Polymer with 2-Butyne-1,4-Diol and (Chloromethyl-)Oxirane, Brominated, Dehydrochlorinated, Methoxylated

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP range finding short term study, available as unpublished report, fewer animals than required, adequate for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The range finding study performed as part of the sub-acute (28-day) inhalation toxicity study comprised four test groups of 3 male and 3 female rats. Three groups were exposed to different concentrations of Polyol IXOL M 125, a negative control group was exposed to clean air, but otherwise treated in the same manner as the exposed groups. The animals were exposed for 6 hours per day, 5 days per week, over a 7-day period (i.e. 5 exposure days in total). Clinical signs, body weights, food consumption were examined throughout the study. Animals were sacrificed on the day after the last exposure, pathology was performed on a macroscopic and microscopic level and organ weights were determined.

GLP compliance:

yes (incl. QA statement)

Remarks:

TNO Triskelion B.V.

Test type:

other: Range finding data from a 28-day inhalation toxicity test.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(11E)-11,12-dibromo-7-(chloromethyl)-2,6,9,14,18-pentaoxanonadec-11-ene-4,16-diol; (12E)-12,13-dibromo-1,21-dichloro-8-(chloromethyl)-5,17-bis(methoxymethyl)-4,7,10,15,18-pentaoxahenicos-12-ene-2,20-diol; (8E)-8,9-dibromo-13-(hydroxymethyl)-2,6,11,15-tetraoxahexadec-8-en-4-ol; (8E)-8,9-dibromo-2,6,11,15-tetraoxahexadec-8-ene-4,13-diol

EC Number:

617-903-6

Cas Number:

86675-46-9

Molecular formula:

(C4H9O2)xC4H4O2Br2(C4H9O2)y with (x+y)= 2.5

IUPAC Name:

(11E)-11,12-dibromo-7-(chloromethyl)-2,6,9,14,18-pentaoxanonadec-11-ene-4,16-diol; (12E)-12,13-dibromo-1,21-dichloro-8-(chloromethyl)-5,17-bis(methoxymethyl)-4,7,10,15,18-pentaoxahenicos-12-ene-2,20-diol; (8E)-8,9-dibromo-13-(hydroxymethyl)-2,6,11,15-tetraoxahexadec-8-en-4-ol; (8E)-8,9-dibromo-2,6,11,15-tetraoxahexadec-8-ene-4,13-diol

Test material form:

liquid: viscous

Details on test material:

- Name of test material (as cited in study report): Polyol IXOL M125
- Substance type: Halogenated polyetherpolyol
- Physical state: viscous, dark brown liquid
- Analytical purity: ≥99%
- Lot/batch No.: TAE6038
- Expiration date of the lot/batch: 31 December 2011
- Storage condition of test material: ambient temperature, protected from light

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 7 weeks
- Weight at study initiation: main study: 222 g (males) and 166 g (females), dose-range finding study: 207 g (males) and 167 g (females)
- Housing: in macrolon cages with a bedding of wood shavings and strips of paper as environmental enrichment; 3 or 5 of the same sex per cage
- Diet: Rat & Mouse No. 3 Breeding Diet, RM3, ad libitum, except during exposure and fasting period before blood withdrawal
- Water: domestic tap water suitable for human consumption, ad libitum, except during exposure and fasting period before blood withdrawal
- Acclimation period: 6 days (dose-range finding study); 5 days (main study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose-only exposure units (a modification of the design of the chamber manufactured by ADG Developments Ltd., Codicote, Hitchin, Herts, SG4 8UB, United Kingdom) consisting of a cylindrical polypropylene (group 1) or aluminium (groups 2-5) column, surrounded by a transparent cylinder.
- Method of holding animals in test chamber: plastic animal holders (Battelle), positioned radially through the outer cylinder around the central column
- Source of air: humidified compressed air
- System of generating particulates/aerosols: heated air-driven atomizer (Schlick type 970/S, Coburg, Germany) placed at the top inlet of the exposure chamber
- Method of particle size determination: Particle size distribution measurements were carried out using a 10-stage cascade impactor (2110k, Sierra Instruments, Canne Valley, California, USA) once weekly and at least once during preliminary generation of the test atmosphere for each exposure
condition. The Mass Median Aerodynamic Diameter (MMAD) and the geometric standard deviation (gsd) were be calculated
- Temperature, humidity, pressure in air chamber: 22.4 (± 0.7) °C (test group) and 22.1 (± 0.5) °C (control group) (main study); 45.4 (± 1.4)% (control group) and 36.3 (± 1.3) % (test group) (main study)


TEST ATMOSPHERE
- Brief description of analytical method used: The actual concentration (by weight) of the non-volatile fraction of Polyol IXOL M125 in the test atmospheres was determined at least three times per day during each exposure by means of gravimetric analysis.
- Samples taken from breathing zone: yes

VEHICLE (if applicable)
- Justification for use and choice of vehicle: To generate the test atmospheres, the test material was diluted with water (880% Polyol IXOL M125 and 12% water, based on weight; solutions were prepared weekly)
- Concentration of test material in vehicle: 88%

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

5 d

Concentrations:

Target: 0, 500, 1700 or 4900 mg/m3
Nominal: 1820 (± 60), 6530 (± 250), 23200 (± 270)
Analytical: ND, 510 (± 20), 1670 (± 20), 4870 (± 30)

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

- Frequency of observations and weighing: prior to exposure on the first day and on day 7.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption, organ weights, gross pathology and histopathology.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4 870 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

5 d

Mortality:

No deaths occured throughout the study.

Clinical signs:

other: Soiled fur was observed on the morning of day 7, prior to necropsy, in all animals of the high concentration Polyol IXOL M125 group. No further clinical abnormalities were observed during the study.

Body weight:

No statistically significant changes in body weight were observed in response to exposure to Polyol IXOL M125.

Gross pathology:

No treatment-related macroscopic abnormalities were observed at necropsy.

Other findings:

Food consumption:
Food consumption was similar among the groups throughout the study period.

Organ weights:
Absolute and relative weights of the kidneys and liver were increased in females of the mid and high concentration groups. Relative liver weight was also increased in females of the low concentration group. In male animals, increased relative liver weights were observed at the mid and high concentration level.

Microscopic examination:
Microscopic examination of the larynx and nose of animals treated with the low, mid and high concentration Polyol IXOL M125, revealed treatment-related histopathological changes. The histopathological changes in the larynx were present in the epiglottis and were characterised by very slight to moderate mixed inflammatory cell infiltration and epithelial hyperplasia and keratinizing squamous metaplasia. In the Polyol IXOL M125 treated animals the incidence and severity of the larynx lesions showed a dose-response relationship. In animals treated with the high concentration Polyol IXOL M125 the histopathological changes in the nose (nasal cavity) were mainly present in the squamous and respiratory epithelium of the ventral meatus of the first 3 levels and in the olfactory epithelium of the dorsal parts of the nasal cavity in levels 4, 5 and 6. The changes of the ventral meatus were characterised by very slight to slight mixed inflammatory cell infiltration, epithelial squamous metaplasia and atrophy. In addition, one high concentration Polyol IXOL M125 male showed focal ulceration in the ventral meatus. The changes of the olfactory epithelium were characterised by very slight to severe erosion and disarrangement. In cases of (very) slight erosion only the superficial part (the microvilli layer or slightly deeper) of the olfactory cells was missing. In those cases the layers of olfactory cells closest to the basal membrane usually showed disarrangement. In severe cases the entire layer of olfactory cells up to the basement membrane was missing. These findings were not present diffusely in the nose but at one or a few spots, mainly in the dorsal areas of the nasal cavity. In one high concentration Polyol IXOL M125 male focal ulceration was observed, which means that the lesion of the olfactory layer extended beyond the basement membrane into the lamina propria. Several mid and high concentration Polyol IXOL M125 animals showed minimal epithelial hyperplasia of the turbinates and/or lateral wall, and in a few cases squamous metaplasia of the maxilloturbinates. These findings were observed mainly in females.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

LC50 was determined at >4900 mg/m3 for male and female rats. As no mortality was observed after 5 days of inhalation exposure, classification for acute inhalation toxicity is not needed.

Executive summary:

In a GLP compliant range finding inhalation toxicity study, the acute inhalation toxicity of Polyol IXOL M125 was investigated. In this study, groups of 3 rats per sex were exposed to 0, 0.5, 1.7 or 4.9 g/m3 Polyol IXOL M125 for 6 hours per day, 5 days per week, over a 7-day period. Clinical signs consisted of increased kidney weights in females of the mid and high concentration, increased liver weights in females of all exposed groups, and increased relative liver weights in males of the mid and high concentration group. Histopathological examination of the upper airways revealed treatment-related changes in the larynx at all concentration levels. Microscopic changes in the nasal tissues were limited to animals of the high concentration and one animal of the mid concentration group. At necropsy, no treatment-related macroscopic abnormalities were observed. Mortality did not occur throughout the study. It is therefore concluded that the LC50 is above 4900 g/m3 for male and female rats.