Reaction mass of (3E)-1,1,1,2,2,3,4,5,6,6,7,7,7-tridecafluoro-5-methoxyhept-3-ene and (2E)-1,1,1,2,3,4,5,5,6,6,7,7,7-tridecafluoro-4-methoxyhept-2-ene and (3E)-1,1,1,2,2,4,5,5,6,6,7,7,7-tridecafluoro-3-methoxyhept-3-ene

Endpoint summary

Description of key information

Oral: OECD 420; rat. The LD50 was >5000 mg/kg. Reliability = 1
Dermal: OECD 402; rat. The LD50 was >5000 mg/kg. Reliability = 1
Inhalation: Equivalent to OECD 403; rat. The LC50 was >15000 ppm (222150 mg/m3). Reliability = 2

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Remarks:

The study was conducted according to the guideline in effect at the time of study conduct.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Remarks:

The study was conducted according to the guideline in effect at the time of study conduct.

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 181-203 g
- Fasting period before study: overnight prior to each dosing. Feed was replaced approximately 3-4 hours after dosing.
- Housing: Singly in suspended stainless steel caging with mesh floors. Enrichment (e.g. nylaobne) was placed in each cage. Litter paper was placed beneath the cage and was changed at least 3 times per week.
- Diet (e.g. ad libitum): amount supplied not reported
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 or 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21°C
- Humidity (%): 20-58% (the humidity was below the targeted lower limit of 30% during the study. A portable humidifier was used to increase the humidity levels during this time.)
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

5000 mg/kg

No. of animals per sex per dose:

5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were observed for mortality, signs of gross toxicity, and behavioural changes within 30 minutes and during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing.
-Frequency of weighing: The rats were weighed on test days 0, 7, and 14.
- Necropsy of survivors performed: yes

Statistics:

Not applicable

Preliminary study:

An initial limit dose of 5000 mg/kg was administered to one healthy female rat by oral gavage. Due to the absence of mortality in this animal, four additional females received a dose level of 5000 mg/kg, simultaneously.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No adverse effects observed. No clinical signs of toxicity and no gross lesions observed.

Mortality:

No mortality was observed.

Clinical signs:

other: All animals appeared active and healthy during the study. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour.

Gross pathology:

No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Interpretation of results:

not classified

Remarks:

Migrated information very low toxicity Criteria used for interpretation of results: EU

Conclusions:

LD50 (rat) >5000 mg/kg

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).

Executive summary:

An acute oral toxicity test (Fixed Dose Procedure) was conducted with rats to determine the potential for the test substance to produce toxicity from a single dose via the oral route. An initial limit dose of 5000 mg/kg was administered to one healthy female rat by oral gavage. Due to the absence of mortality in this animal, four additional females received a dose level of 5000 mg/kg, simultaneously. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days after dosing. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice.

All animals survived, gained body weight, and appeared active and healthy during the study. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. Under the conditions of this study, the acute oral LD₅₀ of the test substance is greater than 5000 mg/kg of body weight in female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 231-314 g (males); 176-217 g (females)
- Fasting period before study: no
- Housing: Except during exposure, animals were housed individually in solid bottom caging with bedding.
- Diet (e.g. ad libitum): ad libitum, except during exposure
- Water (e.g. ad libitum): ad libitum, except during exposure
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26ºC
- Humidity (%): 30-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass (cylindrical) chamber with a nominal internal volume of 19 L. A 1-inch circular glass baffle at the chamber inlet promoted uniform chamber distribution of the test atmosphere.
- Method of holding animals in test chamber: The rats were placed inside a wire-mesh module (sexes separate) that was placed on a stainless steel stand inside the exposure chamber so that the rats were elevated off of the bottom of the glass chamber.
- Source and rate of air: Houseline generation air, was metered to the round-bottom flask with a mass flow controller and carried the vapour and air mixture into a glass transfer tube that led to the exposure chamber. Supplemental or dilutional chamber air was metered via another mass flow controller and was added to the vapour and air mixture in the glass transfer tube.
- Method of conditioning air: Not reported
- System of generating particulates/aerosols: Chamber atmospheres were generated by flash evaporation of the test substance in air. The test substance was metered into a heated round-bottom, flash evaporation flask with a Harvard Apparatus Syringe Infusion Pump. The round-bottom flask was heated to approximately 175°C to vapourize the test substance. Houseline generation air, was metered to the round-bottom flask with a mass flow controller and carried the vapour and air mixture into a glass transfer tube that led to the exposure chamber. Supplemental or dilutional chamber air was metered via another mass flow controller and was added to the vapour and air mixture in the glass transfer tube. Chamber concentrations of the test substance were controlled by varying the test substance feed rate to the round-bottom flask. Chamber airflow was 8 L/min which provided at least 10 air changes per hour.
- Treatment of exhaust air: The test atmosphere was exhausted through a dry-ice cold trap followed by an MSA charcoal/HEPA filter cartridge prior to discharge into the fume hood.
- Temperature, humidity, pressure in air chamber: 20-24°C, 53-84%, pressure not reported; oxygen concentration ranged from 20 to 21%.

TEST ATMOSPHERE
- Brief description of analytical method used: The vapour concentration of the test substance was determined by gas chromatography 13 or 14 times during each test-substance exposure. Chamber concentration was analysed only once during the 0 ppm exposure.
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

2000, 5000, 9700, 15000 ppm

No. of animals per sex per dose:

5/sex/concentration

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Animals were observed for mortality and response to alerting stimuli 3 times during each exposure and observed for mortality and clinical signs of toxicity immediately after they were removed from the exposure chamber following exposure. During the recovery period, all rats were observed each day for mortality. Rats were observed for clinical signs of toxicity on the day following exposure and at least twice more during the recovery period.
- Frequency of weighing: Rats were weighed on the day following exposure and at least twice more during the recovery period.
- Necropsy of survivors performed: yes
- Other examinations performed: The respiratory tract, liver and kidney tissues were collected for microscopic histopathological evaluation and were examined for the 0 and 15000 ppm groups only. Since there were no test-substance related changes at the highest concentration, tissues from lower test concentrations were not evaluated.

Statistics:

Not reported

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 15 000 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: highest practical vapour concentration achievable for this test substance

Sex:

male/female

Dose descriptor:

other: NOAEL (histopathology)

Effect level:

15 000 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: No adverse histopathological effects observed in the respiratory tract, liver, and kidneys.

Sex:

male/female

Dose descriptor:

other: Clinical signs

Effect level:

5 000 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Decreased to no activity, periodic rapid head-bobbing, rapid ear-twitching, excessive grooming, chewing motions, increased startle response at 9700 ppm; no activity at 15000 ppm. No clinical signs upon removal from chamber and during 14-day recovery.

Mortality:

No test substance-related animal deaths occurred during or following any of the exposures.

Clinical signs:

other: There were no noteworthy clinical signs of toxicity observed during the 0, 2000, or 5000 ppm exposures. During the 9700 ppm exposure, rats displayed decreased activity approximately 10 minutes into the exposure, and after approximately 45 minutes, the rat

Body weight:

Two to 5 female rats at all levels (including the 0 ppm exposure group) displayed body weight losses ranging from 1.2 to 10 grams up to the second day after exposure, followed by normal weight gain throughout the remainder of the 14-day recovery period. Four of 5 male rats in the 9700 ppm exposure group, and all 5 male rats in the 15000 ppm exposure group displayed body weight losses ranging from 0.1 to 9.3 grams on the day after the exposure, followed by normal weight gain throughout the remainder of the recovery period.

Gross pathology:

There were no test substance-related gross observations in this study.

Other findings:

There were no test substance-related microscopic observations. All microscopic changes noted occurred in similar incidences across control and treated groups and were consistent with background lesions commonly observed in rats of this strain and age.

Interpretation of results:

not classified

Remarks:

Migrated information very low toxicity Criteria used for interpretation of results: EU

Conclusions:

4-hour LC50 (rats) >15000 ppm
NOAEL (histopathological changes in respiratory tract, liver, kidney) >15000 ppm

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).

Executive summary:

Five groups of 5 male and 5 female rats were exposed whole-body for 4 hours to mean concentrations of 0, 2000, 5000, 9700 and 15000 ppm test substance vapour. Rats were sacrificed 14 days after the exposure and given gross examination at necropsy. The respiratory tract, liver, and kidney tissues were collected for microscopic histopathological evaluation.

No test substance-related animal deaths occurred during or following any of the exposures. There were no noteworthy clinical signs of toxicity observed during the 0, 2000 and 5000 ppm exposures. During the 9700 ppm exposure, male and female rats displayed decreased activity approximately 10 minutes into the exposure, and after approximately 45 minutes, the rats became motionless, except when the startle response was checked. Rats exposed to 15000 ppm periodically displayed rapid head-bobbing, rapid ear-twitching, excessive grooming, chewing motions and an increased startle-response, during the first 45 minutes of the exposure. The rats became motionless (except for when startle response was checked) throughout the remainder of the exposure. The rats’ startle response was normal after approximately 45 minutes of exposure to either 9700 or 15000 ppm. There were no abnormal clinical signs of toxicity observed in any rats when they were removed from the exposure chamber or throughout the 14-day recovery period. Two to 5 female rats at all levels (including the 0 ppm exposure group) displayed body weight losses ranging from 1.2 to 10 grams up to the second day after exposure, followed by normal weight gain throughout the remainder of the 14-day recovery period. Four of 5 male rats in the 9700 ppm exposure group, and all 5 male rats in the 15000 ppm exposure group displayed body weight losses ranging from 0.1 to 9.3 grams on the day after the exposure, followed by normal weight gain throughout the remainder of the recovery period. Gross examinations were performed on all rats at the time of necropsy, and respiratory tract tissues (lung, larynx/pharynx, trachea, and nose), liver and kidneys from the 0 and 15000 ppm exposure groups were evaluated microscopically. There were no test substance-related gross pathology findings in any rats in this study, and there were no test substance-related microscopic findings in the respiratory tissues, liver and kidneys of rats from the 0 or 15000 ppm exposure groups. Since no test substance related changes were observed in rats from the 15000 ppm exposure group, tissues from the lower concentration exposure groups were not evaluated. Under the conditions of this study, the 4-hour LC₅₀  is considered to be greater than 15000 ppm test substance, the highest practical vapour concentration achievable for this test substance. The no-observed-adverse-effect-level (NOAEL) for histopathological changes of the respiratory tract, liver and kidneys is also 15000 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

222 150 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Remarks:

The study was conducted according to the guideline in effect at the time of study conduct.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Remarks:

The study was conducted according to the guideline in effect at the time of study conduct.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Remarks:

The study was conducted according to the guideline in effect at the time of study conduct.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: males 314.6 - 342.2 g; females 213.4 - 235.1 g
- Fasting period before study: No
- Housing: Singly in polycarbonate pans that contained bedding with enrichment
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26°C
- Humidity (%): 30-70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: approximatley 37 cm2
- Type of wrap if used: 2-ply gauze patch, stretch gauze bandage, and self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

5000 mg/kg

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and signs of illness, injury, and abnormal behaviour were made daily throughout the study. Observations for clinical signs of toxicity and dermal irritation were made daily throughout the study (weekends excluded for dermal irritation). Rats were weighed prior to treatment (test day 0) and on test days 7 and 14.
- Necropsy of survivors performed: yes

Statistics:

None

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No adverse effects observed. No clinical signs of toxicity, body weight loss, dermal irritation, and no gross lesions observed.

Mortality:

No mortality was observed.

Clinical signs:

other: No clinical signs of toxicity were observed during the study. No dermal irritation was observed.

Gross pathology:

No gross lesions were present in the rats at necropsy.

Interpretation of results:

not classified

Remarks:

Migrated information very low toxicity Criteria used for interpretation of results: EU

Conclusions:

Dermal LD50 (rat) >5000 mg/kg

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).

Executive summary:

A single dose of the test substance was applied to the shaved, intact skin of 5 male and 5 female rats at a dose of 5000 mg/kg of body weight. The application site was covered with a semi-occlusive dressing for 24 hours, after which the test substance was removed. The rats were observed for 14 days following application. The rats were necropsied to detect grossly observable evidence of organ or tissue damage at the end of the 14-day test period.

No deaths occurred. The rats exhibited no clinical signs of toxicity, body weight loss, or dermal irritation. No gross lesions were present in the rats at necropsy. Under the conditions of this study, the dermal LD₅₀ for the test substance was greater than 5000 mg/kg for male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Additional information

The substance has low inhalation, oral, and dermal toxicity in the rat. The rat 4-hour inhalation LC₅₀ as well as NOAEL was >15000 ppm (222150 mg/m³), which was the highest achievable vapour concentration. All rats displayed normal startle response throughout the exposure period for all test concentrations. During inhalation to substance concentrations of 9700 ppm and higher, the animals displayed periodic hyperactivity as well as decreased activity levels. There were no abnormal clinical signs of toxicity observed in any rats when they were removed from the exposure chamber or throughout the 14-day recovery period. There were no test substance-related gross pathology findings in any rats in this acute inhalation study, and there were no test substance-related microscopic findings in the respiratory tissues, liver and kidneys of rats from the 0 or 15000 ppm exposure groups. Since no test substance related changes were observed in rats from the 15000 ppm exposure group, tissues from the lower concentration exposure groups were not evaluated. Under the conditions of the study, the NOAEL was 15000 ppm. The rat oral and dermal LD₅₀s were >5000 mg/kg body weight. No signs of toxicity were observed with oral or dermal routes of exposure.

Justification for selection of acute toxicity – oral endpoint
OECD Guideline, GLP study

Justification for selection of acute toxicity – inhalation endpoint
Equivalent to OECD Guideline, GLP study

Justification for selection of acute toxicity – dermal endpoint
OECD Guideline, GLP study

Justification for classification or non-classification

Based on the acute oral LD₅₀ in rats of >5000 mg/kg, the inhalation 4-hour LC₅₀ in rats of >15000 ppm (222.15 mg/L), and dermal LD₅₀ in rats of >5000 mg/kg, no classification is required for acute oral, inhalation, or dermal endpoints according to EU Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. The observations of periodic hyperactivity and decreased activity in the acute inhalation study are not consistent with a substance, such as a narcotic, that could adversely alter human function for a short duration after exposure as all animals maintained a normal startle response throughout the four-hour exposure period and no observations such as ataxia, or lack of coordination were noted. No classification is required for specific target organ toxicity single exposure according to EU Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.