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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:
guideline study
Justification for type of information:
Data is from experimental study report.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Principles of method if other than guideline:
The objective of this acute oral toxicity study was to assess the toxicological profile of the test item when administered to rats by a single oral gavage.
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(2-methoxyethyl)benzene
EC Number:
222-619-7
EC Name:
(2-methoxyethyl)benzene
Cas Number:
3558-60-9
Molecular formula:
C9-H12-O
IUPAC Name:
(2-methoxyethyl)benzene
Test material form:
liquid
Details on test material:
- Name of test material: Benzene(-2-methoxyethyl)
- Molecular formula: C9H12O
- Molecular weight: 136.193 g/mole
- Smiles : COCCc1ccccc1
- Inchl: InChI=1/C9H12O/c1-10-8-7-9-5-3-2-4-6-9/h2-6H,7-8H2,1H3
- Substance type: Organic
- Physical state: Liquid
Specific details on test material used for the study:
- Name of test material: (2-methoxy ethyl) benzene
- Molecular formula: C9H12O
- Molecular weight: 136.193 g/mole
- Smiles : COCCc1ccccc1
- Inchl: InChI=1/C9H12O/c1-10-8-7-9-5-3-2-4-6-9/h2-6H,7-8H2,1H3
- Substance type: Organic
- Physical state: Clear colourless, mobile liquid, almost insoluble in water
- Purity as per Certificate of Analysis : 99.7302%
- Lot No. : PE0201/18
- Manufactured date : Jan 2018
- Expiry Date : Dec 2022
- pH : 3.98 at 26.8°C
- Density : 0.952g/cm3
- Storage conditions : Ambient (+18 to +36ºC)

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: In-vivo Biosciences,Karnataka,India
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10 to 12 weeks
- Weight at study initiation: 207.5 to 226.5 g
- Identification:By rat accession number, cage card and turmeric colour body marking. The rat accession numbers were allotted during the course of the study. The temporary body marking during acclimatization period was done with crystal violet.
- Fasting period before study: rats were fasted for approximately 16 to 18 hours
- Housing:Rats were housed individually in standard polysulfone cages (Size: L 425 x B 266 x H 185 mm), with stainless steel top grill
- Diet (e.g. ad libitum): Hypro Rat & Mice pellet feed, ad libitum
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier, Mumbai, ad libitum
- Acclimation period: the animals were acclimatized for six to twenty two days (Steps 1 to 7) under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 25°C
- Humidity (%):64 to 68%
- Air changes (per hr): air conditioned with adequate fresh air supply (between 13.13 and 14.1 air changes/hour).
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle.

IN-LIFE DATES: From: 05 December 2018 To: 05 January 2019

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2000 and 550 mg/kg bw.
- Amount of vehicle (if gavage):2.1 mL/kg body weight to attain the dose of 2000 mg/kg body weight (Step 1, 3, 5 and 7) and 0.58 mL/kg body weight to attain the dose of 550 mg/kg body weight (Step 2, 4, 6) respectively.

MAXIMUM DOSE VOLUME APPLIED: 2.1 mL/kg body weight
Doses:
Step 1 :2000 mg/kg body weight
Step 2 :550 mg/kg body weight
Step 3 :2000 mg/kg body weight
Step 4 :550 mg/kg body weight
Step 5: 2000 mg/kg body weight
Step 6 :550 mg/kg body weight
Step 7 :2000 mg/kg body weight
No. of animals per sex per dose:
TOTAL: 7 animals
Step 1 :2000 mg/kg body weight :1
Step 2 :550 mg/kg body weight:1
Step 3 :2000 mg/kg body weight:1
Step 4 :550 mg/kg body weight:1
Step 5: 2000 mg/kg body weight:1
Step 6 :550 mg/kg body weight:1
Step 7 :2000 mg/kg body weight:1
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Clinical signs and pre-terminal deaths:The animals were observed five times on test day 1 (day of administration) i.e., at 30 minutes and 1, 2, 3 and 4 hours after dose administration and once daily during days 2 to 15. Additional observation was done for Rw2351, Rw2353 and Rw2357.Observation was included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern. All observed clinical signs were recorded.
- Body weights:Individual body weights of animals were recorded on test day 1 (Pre-administration), day 8 (7 days post administration) and day 15 (14 days post administration) and at death.
- Necropsy of survivors performed: yes, At the end of the observation period all the surviving rats were euthanized by using deep isoflurane anaesthesia and the pre-terminally dead animals were also subjected to detailed necropsy by an experienced prosector. Microscopic examination was not carried out as no gross pathological changes were observed.
Statistics:
not specified

Results and discussion

Preliminary study:
As per the Material Safety Data Sheet provided by the Sponsor, the acute oral LD50 of test chemical in rats is 2292.314 mg/kg body weight. Hence the study was initiated with the starting dose of 2000 mg/kg body weight (Step 1). The rat died and as per the AOT425 Statistical program, the six rats (Step 2 to Step 7) were administered with dose of 550, 2000, 550, 2000, 550 and 2000 mg/kg sequentially. The stopping criteria was met with 5 reversals occurred in 6 consecutive animals tested (as per AOT statistical program).Dose progression and stopping criteria was calculated using a dedicated software program (Acute Oral Toxicity (Guideline 425) Statistical Program) provided by the EPA.
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 049 mg/kg bw
Based on:
test mat.
95% CL:
>= 550 - <= 2 000
Remarks on result:
other: 50% mortality was observed
Mortality:
2000 mg/kg body weight – Step 1: animal found dead on during day 3 observation.
2000 mg/kg body weight – Step 3: animal found dead on during end of treatment day 1 observation.
2000 mg/kg body weight – Step 5: animal found dead on 4th hour post dose observation.
2000 mg/kg body weight – Step 7: animal found dead on day 2.
550 mg/kg body weight – Step 2, 4 and 6: no pre-terminal deaths were observed.
Clinical signs:
2000 mg/kg body weight – Step 1: Slight ataxia was observed during 4th hour post dose to end of the treatment day1 and recumbent, slight lacrimation, dyspnoea on day 2 observation.
2000 mg/kg body weight – Step 3: Slight ataxia was observed 3rd hour post dose. Recumbent and dyspnoea 4th hour post dose.
2000 mg/kg body weight – Step 5: Moderate tremors and gasping were observed during 3rd hour post dose.
2000 mg/kg body weight – Step 7: Hypoactivity observed 3rd hour to 4th hour post dose, Recumbent was observed on end of the treatment day 1.
550 mg/kg body weight – Step 2, 4 and 6: There were no clinical signs of toxicity.
Body weight:
2000 mg/kg body weight – Step 1, 3, 5 and 7: The body weight of all the dead rats decreased at death.
550 mg/kg body weight – Step 2, 4 and 6: All rats gained body weight throughout the observation period when compared to their initial weight.
Gross pathology:
There were no abnormalities detected at necropsy.
Other findings:
not specified

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the results, the acute oral LD50 value for the given test chemical is considered to be 1049 mg/kg body weight (approximate 95% confidence interval is 550 to 2000) in female wistar rats.The test item is classified as “Category 4 (300-2000 mg/kg bw)” as per the criteria of CLP.
Executive summary:

The acute oral toxicity study was conducted to assess the toxicological profile of the given test item (2-methoxy ethyl) benzene (CAS no.: 3558 -60 -9, E.C. no.: 222 -619 -7) as per OECD Guideline 425 ( Acute Oral Toxicity -Up-and-Down Procedure, adopted- 3rd october 2008), in Wistar rats to produce toxicity when a single dose was administered via the oral route.The undiluted test item was administered as a single oral gavage to rats fasted for 16 to 18 hours.In Preliminary test,the acute oral LD50 of test chemical in rats was considered to be 2292.314 mg/kg body weight. Hence the study was initiated with the starting dose of 2000 mg/kg body weight (Step 1). The rat died and as per the AOT425 Statistical program, the six rats (Step 2 to Step 7) were administered with dose of 550, 2000, 550, 2000, 550 and 2000 mg/kg sequentially. The stopping criteria was met with 5 reversals occurred in 6 consecutive animals tested.Dose progression and stopping criteria was calculated using a dedicated software program (Acute Oral Toxicity (Guideline 425) Statistical Program) provided by the EPA.Clinical signs and pre-terminal deaths, Body weights and Necropsy were observed in treated animals.At dose 2000 mg/kg body weight (Step 1) Slight ataxia was observed during 4th hour post dose to end of the treatment day1 and recumbent, slight lacrimation, dyspnoea on day 2 were observed and found dead on during day 3 observation.At dose 2000 mg/kg body weight (Step 3) Slight ataxia was observed 3rd hour post dose with recumbent and dyspnoea 4th hour post dose and found dead on during end of treatment day 1 observation.At dose 2000 mg/kg body weight (Step 5) moderate tremors and gasping were observed during 3rd hour post dose.At dose 2000 mg/kg body weight (Step 7) hypoactivity observed 3rd hour to 4th hour post dose with respect to recumbent which was observed on end of the treatment day 1 and found dead on day 2.At dose 550 mg/kg body weight (Step 2, 4 and 6) there were no clinical signs of toxicity and no pre-terminal deaths were observed.Changes in body weight were seen at dose 2000 mg/kg body weight (Step 1, 3, 5 and 7) and 550 mg/kg body weight (Step 2, 4 and 6). There were no abnormalities detected at necropsy.Based on the results of the present study, the LD50 value for the given test chemical is considered to be 1049 mg/kg (approximate 95% confidence interval is 550 to 2000).Therefore, The test item is classified as “Category 4 (300-2000 mg/kg bw)” as per the criteria of CLP. This test was performed according to GLP.

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