Registration Dossier

Administrative data

Description of key information

Two acute oral, two acute dermal and two acute inhalation toxicity studies were conducted on PPVE. The result of the studies were:

 

The rat oral LD50 is greater than 2,000 mg/kg when tested according to OECD 401 (1987).

 

The rat oral LD50 is 13,267 mg/kg when tested in a method similar to OECD 401.

 

The rat dermal LD50 is greater than 2,000 mg/kg when tested according to OECD 402 (1987).

 

The rat dermal LD50 could not be determined due to methodological deficiencies in the study design when tested according to a custom protocol.

 

The rat inhalation LC50 is greater than 58.7 mg/L when tested according to OECD 403.

 

That rat inhalation LC50 was not determined due to variability in results.

Key value for chemical safety assessment

Additional information

Acute Oral Lethality:

 

The acute oral toxicity potential of the test article (liquid, batch 10B1001) was evaluated in male and female rats. This study was performed in accordance with OECD GLP (1999). The study design was based on OECD 401 (1987) and Directive 92/69/EEC, guideline B.1 (1992). The test article was emulsified at 20% in deionized water. Rats (5/sex) received 2000 mg/kg test article via a single oral gavage. Parameters evaluated: clinical observations (daily), body weights (weekly), and gross necropsy (termination). All animals were terminated 14 days post-dose. All animals survived. Squatting posture (9 of 10 animals, 9/10), drawn in flanks (2/10), irregular respiration (10/10), and swollen abdomen (6/10) were noted in animals from 1 hour to 8 hours post-dose. Drawn in flanks and irregular respiration were not present at 24 hours after dosing. Swollen abdomen persisted in males (1 to 4 of 5 animals) through Day 11 and in females (2/5) through Day 4. Squatting posture persisted in males (2/5) through Day 4 and was not present in females at 24 hours after dosing. All animals were normal on Day 12. There were no abnormalities in body weights or gross necropsy observations. Based on the results of this study, the oral LD50 of the test article is greater than 2000 mg/kg body weight.

 

 

The acute oral toxicity potential of the test article was was evaluated in Wistar rats. The study was conducted prior to the adoption of GLP regulations. The test method was similar to OECD Guideline 401. The test article was deep-frozen, mixed with cold starch. Fasted rats (10 males/dose) were dosed with 6300, 8000, 10000, 12500 or 15000 mg/kg via oral gavage. Clinical signs were recorded daily and body weights recorded on Days 0, 7 and 14. All surviving animals were subjected to gross necropsy following a 14 day observation period. All animals in the 6300 mg/kg dose group survived throughout the study. Deaths occurred in the 8,000 mg/kg dose group (2/10), 10000 mg/kg group (2/10), 12500 mg/kg group (6/10), and the 15000 mg/kg group (5/10). Animals in the 12500 mg/kg and 15000 mg/kg groups exhibited lethargy until Day 2. No other abnormal clinical signs were noted in surviving animals during the observation period. Body weight gain was normal in surviving animals. No abnormal findings were noted upon gross examination. Based on the results of the study, the oral LD50 of the test article was determined to be 13267 mg/kg body weight.

 

Acute Dermal Lethality:

 

The acute dermal toxicity of the test article (clear, colorless liquid, batch 114B1005) was evaluated in male and female Sprague-Dawley rats. This study was performed in compliance with OECD GLP regulations. The test method was based on OECD 402 (1987). Rats (5/sex) were clipped of hair to create a dorsal trunk test site that was not less than 10% of the total body surface area. Animals were dosed with 2000 mg/kg (1.29 mL/kg) of the test article. The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only. At 24 hours, the wrappings were removed and the test sites were washed with tap water. Clinical observations were recorded periodically on the day of dosing and then once daily for 14 days. Body weights were recorded pretest, day 8 and day 15. All animals were examined for gross pathology after termination on Day 15. All animals survived. Restless behavior, piloerection and/or chromodacryorrea were noted for the animals on day 1. The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. No abnormalities were found at macroscopic post mortem examination of the animals. Based on the results of this study, the dermal LD50 of the test article is greater than 2000 mg/kg.

 

The acute dermal toxicity of the test article was determined in female SPF-Wistar rats. The study was conducted prior to the adoption of GLP regulations. The study method was based on a custom protocol. The tail of each animal was submerged in 20 mL of cooled (0 -10 degrees C) test article in a test tube for 60 minutes. During the test, 0.5 to 1.5 mL of the test article evaporated. Following exposure, the animals were observed for 14 days with clinical signs (daily) and body weights (Day 0, 7 and 14) recorded. All animals were examined macroscopically upon necropsy. No abnormal clinical signs were noted during the study period. All animals gained weight during the study. No abnormal macroscopic findings were noted upon necropsy. A dermal LD50 value could not be determined based on methodological deficiencies in the study design.

 

Acute Inhalation Lethality:

 

The 4-hour acute inhalation lethality of the test article was determined in Sprague-Dawley rats. The study was conducted in compliance with GLP (1982) regulations. The test method was based on OECD Guideline 403. Rats (5/sex/group) were exposed to 0 (negative control), 12.4, 21.8, 40.8, or 58.7 mg/L test article for a single, whole body 4-hour exposure. Rats were observed continuously during exposure and at least twice daily throughout the study. Clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5, and 1.0 hours and then at hourly intervals during the exposure. During the recovery period clinical signs were recorded once in the morning and then as necessary following a later check for clinical signs of toxicity. All rats were weighed daily until the end of the recovery period (Day 14). A gross necropsy was performed on all surviving rats on Day 14 following exposure.

Following review by the sponsor of the procedures for cleaning of the sample cylinders for the 2 consignments of the test compound, the sponsor considers that the first consignment, which was used for the 12.4, 21.8 and 40.8 mg/L exposures, may have been contaminated with hydrofluoric acid formed following incomplete drying of the cylinder used. The second consignment was used for the exposure at 58.7 mg/L test article.

No mortality was observed in animals exposed to 58.7 mg/L; clinical signs of toxicity observed during the exposure included fast respiration and piloerection which had resolved by one day post-exposure. Food consumption was normal and water consumption was slightly above that of the control animals during the recovery period. At necropsy, no abnormalities were observed in rats exposed to 58.7 mg/L except for one female that demonstrated pale raised areas in the lungs.

During the 40.8 mg/L exposure, partially closed eyes, fast respiration and restless behavior were observed which lasted for up to 4 days post-exposure. Three males and 1 female (total mortality 4/10) died within 2 days of the exposure. Food and water consumption was reduced for up to 3 days following the 40.8 mg/L exposure and animals demonstrated body weight losses for 2 days post-exposure. At necropsy, slight to sever congestion and dark subpleural foci in the lungs, wet fur, red or clear discharge from the nose and white frothy fluid were observed. No adverse clinical signs of toxicity were noted during the 21.8 mg/L exposure; however, exaggerated and fast respiration, immobility convulsions in response to sound were noted for up to 3 days post-exposure. Two male and 3 females were found dead (5/10 total mortality) between days 1 and 2 post-exposure. Food and water consumption was reduced for up to 3 days following the 21.8 mg/L exposure and animals demonstrated body weight losses for 2 days post-exposure. At necropsy, slight to severe congestion and dark subpleural foci in the lungs, wet fur, red or clear discharge from the nose and white frothy fluid were observed. Restless behavior and fast respiration were noted during the 12.4 mg/L exposure and exaggerated respiration was noted for up to 3 days post-exposure. One female was found dead (1/10 total mortality) one day post-exposure. Food and water consumption was reduced for up to 3 days following the 12.4 mg/L exposure and animals demonstrated body weight losses for 2 days post-exposure. At necropsy, slight to severe congestion and dark subpleural foci in the lungs, wet fur, red or clear discharge from the nose and white frothy fluid were observed.

Therefore, based on the results of this study, the 4-hour acute inhalation LC50 of the test article is greater than 58.7 mg/L, vapor.

 

The acute inhalation toxicity of the test article was evaluated in female Wistar rats. The study was not performed in compliance with OECD GLP regulations. The test method was based on a custom protocol. Two different batches of the test article were tested. The first sample (November 1974) was tested at concentrations of 2564, 6410, 8546.7, and 12820 ppm. The second sample (April 1975) was tested at concentrations of 11864, 12820, 17093, and 25640 ppm. Each concentration was tested in 6 female rats for 4 hours. Animals were exposed whole body in a 39 liter glass vessel. During the exposure, the behavior was monitored and recorded. After exposure, a 14 day observation period followed. All animals were subject to macroscopic examination upon necropsy. All 6 animals died within 20 hours following exposure to the November 1974 sample at 12820 ppm. One animal died 48 hours after exposure to the April 1975 sample at 17093. Rats exposed to all other airborne concentrations survived the exposure and subsequent 14-day recovery period. All 6 animals in the November 1974 12820 ppm group exhibited gasping and ruffled fur prior to death. No other abnormal clinical signs were noted in animals in any other exposure groups. The majority of animal exposed to the November 1974 sample had reduced body weight gains up to 6 days following exposure. All animals exposed to the April 1975 sample gained weight during the observation period. The lungs of 6/6 animals exposed to 12820 ppm of the November 1974 sample had red coloration. Upon dissection, bloody and frothy liquid was noted in the lungs. Under microscopic examination, intense hyperemia and lung edema was noted. No other abnormal gross or microscopic findings were noted in any other exposure groups. An inhalation LC50 value was not determined due to variability in results when two different samples of the test article were tested.

Justification for classification or non-classification

Based on the results of the studies, PPVE does not meet the GHS classification criteria for acute lethality.