Paraquat-dichloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 Jun 2005 to 23 Jul 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

17 December 2001

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

GLP compliance:

yes (incl. QA statement)

Remarks:

Safepharm Laboratories Limited, Shardlow Business Park Shardlow, Derbyshire, DE722GD UK

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Paraquat-dichloride

EC Number:

217-615-7

EC Name:

Paraquat-dichloride

Cas Number:

1910-42-5

Molecular formula:

C12H14N2.2Cl

IUPAC Name:

1,1’-dimethyl-4,4’-bipyridyldiylium dichloride

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 207 to 253 g
- Fasting period before study: overnight fasting immediately before dosing and for approximately three to four hours after dosing
- Housing: individually housed in suspended solid-floor polypropylene cages furnished with woodflakes, animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level
- Diet: free access to food, Certified Rat and Mouse Diet (Code 5LF2)
- Water: free access to mains drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5.5, 17.5, 55.0 mg/kg bw
- Amount of vehicle: 10 mL/kg

DOSING PROCEDURE
- The default value was entered into the AOT425 Statistical Program with the slope of the dose-response curve also set to the default value (sigma = 0.5). The statistical program gave a recommended dose progression of 2000, 550, 175, 55, 17.5, 5.5 and 1.75 mg/kg. The first animal was dosed at a dose level of 175 mg/kg. Further animals were then treated as follows: 55, 175, 550, 175 and 550 mg/kg bw for animals 2, 3, 4, 5 and 6, respectively.
- The test was complete after the sixth animal had been dosed as the following stopping criterion was met: at least four animals have followed the first reversal and the specified likelihood-ratios exceeded the initial value.
- Sufficient time (at least 48 hours) was allowed between each individual animal to confirm the survival of the previously dosed animals.

Doses:

55, 175, 550 mg/kg bw

No. of animals per sex per dose:

6 female animals in total (1 animal exposed to 55 mg/kg bw, 3 animals exposed to 175 mg/kg bw and 2 animals exposed to 550 mg/kg bw)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for up to 14 days.
- Body weights were recorded prior to fasting (Day -1 ), prior to dosing (Day 0) and 7 and 14 days after treatment or at death.
- Necropsy of survivors performed: yes (external examination and opening of the abdominal and thoracic cavities for examination of major organs)

Statistics:

The oral LD50 was calculated by the maximum likelihood method

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

80.7 mg/kg bw

Based on:

test mat.

Remarks on result:

other: recalculated value, expressed as pure test substance, see ‘Any other information on results incl. tables’ for respective calculation.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

175 mg/kg bw

Based on:

test mat.

95% CL:

> 42.8 - < 1 040

Remarks on result:

other: original value presented in study.

Mortality:

- At 55 mg/kg bw: 0 out of 1 animal died
- At 175 mg/kg bw: 1 out of 3 animals died
- At 550 mg/kg bw: 2 out of 2 animals died

Clinical signs:

other: Signs of systemic toxicity noted in one animal treated at a dose level of 175 mg/kg bw and one animal treated at a dose level of 550 mg/kg bw were hunched posture, pilo-erection, dehydration and pallor of the extremities. Additional signs of systemic toxi

Gross pathology:

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver, dark kidneys, haemorrhage or epithelial sloughing of the gastric mucosa and non-glandular region of the stomach and haemorrhagic small intestine. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Any other information on results incl. tables

Calculation of key result

The doses of the test substance were expressed in technical test substance, which relates to an aqueous solution of the registered substance. The key effect levels are calculated by correction for the amount of water: 33.4 % x 175 mg technical test substance/kg bw = 80.7 mg pure test substance/kg bw.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

In this OECD 425 study, the test substance is classified in Acute Tox. 3 (H301: Toxic if swallowed) for acute toxicity via the oral route based on a LD50 of 80.7 mg/kg bw (original LD50 reported for technical test substance is 175 mg/kg bw).

Executive summary:

The GLP study was performed to assess the acute oral toxicity of the test material following a single oral administration in the Sprague-Dawley strain rat. The method was designed to meet the requirements of the following OECD 425. A total of 6 female animals were dosed individually in sequence with sufficient time (at least 48 hours) between each animal, at dose levels in the range of 55 mg/kg bw to 550 mg/kg bw. The test material was administered orally as a solution in distilled water. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Two animals treated at a dose level of 550 mg/kg bw were found dead three or six days after dosing. One animal treated at a dose level of 175 mg/kg bw of the test material was killed in extremis five days after dosing. No deaths were noted at a dose level of 55 mg/kg bw. Signs of systemic toxicity noted in one animal treated at a dose level of 175 mg/kg bw and one animal treated at a dose level of 550 mg/kg bw were hunched posture, pilo-erection, dehydration and pallor of the extremities. Additional signs of systemic toxicity noted in one animal treated at a dose level of 175 mg/kg bw were decreased respiratory rate, laboured or noisy respiration, lethargy, ptosis, ataxia, tiptoe gait, loss of righting reflex and emaciation. There were no signs of systemic toxicity noted in two animals treated at a dose level of 175 mg/kg bw and the animal treated at a dose level of 55 mg/kg bw. The surviving animals showed expected gains in body weight over the study period. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver, dark kidneys, haemorrhage or epithelial sloughing of the gastric mucosa and non-glandular region of the stomach and haemorrhagic small intestine. No abnormalities were noted at necropsy of animals that were killed at the end of the study. The LD50 was determined to be 175 (42.89 – 1040) mg technical test substance/kg bw, although 2 out of 3 animals dosed at 175 mg/kg bw survived and showed no clinical signs of toxicity. The key effect resulting from the pure test substance is calculated based on the following calculation: Key effect level = purity of test material * effect level (LD50). It was determined to be 80.7 mg/kg bw.