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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted in a GLP facility to OECD guidelines

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Butyronitrile
EC Number:
203-700-6
EC Name:
Butyronitrile
Cas Number:
109-74-0
Molecular formula:
C4H7N
IUPAC Name:
butyronitrile
Details on test material:
Sponsor's identification : N-butyronitrile
Description : clear colourless liquid
Batch number : TXTXOL
Purity : 99.891%
Date received : 30 September 2012
Expiry date : not supplied
Storage conditions : room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non-pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study and identified by a number written on a cage card. At the start of the study the animals were
eight to twelve weeks of age. The bodyweights fell within an interval of ±20% of the mean weight of any previously dosed animals.
The animals were individually housed in suspended solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories U.K. Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the
study. The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness. The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
For the purpose of the 1110 mg/kg dose level, the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. For the purpose of the 35, 111 and 350 mg/kg dose levels, the test item was freshly prepared, as required, as a solution at the appropriate concentration in distilled water. The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration. All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time (at least 48 hours) was allowed between each individual animal to confirm the outcome of the previously dosed animals.
Doses:
Using information available on the test item an estimate of the LD50 value was made. This value (111 mg/kg) was entered into the AOT425 Statistical Program with the slope of the dose-response curve set to the default value (sigma = 0.5). The statistical program gave a recommended dose progression of 1.11, 3.5, 11.1, 35, 111, 350, 1110 and 2000 mg/kg.
No. of animals per sex per dose:
1 Animal per dose
Control animals:
no
Details on study design:




Animal Dose Level
number mg/kg
Dose vol

1
35 0
2
111 0
3
350 0
4
1110 X*
5
350 X
6
111 0
7
350 0
8
1110 X
9
350 X
10
111 0

X* = animal humanely killed, X= animal died, 0= Animal survived
Statistics:
The oral LD50 was calculated by the maximum likelihood method. Data evaluations also included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects. Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was calculated by the statistical program

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
350 mg/kg bw
95% CL:
174.2 - 885
Mortality:
2/2 mortalities at 1110 mg/kg, 2/3 at 350 mg/kg, 0/3 at 111 mg/kg and 0/1 at 35 mg/kg
Clinical signs:
Signs of systemic toxicity noted were hunched posture, lethargy, ataxia, pilo-erection, ptosis, occasional body tremors, pallor of the extremities abdominal discomfort, increased salivation and splayed gait. Additional signs of systemic toxicity noted in the animal treated at a dose level of 1110 mg/kg that was humanely killed were prostration, emaciation, hypothermia, laboured respiration and decreased respiratory rate. There were no signs of systemic toxicity noted in animals treated at dose levels of 35 and 111 mg/kg or one animal treated at a dose level of 350 mg/kg.
Body weight:
Surviving animals showed expected gains in bodyweight over the study period, except for one animal treated at a dose level of 111 mg/kg which showed expected gain in bodyweight during the first week but slight bodyweight loss during the second week.
Gross pathology:
Abnormalities noted at necropsy of animals that died or were humanely killed during the study were patchy pallor or dark liver, dark or pale kidneys and haemorrhage and epithelial sloughing of the gastric mucosa. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits of the test item in the female Wistar strain rat were calculated to be 350 (174.2 – 885.0) mg/kg bodyweight (based on an assumed sigma of 0.5).
Executive summary:

A total of ten female animals were dosed individually in sequence with sufficient time (at least 48 hours) between each animal, at dose levels ranging from 35 mg/kg bodyweight to 1110 mg/kg bodyweight. The test item was administered orally undiluted at a concentration of 1110 mg/kg or as a solution in distilled water at concentrations of 35, 111 or 350 mg/kg. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. One day after dosing two animals treated at a dose level of 350 mg/kg and both animals treated at a dose level of 1110 mg/kg were found dead or killed for humane reasons due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence. Signs of systemic toxicity noted were hunched posture, lethargy, ataxia, pilo-erection, ptosis, occasional body tremors, pallor of the extremities abdominal discomfort, increased salivation and splayed gait. Additional signs of systemic toxicity noted in the animal treated at a dose level of 1110 mg/kg, that was humanely killed were prostration, emaciation, hypothermia, laboured respiration and decreased respiratory rate. There were no signs of systemic toxicity noted in animals treated at dose levels of 35 and 111 mg/kg or one animal treated at a dose level of 350 mg/kg. Surviving animals showed expected gains in bodyweight over the study period, except for one animal treated at a dose level of 111 mg/kg which showed expected gain in bodyweight during the first week but slight bodyweight loss during the second week. Abnormalities noted at necropsy of animals that died or were humanely killed during the study were patchy pallor or dark liver, dark or pale kidneys and haemorrhage and epithelial sloughing of the gastric mucosa. No abnormalities were noted at necropsy of animals that were killed at the end of the study. The acute oral median lethal dose (LD50) and 95% confidence limits of the test item in the female Wistar strain rat were calculated to be 350 (174.2 – 885.0) mg/kg bodyweight (based on an assumed sigma of 0.5).