Methyl chloroacetate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline and GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyl chloroacetate

EC Number:

202-501-1

EC Name:

Methyl chloroacetate

Cas Number:

96-34-4

Molecular formula:

C3H5ClO2

IUPAC Name:

methyl 2-chloroacetate

Details on test material:

- Name of test material (as cited in study report): chloressigsäuremethylester
- Physical state: colourless liquid
- Analytical purity: 99%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Pharma-Forschung-Toxikologie, Kastengrund
- Age at study initiation: 45 days
- Weight at study initiation: males: 147-161 g; females: 144-158 g
- Diet (e.g. ad libitum): Altromin R1324 - Pellets (Altromin GmbH, Lage/Lippe), ad libitum.
- Water (e.g. ad libitum): tap water, ad libitum.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): 50 ± 20%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The substance was applied continuously with a evaporator at 130 ºC. The preparation-air mixture was led by an air current of 800 l/h by a tube administration in the inhalation chamber. To reach the wished concentration as quickly as possible, the preparation was brought in two phases in the chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: single-beam photometer
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

28 days

Frequency of treatment:

5 days per week (20 treatments), 6 hours daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 10, 33, 100 ppm (0, 0.04, 0.14, 0.45 mg/l)
Basis:
nominal conc.

No. of animals per sex per dose:

10 animals per sex per dose

Control animals:

yes

Details on study design:

- Post-exposure recovery period in satellite groups: five animals per sex per dose were necropsied on day 1 after the 28-day exposure and five animals per sex per dose were necropsied on day 14 after the 28-day exposure.

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: The behaviour and the general state of health of the animals were judged in each case once before the exposition beginning and after the exposition end as well as continuously during the exposition. Once at weekends as well as during the recovery periode the animals were examined daily.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: two groups of animals: day 1 after the 28-day exposure and day 14 after the 28-day exposure
- How many animals: Group 1: 5 animals per sex per dose; Group 2: 5 animals per sex per dose
- Parameters: erythrocyte count, haemoglobin, haematocrit, total and differential leucocyte count, platelet count, reticulocyte count (only for control and highest concentration groups), coagulation, thromboplastin time and partial thromboplastine time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: two groups of animals: day 1 after the 28-day exposure and day 14 after the 28-day exposure
- How many animals: Group 1: 5 animals per sex per dose; Group 2: 5 animals per sex per dose
- Parameters: sodium, potassium, phosphorus, bilirubin, total bilirubin, creatinine, glucose, urea nitrogen, calcium, chloride, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, alkaline phosphatase, gamma glutamyl transpeptidase, cholesterol, triglycerides, total lipids, albumin, globulin and methaemoglobin.

URINALYSIS: Yes
- Time schedule for collection of blood: two groups of animals: day 1 after the 28-day exposure and day 14 after the 28-day exposure
- How many animals: Group 1: 5 animals per sex per dose; Group 2: 5 animals per sex per dose
- Parameters: appearance, colour, glucose, haemoglobin, bilirubin, pH and sediment.


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: weekly

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Organ weights: absolute and relative weights of the following organs: heart, lungs, liver, kidneys, spleen, testicles, ovaries, adrenal glands, thyroid, brain.

Statistics:

The evaluation was executed using a program package for the evaluation of toxicological studies (Standard Operating Procedure von Dr. Passing, Abt. fur praktische Mathematik, durch Abt. Pharma Forschung Dokumentation).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Effect levels

1

Dose descriptor:

NOEL

Effect level:

33 ppm

Sex:

female

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOEL

Effect level:

10 ppm

Sex:

male

Basis for effect level:

other: At 33 ppm: clinical signs such as narrowed eye lids, increased tendency to clean themselves, sneezing, retardation of the body weight development, reduced food consumption.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

All test animals of the 10 and 33 ppm groups were free of clinical symptoms during the recovery period. In the animals of the 100 ppm group, the symtoms were still observable during the recovery period, up to day 35.

Applicant's summary and conclusion

Conclusions:

Based on the effects observed in a 28-day subacute inhalation study, the NOEL was 33 ppm for females and 10 ppm for males.

Executive summary:

A subacute inhalation study was carried out with the substance Methyl chloroacetate in Wistar rats. Ten animals per sex per group received 5 treatments per week during 28 days. The duration of each treatment was 6 hours and the following concentrations were used: 0, 10, 33 and 100 ppm. Five animals per sex per dose were necropsied on day 1 after the 28-day exposure. A satellite groups of five animals per sex per dose was maintained during a post-exposure period of 14 days. The following examinations were conducted: clinical signs, mortality, body weight, food consumption and food efficiency, water consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, neurobehavioural examination, gross pathology, histopathology and organ weights. Based on the effects observed, such as clinical signs, retardation of the body weight development or changes in lung weight with no evidence of organ dysfunction, the NOEL was 33 ppm for females and 10 ppm for males.