1,1,2,2,3,3,4,4-octafluoro-1,4-diiodobutane

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19-APR-2001 to 30-MAY-2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not applicable

Remarks:

The 1981 guideline did not require to stagger the doses as in the current guideline. The fact that exposure to the different concentrations was not delayed does not constitute a deviation that would have an impact on the conclusions of the study.

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,1,2,2,3,3,4,4-octafluoro-1,4-diiodobutane

EC Number:

206-788-4

EC Name:

1,1,2,2,3,3,4,4-octafluoro-1,4-diiodobutane

Cas Number:

375-50-8

Molecular formula:

C4F8I2

IUPAC Name:

1,1,2,2,3,3,4,4-octafluoro-1,4-diiodobutane

Test material form:

other: liquid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: batch 1/2000
- Expiration date of the lot/batch: march 2013

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient temperature in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Alpk:APfSD (Wistar-derived) rats (20 males and 20 females, plus 6 spare males)
- Source: Rodent Breeding Unit (UK)
- Age at study initiation: 8 to 9 weeks
- Weight at study initiation: 298 to 342 g for males; 226 to 264 g for females
- Fasting period before study: yes
- Housing: 5 per cage, sexes separately; additional animals were housed 3 per cage.
- Diet: ad libitum, except during exposure (diet (RMI) supplied by Special Diet Services Limited (UK))
- Water: ad libitum, except during exposure
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 30 to 70%
- Air changes: at least 15 air changes per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From 22-MAY-2001 to 18-OCT-2001

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: polycarbonate tubes inserted into a PERSPEX exposure chamber covered with an aluminium cone and stood on an aluminium base.
- Exposure chamber volume: internal volume of ca. 27.6 L
- Method of holding animals in test chamber: animals were restrained in polycarbonate tubes supplied by Battelle (Switzerland).
- Source and rate of air: clean, dry air was passed at a nominal flow rate of 30 L/min (at normal temperature and pressure) at a concentration of 63.5 ppm and 20 L/min at a concentration of 613, 1275, or 2576 ppm. Air flows were monitored continuously and recorded at least 3 times using variable area flowmeters (KDG Flowmeters, UK).
- Method of conditioning air: air was dried and filtered using equipment supplied by Atlas-Copco (Sweden).
- System of generating particulates/aerosols: each test atmosphere was generated using a jacketed glass condenser. The test substance was pumped to the condenser using a Watson Marlow peristaltic pump. Before exposure of the test animals, the atmosphere was shown to be acceptably stable over ca. 30 min.
- Method of particle size determination: not applicable
- Treatment of exhaust air: no data available
- Temperature, humidity, pressure in air chamber: 12 air changes per hr; the temperature and relative humidity in each chamber were recorded at least 3 times during exposure using a portable, digital temperature and relative humidity monitor: they were within the range of 20.6 to 21.5°C and 5 to 44%, respectively.

TEST ATMOSPHERE
- Brief description of analytical method used: the atmospheric concentration of the test substance was determined for each exposure concentration by analysis of the material collected using a gas tight syringe (see in Table 1 below for details).
- Samples taken from breathing zone: test atmospheres were sampled from a front-facing port of the relevant exposure chamber, using a 5-mL gas-tight syringe equipped with an integral on-off valve and detachable sampling probe.

VEHICLE
- Composition of vehicle, concentration of test material in vehicle, justification of choice of vehicle, lot/batch no., purity: not applicable

- Rationale for the selection of concentrations: atmospheric concentrations of 50, 500, or 2500 ppm were selected on the basis of the results of trial exposures at 250 and 2000 ppm (3 males in both trials). In addition, a further concentration of 1275 ppm was carried out to meet specific safety labelling criteria.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

target : 50, 500, 1275, 2500 ppm (i.e. equivalent to 0.93, 9.26, 23.62, 46.31 mg/L)
achieved: 63.5, 613, 1238, 2576 ppm

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: see below
- Necropsy of survivors performed: yes
- Other examinations performed:
* Clinical signs: during exposure, animals were observed frequently. At the end of the 4-hour exposure period, each rat was given a detailed clinical examination. The animals were also given detailed clinical observations, (including the finding of "no abnormalities detected"), daily during the 14-day observation period.
* Body weight: the body weight of each rat was recorded on day -1 (to ensure animals of one sex were within a similar weight range), 1, 8 and prior to termination on day 15.
* Macroscopic examination: all animals were examined post mortem. This involved an external observation and an internal examination of all thoracic and abdominal viscera.

Results and discussion

Preliminary study:

Two preliminary groups, of 3 males each, were used for trial. A first group (animals A-C) was exposed to a target concentration of 250 ppm for periods of 1, 2 or 4 hours respectively. The second group (animals D-F) was exposed to a target concentration of 2000 ppm for periods of 1, 2 or 4 hours, respectively.

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1 238 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: The LC50 (lower and upper confidence limits) and slope of the regression lines could not be calculated from the data but the LC50 was estimated to be higher than 1238 ppm (i.e., 23 mg/L).

Effect levels 2

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 23 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: converted from 1238 ppm

Mortality:

There were no deaths in animals in the 63.5-, 613-, 1238-ppm group during the exposure or observation periods. Animals in the 2576-ppm group survived the exposure period but some animals were killed following exposure due to severe clinical effects (see in Table 2 below for details).

Clinical signs:

other: - DURING EXPOSURE: Wet fur was observed in all animals (an abnormality generally associated with restraint). Some animals exposed to 63.5 or 613 ppm had stains around the snout. There were no other clinical changes at these dose levels. Animals exposed to

Body weight:

At an exposure concentration of 63.5 ppm, all gained weight to the end of the study. At an exposure concentration of 613 ppm, all animals were gaining weight by day 15 of the study. At an exposure concentration of 1238 ppm, 2 females had gained a small amount of weight by day 15 of the study but the body weights of the remaining animals were equal to or below their initial body weight. At an exposure concentration of 2576 ppm, 1 female had gained weight on day 15 of the study but the body weights of the other surviving male and female were below their initial weight on day 15 of the study.

Gross pathology:

At an exposure concentration of 2576 ppm, some males had stained eyelids and stains around the nose and mouth. At an exposure concentration of 1238 ppm, 1/5 females and 5/5 males had a mass at the base of the tail from day 13 to 15. In the absence of similar findings in the highest dose and clear compound-related effects, the significance of this observation remains unclear.

Any other information on results incl. tables

Table 2: Mortality

Group	Analytical concentration (ppm)	Died or killed in extremis	Day of death
1	63.5	0	NA
2	613	0	NA
4	1238	0	NA
3	2576	4 males 3 females	6 (2 animals), 7 and 8 2, 3 and 8

Table 3: Clinical observations immediately after exposure

Table 2: Mortality Group Analytical concentration (ppm) Died or killed in extremis Day of death 1 2 4 3   63.5 613 1238 2576   0 0 0 4 males 3 females NA NA NA 6 (2 animals), 7 and 8 2, 3 and 8     Table 3: Clinical observations immediately after exposure Clinical observation Analytical concentrations (ppm) Incidence in males Incidence in females Lachrymation 63.5 2/5 1/5 613 0/5 1/5 1238 - - 2576 0/5 0/5 Wet fur 63.5 5/5 5/5 613 5/5 5/5 1238 5/5 5/5 2576 5/5 5/5 Stains around nose 63.5 2/5 1/5 613 5/5 1/5 1238 - - 2576 - - Piloerection 63.5 - - 613 3/5 5/5 1238 3/5 4/5 2576 - - Salivation 63.5 - - 613 2/5 0/5 1238 5/5 5/5 2576 5/5 5/5 Coat stained 63.5 - - 613 4/5 2/5 1238 - - 2576 - - Activity decreased 63.5 - - 613 - - 1238 5/5 5/5 2576 - - Breathing depth increased 63.5 - - 613 - - 1238 5/5 5/5 2576 5/5 5/5 Breathing rate decreased 63.5 - - 613 - - 1238 5/5 5/5 2576 5/5 5/5 Cold 63.5 - - 613 - - 1238 5/5 5/5 2576 5/5 5/5 Reduced foot withdrawal reflex 63.5 - - 613 - - 1238 5/5 5/5 2576 5/5 5/5 Palpebral reflex absent 63.5 - - 613 - - 1238 1/5 1/5 2576 5/5 5/5 Pinna reflex absent 63.5 - - 613 - - 1238 3/5 2/5 2576 5/5 5/5 Prostrated 63.5 - - 613 - - 1238 5/5 4/5 2576 - - Reduced righting reflex 63.5 - - 613 - - 1238 5/5 5/5 2576 - - Reduced response to sound 63.5 - - 613 - - 1238 5/5 5/5 2576 - - Decreased visual placement response 63.5 - - 613 - - 1238 5/5 5/5 2576 5/5 5/5 Gasping 63.5 - - 613 - - 1238 0/5 1/5 2576 3/5 3/5 Increased response to touch 63.5 - - 613 - - 1238 5/5 5/5 2576 - - Comatose 63.5 - - 613 - - 1238 - - 2576 5/5 5/5 Abnormal respiratory noise 63.5 - - 613 - - 1238 - - 2576 1/5 3/5

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

LC50 > 20 mg/L

Conclusions:

Nose-only exposure to vapours of the test substance at a concentration of 1238 ppm resulted in no deaths. It was thus concluded that the LC50 of the test substance was higher than 1238 ppm (or 23 mg/L) for male and female rats.

Executive summary:

This acute inhalation toxicity study was conducted according to OECD guideline 403 and in compliance with good laboratory practices (GLP).

Groups of five male and five female Alpk:AP_fSD (Wistar-derived) rats were exposed nose-only for a single 4-hour period to a vapour of the test substance at target concentrations of 50 ppm, 500, 1275, or 2500 ppm. Test atmospheres were analysed for vapour concentration. Following exposure, the animals were retained without treatment for 14 days. Clinical observations and body weights were recorded throughout the study and at the end of the schedule period, the animals were killed and given a gross examination post-mortem.

 

The achieved test atmospheres had the following characteristics:

 

Target concentration (ppm)	Achieved concentration (ppm)
2500	2576
1275	1238
500	613
50	63.5

 

At an exposure concentration of 2576 ppm, 4 males and 3 females died during the maintenance period. Of the 3 surviving animals only 1 female regained its initial body weight by day 15 of the study. There were a number of clinical changes indicative of both respiratory irritation and general toxicity including comatose state in all males and females on the first day, reduced activity days 3 to 6 in most animals, loss of reflex, which generally persisted until termination in one or more animals. There were some minor macroscopic changes.

 

At an exposure concentration of 1238 ppm, there were no mortalities. Two females had exceeded their initial body weights by day 15 of the study but the body weights of the remaining animals were equal to or below their initial body weights by day 15 of the study. There were a number of clinical changes indicative of both respiratory irritation and general toxicity, including decreased activity (day 1 to 5) which had resolved by day 12 of the maintenance period. There were no compound-related macroscopic changes.

 

At an exposure concentration of 613 ppm there were no mortalities. All animals were gaining weight by day 15 of the study. There were minimal clinical changes which had resolved by day 3 of the study and no macroscopic changes.

 

At an exposure concentration of 63.5 ppm there were no mortalities, no effects on body weight, minimal clinical changes which had resolved by day 3 of the study and no macroscopic changes.

 

Nose-only exposure for 4 hours to the test substance at a concentration of 1238 ppm resulted in no deaths. It was thus concluded that under the conditions of this study the LC50 of the test substance was higher than 1238 ppm (23 mg/L) for male and female rats, therefore the test substance does not meet the classification criteria of EC Regulation No. 1272/2008 (CLP / EU GHS) for acute inhalation toxicity.