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Description of key information

ORAL

The LD50 for propargite was determined to be 2800 mg/kg bw according to a study performed in line with EPA OPP Guideline 81-1.

INHALATION

The LC50 for propargite was determined to be 0.89 mg/m3 according to a study performed in line with EPA OPP Guideline 81-3. In this study, the lowest concentration tested was 0.3 mg/L which caused marked effects including mortality. As the lowest concentration tested for inhalation, and withpropargite known to be an irritant, this concentration is used as a LOEC for local irritant effects by inhalation.

DERMAL

The LD50 for propargite was determined to be > 4000 mg/kg bw according to a study performed in line with EPA OPP Guideline 81-2.

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
Study period:
26th July 1991 to 2nd September 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OTS 798.1175 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: young adult
- Weight at study initiation: 203-278 g
- Fasting period before study: yes (approximately 18-20 hours)
- Housing: individual suspended wire-mesh cages
- Diet: Purina® Certified Rodent Chow® #5002 ad libitum
- Water: tap water ad libitum
- Acclimation: 7 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature: 70-75 ºF
- Humidity: 54-86 %
- Photoperiod: 12 hours light/12 hours dark
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
RATIONAL FOR THE SELECTION OF THE STARTING DOSE
- A range-finding study was conducted in which groups of one male and one female were dosed at levels of 500, 1000, 2000, 3500 and 5000 mg/kg. The male dosed at 2000 mg/kg, the female dosed at 3000 mg/kg and all animals dosed at 5000 mg/kg died. Both animals dosed at 500 and 1000 mg/kg survived. Based on these results 2000 mg/kg was selected as the first dose level on the definitive study.

- Three groups of five male and five female rats were administered single doses at levels of 2000, 2800 and 3920 mg/kg. Dose levels were selected using a progression of 1.4.
Doses:
2000, 2800 and 3920 mg/kg bw (dose volumes of 1.8, 2.57 and 3.6 mL/kg respectively)
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations at 1, 3 and 4 hours post-dose and twice daily thereafter; body weights at days -1, 0, 7 and 14 (and at death)
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 800 mg/kg bw
Based on:
test mat.
95% CL:
>= 2 511 - <= 3 122
Mortality:
All mortalities occurred in the second week of the study (days 6- 11), during which the combined mortality was 0/10, 5/10 and 10/10 in the 2000, 2800 and 3920 mg/kg bw groups, respectively (see Table 1).
Clinical signs:
All animals displayed various signs of urogenital staining/matting. Abnormal defecation was observed in 28 animals, while 20 animals exhibited decreased urination. Hypoactivity was observed for 23 animals. The hindpaws and/or forepaws were red/swollen in 27 animals, while 19 appeared to have red/swollen mouths. Red swelling was also seen in the ears, the female urogenital area and on the male penis and prepuce. In addition, necrotic areas were observed on the scrotum in 8 rats from the 2000 and 2800 mg/kg bw groups. Other signs included hair loss on the tail, hypothermia, hypersensitivity to touch, abdominal staining and apparent dehydration.
Body weight:
Weight loss was observed in 24 animals over days 0-7. All surviving animals regained lost weight and surpassed their day 0 body weights by day 14, with the exception of two animals which regained some lost weight, but did not reach their day 0 body weights.
Gross pathology:
Findings of gross necropsy on animals that died during the study, included stomach abnormalities (thickened mucosa and red areas/contents), intestinal abnormalities (distended red with contents), reddened adrenal glands, red lungs, reddened pituitary, dark red prostate and red streaks in the bladder.

Table 1: Mortality

 Dose level (mg/kg bw)  Male mortality  Female mortality  Total mortality
 2000  0/5  0/5  0/10
 2800  4/5  1/5  5/10
 3920  5/5  5/5  10/10
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
The acute oral LD50 of the test material in rats was calculated to be 2800 mg/kg (95 % C.I. 2511-3122 mg/kg).
Executive summary:

The test material was administered once orally via gastric intubation to groups of five male and five female fasted albino rats at dose levels of 2000, 2800 and 3920 mg/kg. Mortality, clinical observations, body weights and gross necropsy findings were evaluated.

Clinical findings were generally noted throughout the study and in all dose groups. All animals had various urogenital staining. The majority of the animals had abnormal defecation and swollen hindpaw(s) and/or forepaw(s). The urogenital area appeared swollen on the majority of females. Essentially all males had a red and swollen penis and prepuce and the majority of animals in the 2000 and 2800 mg/kg groups had necrotic areas on the scrotum. Hypoactivity, wet and/or dried material on the forepaw(s), dried red material around the mouth, decreased urination and a red and swollen mouth were noted for approximately two-thirds of the animals. More than one-half of the animals had hair loss at the base of the tail. Approximately one-third of the animals had red and swollen ears and hypothermia. Eight animals were hypersensitive to the touch. Other clinical findings included rales, scabbing of the right and/or left ear, dried red material around the eye(s), ataxia, moist alopecia on the forepaw(s) and/or hindpaw(s), dried red abdominal staining, dehydration, prostration and greenish discolouration of the tissues in the urogenital area.

No mortality was observed in the 2000 mg/kg group. Five and ten deaths were observed in the 2800 and 3920 mg/kg groups respectively.

Twenty-four animals lost weight from day 0 to day 7; all surviving animals gained weight during the second week of the study.

G.I. abnormalities were noted for 14/15 animals that died and were considered to be due to the irritative properties of the test material. Dark red or reddened adrenal glands, a typical agonal or stress-related change, were observed for six animals that died. Five animals had bright red lungs and three animals were icteric. Other findings observed for one animals included a reddened pituitary gland, a dark red prostate gland and dark red streaks on the urinary bladder. 14/15 animals that died had external matting. Reddened forepaw(s) and/or hindpaw(s) were observed on six animals. Two animals had reddened ear(s) and a red and swollen penis. Scabbing on the forepaw and hair loss were each noted for one animal.

External surface findings were noted on all animals that were terminally necropsied. Various scabbing, hair loss and swelling were noted for approximately two-thirds of the animals. Approximately one-third of the animals had reddened hindpaw(s) and/or forepaw(s). Red nasal matting and a thickened mucosa in the stomach were noted for two animals each. One 2800 mg/kg male had small, soft testes. No other significant changes were observed at terminal necropsy.

The LD50 was determined to be 2800 mg/kg (95 % C.I. 2511-3122 mg/kg).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 800 mg/kg bw
Quality of whole database:
The study was performed to GLP and has a Klimisch score of 1.

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
Study period:
21st January 1992 to 25th February 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
yes
Remarks:
(relative humidity and temperature decreased on occasion below that stated in the protocol. The test chambers were cleared at a flow rate of 8 L/min after exposure instead of at the same flow rates used in the exposure phase as intended)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
yes
Remarks:
(relative humidity and temperature decreased on occasion below that stated in the protocol. The test chambers were cleared at a flow rate of 8 L/min after exposure instead of at the same flow rates used in the exposure phase as intended)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
(relative humidity and temperature decreased on occasion below that stated in the protocol. The test chambers were cleared at a flow rate of 8 L/min after exposure instead of at the same flow rates used in the exposure phase as intended)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, New York, USA
- Age at study initiation: 7-9 weeks
- Weight at study initiation: 248-333 g (males); 207-233 g (females)
- Housing: stainless steel, wire mesh cages
- Diet: Purina Mills Rodent Laboratory Chow® Brand Animal Diet #5001 ad libitum
- Water: municipal water supply ad libitum
- Acclimation period: 12 to 21 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 ºC
- Humidity: 19-66 %
- Photoperiod: 12 hours light/12 hours dark
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cast aluminium and alloy exposure chamber
- Exposure chamber volume: 40 litres
- Method of holding animals in test chamber: polycarbonate nose-only tubes
- Exposure procedure: flask containing test material was heated to 50 ºC. House-line air was delivered through a regulator and backpressure gauge via plastic tubing to a plastic 'Y' where it split into a generation flow and a dilution flow. The generation flow was delivered to a flowmeter fitted with a backpressure gauge and regulated by a valve to a neubiliser inserted into the centre neck of the flask. The test material-laden airstream exited the flask and passed through a brass cyclone before entering the nose-only chamber. The dilution flow was delivered to a flowmeter regulated by a valve and then into the side inlet of the nose-only chamber.
- Method of particle size determination: samples were drawn each hour using a cascade impactor. Mass median aerodynamic detector, geometric standard deviation and percent of particles ≤1.0 and ≤10 µm were calculated based on the amount of material collected on the six impactor stages (stainless steel slides) and a final filter stage.
- Treatment of exhaust air: through the in-house filtration system consisting of a coarse filter, HEPA filter and an incinerator
- Temperature, humidity, pressure in air chamber: 19-23 ºC, 8-32 %

TEST ATMOSPHERE
- Brief description of analytical method used: samples were withdrawn from the exposure chamber through glass-fibre filters each hour. Once during each exposure, an extended probe was used to obtain a sample from the other side of the chamber to measure the distribution of aerosol within the chamber. Sample flow rates were 5 lpm for all groups and sample duration was 10 minutes (0.31 mg/L), 1 minute (0.8 mg/L) and 2 minutes (1.3 mg/L). Samples were analysed by GC-FID.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.31, 0.8 and 1.3 mg/L (air concentration)
No. of animals per sex per dose:
Five
Details on study design:
- Duration of observation period following administration: 14 days (0.31 mg/L); 21 days (0.8 and 1.3 mg/L)
- Day of exposure (day 1): all animals were observed individually prior to exposure, as a group at approximately 15 minute intervals during the first hour of exposure and hourly for the remainder of the exposure period. All animals were observed individually upon removed from the exposure chamber and hourly for two hours post-exposure.
- Days 2 through 22: detailed observations were recorded for survivors once daily; viability was assessed twice daily.
- Body weight: days 1 (prior to exposure), 2, 3, 5, 8, 15 and 22
- Necropsy of survivors performed: yes
Statistics:
LC50 and 95 % confidence limits calculated using the method of Litchfield and Wilcoxon.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.89 mg/L air
Based on:
test mat.
95% CL:
>= 0.11 - <= 7
Exp. duration:
4 h
Mortality:
All mortalities occurred between one and seventeen days post-exposure, with the exception of a single accidental death during the first 15 minutes of exposure. This animal was immediately replaced. Total mortalities were 1/10, 2/20 and 10/10 at 0.31, 0.8 and 1.3 mg/l, respectively.
Clinical signs:
other: During the exposure period, the most common symptom was laboured breathing and ano-genital staining. The same signs were evident during the 2 hour post-exposure period, accompanied by nasal discharge, matted coats and several gasping animals in the 1.3 mg
Body weight:
Body weight was reduced by up to 32 % during the first week post-exposure. However, recovery of lost weight occurred over time and all surviving animals were in excess of their starting weight at test termination.
Gross pathology:
The only treatment related finding at necropsy appeared to be a reddening of the lungs of some animals that died during the course of the study.

Table 1: Summary of mortality

     Mortality  
 Group  Conc. (mg/L)  Male  Female  Total  Day of last spontaneous death
 I  0.31  1/5  0/5  1/10  5
 II  1.30  5/5  5/5  10/10  18
 III  0.80  1/5  1/5  2/10  4
Interpretation of results:
other: Classified as Category 3 in accordance with EU criteria
Conclusions:
The acute nose-only inhalation LC50 of the test material in rats was determined to be 0.89 mg/L.
Executive summary:

The test material was administered by nose-only inhalation as a liquid aerosol to three groups of five rats for four hours. Exposure levels were determined gravimetrically and by GC during each hour of exposure. Particle size distributions were determined during each hour of exposure. Physical observations for abnormal signs were conducted on all exposure animals as a group, at fifteen minute intervals during the first hour of exposure and hourly for the remainder of exposure. All animals received detailed physical observations just prior to exposure, immediately upon removal from the chamber, hourly for two hours post-exposure and once daily thereafter. Body weight measurements were obtained just prior to exposure on day 1 and on days 2, 3, 5, 8, 15 and 22. After a 14 or 21 day post-exposure observation period, all survivors were sacrificed and complete post-mortem examinations performed.

The mean exposure concentrations were determined to be 0.31, 0.80 and 1.3 mg/L air resulting in mortalities of 10, 20 and 100 %, respectively. Particle size distribution determinations showed, on average, the mass median aerodynamic diameter to be 1.6 µm with a geometric standard deviation of 1.8. 22 % of the particles were <1 µm and 100 % of the particles were <10 µm in size.

The LC50, based on analytical concentrations, was determined to be 0.89 mg/L for the combined sexes with 95 % C.I. of 0.11 to 7.0 mg/L. There was no difference in lethality between males and females. Signs of treatment included respiratory responses during exposures and secretory/respiratory responses following the exposures leading to mortality within 1 to 17 days. A substantial adverse effect upon body weight was produced by treatment. Gross post-mortem examinations included possible treatment-related lung discolouration.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
0.89 mg/m³
Quality of whole database:
The study was performed to GLP and has a Klimisch score of 1.

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
Study period:
12th August 1991 to 26th August 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OTS 798.1100 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Inc., Denver, Pennsylvania, USA
- Age at study initiation: young adult
- Weight at study initiation: 2097-2231 g
- Housing: individual suspended mesh-bottom cages
- Diet: Purina® Certified Rabbit Chow® #5322 ad libitum
- Water: tap water ad libitum
- Acclimation period: a minimum of 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 67-76 ºF
- Humidity: 62-80 %
- Photoperiod: 12 hours light/12 hours dark
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- % coverage: approximately 23 %
- Type of wrap if used: gauze binders

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.7 mL/kg
Duration of exposure:
24 hours
Doses:
4000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and clinical observations at 1, 3, 4 hours post-dose and thereafter twice daily; dermal observations approximately 30-60 minutes after bandage removal and daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: body weights on days 0, 7 and 14
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
Abnormal defecation was generally noted during the first week post treatment. Loss of appetite was noted for six animals, while scabbing/swelling around the mouth and dry yellow staining around the nose were observed for eight animals. By the end of the study four animals appeared normal. The test material caused significant signs of irritation (erythema, oedema, eschar, desquamation and exfoliation).
Body weight:
Two males exhibited a loss in body weight from day 0 to day 7, but these animals regained the lost weight and surpassed their day 0 body weight by the end of the study. There were no other remarkable body weight changes during the study.
Gross pathology:
The only finding on necropsy was reddened lungs in a single male.
Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
The acute dermal LD50 of the test material in rabbits is greater than 4000 mg/kg.
Executive summary:

The test material was administered once dermally at a dose of 4000 mg/kg to the shaved intact skin of five male and five female albino rabbits for a 24 hour period under semi-occlusive dressing. Mortality, clinical observations, dermal findings, body weights and gross necropsy findings were evaluated.

There were no deaths or remarkable body weight changes during this study.

Two animals vocalised at the time of bandage and test material removal. Abnormal defecation was generally noted during the first week of the study. Inappetence was observed early in the study for six animals. Scabbing and swelling around the mouth and dry yellow staining around the nose were each noted for eight animals during the second week of the study. One animal had wet yellow urogenital staining. Four animals appeared normal by study termination or earlier.

The test material induced severe erythema and edema on all animals. Additional dermal observations generally appeared during the second week of the study and persisted through to study termination. These findings included eschar, white-yellow areas present within the application site, fissuring and desquamation for all animals. Six animals had white-yellow exudate on the application site. Exfoliation was observed on four sites late in the study.

Thickened skin and desquamation within the application site were noted for all animals at terminal necropsy. One animal had reddened lungs. There were no other remarkable gross necropsy findings.

The LD50 value was found to be greater than 4000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw
Quality of whole database:
The study was performed to GLP and has a Klimisch score of 1.

Additional information

Propargite technical is not acutely toxic to rats following oral (LD50 2800 mg/kg bw) or dermal (LD50 > 4000 mg/kg bw) administration. In an inhalation study, propargite was toxic to rats under a 'nose-only' exposure system with an LC50 of 0.89 mg/m3 air.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute oral and dermal toxicity.

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does require classification with respect to acute inhalation toxicity as Category 3 (H331: Toxic if inhaled).

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