the substance in rat was considered to be greater 4,900 mg/m3 (Wesson, 2003).