Reaction mass of methyl chloroacetate and chloroacetic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test in compliance with Food and Drug Administration (FDA) and Good Laboratory Practice Regulations (GLP), and all aspects of the chronic studies were subjected to retrospective quality assurance audits.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Food and Drug Administration (FDA) Regulations

Deviations:

no

Principles of method if other than guideline:

Internal method of International Research and Development Corporation, Mattawan (MI), USA.

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Type:

Constituent

Details on test material:

- Name of test material (as cited in study report): monochloroacetic acid
- Physical state: colorless crystalline material
- Analytical purity: 99%
- Lot/batch No.: C035826

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (portage, MI, USA).
- Age at study initiation: 6 - 7 weeks old.
- Housing: Animals of the same sex were housed in groups of five, in polycarbonate with Edstrom grommets cages (HazIeton System Inc., Aberdeen, MD).
- Diet (e.g. ad libitum): NIH-07 open formula mash diet (Zeigler Bros., Inc., Gardners, PA); ad libitum.
- Water (e.g. ad libitum): Water was available ad libitum.
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Average temperature: 74.2 ºF
- Average humidity: 38.9 %
- Light: fluorescent, 12 hours/day
- Room air flow: 10-12 changes/hour

IN-LIFE DATES: From: 17.08.1981 To: 16.11.1981

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared by mixing appropriate amounts of monochloroacetic acid and deionized water. Stability studies conducted by the analytical chemistry laboratory and by the study laboratory confirmed the stability of monochloroacetic acid solutions for at least 3 weeks.
During the study, the dose formulations were stored at room temperature for no longer than 2 weeks.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The study laboratory conducted periodic analyses of the monochloroacetic acid dose formulations using gas chromatographic procedures.

Duration of treatment / exposure:

13 weeks (plus an additional day of dosing in week 14).

Frequency of treatment:

Daily, five days per week.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
30 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
60 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
90 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:
120 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 5

Remarks:

Doses / Concentrations:
150 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Groups of 20 rats of each sex.

Control animals:

yes, concurrent vehicle

Details on study design:

Five animals per dose group were designated for interim evaluations after 4 and 8 weeks of chemical administration.
A computerized random number generator randomIy selected the animals for use. A computerized sort produced a listing of the animals by ascending body weight per sex. Blocks were arranged by weight, and the animals were then assigned to groups by sets of random numbers.

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

Animals were observed twice daily for morbidity and mortality and were given physical examinations weekly (twice during week 1).
Animals were weighed prior to the first dosage and individual animal weights were recorded on a weekly basis and at interim evaluations and at the end of the studies.
Blood and urine were collected from 5 rats in each dose group (fewer in the highest dose group due to mortality) at weeks 4 and 8 and from all surviving animals at the end of the studies.

Sacrifice and pathology:

Moribund animals were killed and necropsied.
After 13 weeks, all surviving animals were killed, and a complete necropsy was performed. Organ weights were determined for the liver, right kidney, adrenal gland, brain, heart, thymus and lungs of all animals and the right testis of all males. Histopathology was performed on all rats dying before the end of the studies and all rats in the control, 60, 90, 120, and 150 mg/kg dose groups. The heart, liver, and lungs from rats in the 30 mg/kg group were also examined.

Statistics:

Dunn's or Shirley's test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

All rats receiving 120 or 150 mg/kg monochloroacetic acid, and all but one receiving 90 mg/kg, died before the end of the study. Other deaths included two male rats and one female rat receiving 60 mg/kg and one female rat receiving 30 mg/kg.
The mean body weights of dosed animals that survived to the end of the studies were similar to those of the controls.
Absolute and relative heart weights of males and females receiving 60 mg/kg were significantly lower than control values; relative heart weight was also decreased in females receiving 30 mg/kg. Relative liver weights of males and females that received 60 mg/kg were significantly greater than the control values, but absolute liver weights were significantly increased only in males. Relative, but not absolute, kidney weights were increased in males receiving 60 mg/kg.
A significant, dose-related increase in blood urea nitrogen occured in male rats receiving 90 to 150 mg/kg and in female rats receiving 60 to 150 mg/kg. Significant dose-related increases in alanine aminotransferase and aspartate aminotransferase levels were observed in male and female rats receiving 60, 120, or 150 mg/kg.
Cholinesterase levels were significantly lower than that of controls in male rats receiving 90 mg/kg for 8 weeks and in male rats receiving 30 or 60 mg/kg for 13 weeks.
Levels of thyroxin (T4) were significantly higher than those of controls in male rats receiving 90, 120 or 150 mg/kg for 4 weeks, and in males receiving 90 mg/kg for 8 weeks.
Hematocrit, hemoglobin and erythrocyte counts for male rats that received 150 mg/kg were significantly higher than control values after 4 weeks of compound administration.
Chemical-related degenerative and inflammatory changes (cardiomyopathy) were observed microscopically in the hearts of male and female rats receiving 60,90, 120, or 150 mg/kg. Acute or subacute cardiomyopathy was observed in rats that died during the studies after receiving 60, 90, 120 or 150 mg/kg and was considered to be the cause of death. The most extensive and severe lesions occured in rats surviving several days or weeks after treatment was initiated.

Effect levels

Dose descriptor:

NOAEL

Sex:

male/female

Basis for effect level:

other: changes in heart, liver and kidney weights, clinical chemistry values and mortality; at doses ≥60 mg/kg bw/day cardiopathy was observed.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 07.05.01_03. Mortality rate in rats.

Doses (mg/kg bw)	Dead animals/Exposed animals
MALES
0	0/10
30	0/10
60	2/10
90	9/10
120	13/13
150	15/15
FEMALES
0	0/10
30	1/10
60	1/10
90	10/10
120	15/15
150	17/17

Applicant's summary and conclusion

Conclusions:

Compound-related deaths occurred in the three highest dose groups (all males given 120 or 150 mg/kg bw/day, 9/10 males given 90 mg/kg bw/day, and a 11 females given 90 to 150 mg/kg bw/day). Final mean body weights of surviving rats receiving monochloroacetic acid were similar to those of controls. In rats, dose-related increases in blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase levels were observed, and relative liver and kidney weights were elevated. A dose-related increase in the incidence and severity of cardiomyopathy was observed in male and female rats receiving monochloroacetic acid.

Executive summary:

A toxicology study was conducted by administering monochloroacetic acid in deionized water by gavage to groups of F344/N rats of each sex once daily, 5 days per week for 13 weeks.Groups of 20 rats of each sex received 0,30, 60, 90, 120 or 150 mg/kg bw /day. Five animals in each dose group were killed at weeks 4 and 8 for the evaluation of haematology parameters.

Animals were observed twice daily for morbidity and mortality and were given physical examinations weekly (twice during week 1). Animals were weighed prior to the first dosage and individual animal weights were recorded on a weekly basis and at interim evaluations and at the end of the studies. Blood and urine were collected from 5 rats in each dose group (fewer in the highest dose group due to mortality) at weeks 4 and 8 and from all surviving animals at the end of the studies.

Moribund animals were killed and necropsied. After 13 weeks, all surviving animals were killed, and a complete necropsy was performed. Organ weights were determined for the liver, right kidney, adrenal gland, brain, heart, thymus and lungs of all animals and the right testis of all males. Histopathology was performed on all rats dying before the end of the studies and all rats in the control, 60, 90, 120, and 150 mg/kg bw /day dose groups. The heart, liver, and lungs from rats in the 30 mg/kg bw /day group were also examined.

Compound-related deaths occurred in the three highest dose groups (all males given 120 or 150 mg/kg bw /day, 9/10 males given 90 mg/kg bw /day, and a 11 females given 90 to 150 mg/kg bw /day). Final mean body weights of surviving rats receiving monochloroacetic acid were similar to those of controls. In rats, dose-related increases in blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase levels were observed, and relative liver and kidney weights were elevated. A dose-related increase in the incidence and severity of cardiomyopathy was observed in male and female rats receiving monochloroacetic acid.