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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
August 1981-November 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Data are reliable, but no information in document on ophthalmoscopy, neurobehavioral tests and food consumption.
Justification for data waiving:
other:

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
no information in document on ophthalmoscopy, neurobehavioral tests and food consumption.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): monochloro acetic acid
- Source: American Hoechst (Somerville, NJ)
- Physical state: solid
- Analytical purity: approximately 99% by Karl Fischer water analysis, elemental analysis, thin layer chromatography, gas chromatography, and potentiometric titration. The test substance was identified as monochloroacetic acid by infrared, ultraviolet/visible, and nuclear magnetic resonance spectroscopy.
- Impurities (identity and concentrations): Three impurities with combined area of less than 0,4% were detected. Identity not specified
- Lot/batch No.: lot no. C035826
- Expiration date of the lot/batch: not specified.
- Stability under test conditions: Stability studies using gas chromotography showed that the bulk chemical was stable for at least 2 weeks at temperatures up to 60 C. The stability of the bulk chemical was monitored by potentiometric titration and by flame-ionization gas chromatography periodically at the study laboratory during all phases of the studies. No change in the study material was detected.
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding laboratories, Inc. Portage, MI
- Age at study initiation: 6-7 weeks
- Weight at study initiation: males 140 gram, females 112 grams
- Fasting period before study:-
- Housing: 5/cage, polycarbonate cages
- Diet (e.g. ad libitum): ad libitum (NIH-07 open formula mash diet)
- Water (e.g. ad libitum): automatic watering system, ad libitum
- Acclimation period:13 days

ENVIRONMENTAL CONDITIONS
- Temperature: 74.2 °F
- Humidity (%): 38.9%
- Air changes (per hr): 10-12 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hrs light / 12 hours dark

IN-LIFE DATES: From: 17 August 1981 To: 17 November 1981

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Deionised
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0, 6.0, 12.0, 18.0, 24.0 and 30.0 mg/mL, dose volume 5 mL/kg
- Amount of vehicle (if gavage): not specified

PREPARATION OF DOSING SOLUTIONS:
Dose formulations were prepared by mixing appropriate amounts of MCAA and deionized water to obtain required concentrations
Formulations were stored at room temperature for a maximum of 2 weeks
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses on the monochloroacetic acid dose formulations were conducted twice, and confirmed that the dose formulations were within 10% of the target concentrations; values ranged from -9% to +8% of target concentration.
The method involved di ethylether extraction and subsequent flame ionisation gas chromatography using nitrogen as the carrier gas, ether as diluent, and decanol as an internal standard.

Stability analyses on 3 mg/mL solutions on three occasions during a 2-year study confirmed the stability for at least 3 weeks.
The method involved dilution of the dose formulations with acetonitrile and injection into a GC-FID equipped with a 1.8 x 2 mm ID column packed with 10% SP-1200/1% H3PO4 in 100/120 mesh Supelcoport; a column temperature of 135 degrees C and a N2 carrier flow rate of 30 mL per minute.


Duration of treatment / exposure:
13-weeks
(for interim animals 4 and 8 weeks respectively)
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 60, 90, 120 and 150 mg/kg bw/day, dose volume 5 mL/kg
Basis:
actual ingested
No. of animals per sex per dose:
20 animals/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on 16-day range finding study
- Rationale for animal assignment (if not random): by computerized random number generator
- Section schedule rationale (if not random): not specified
5 animals/sex/group were killed at week 4 and 8 for haematology, clinical chemistry and urinalysis parameters.
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: checked twice daily for morbidity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice in week 1 and weekly thereafter: signs of toxicity and palpated for masses

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 4, 8 and at end study
- Anaesthetic used for blood collection: No data (animals were killed for sampling)
- Animals fasted: assumed yes (animals for clin chem were fasted)
- How many animals: Weeks 4 and 8: 5/sex/group, at end of study, all surviving
- Parameters examined: rbc, wbc, diff leuco count, haematocrit, Hb, MVH, MCHC, MCV and metHb, bone marrow smears made.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:weeks 4, 8 and at end study
- Animals fasted: Yes
- How many animals: Weeks 4 and 8: 5/sex/group, at end of study, all surviving
- Parameters were examined. electrolytes, Na, K, chloride, phosphorus, Calcium, BUN, creatinine, total bilirubin, ASAT, ALAT, LDH, total protein, albumin, alb-glob ratio, cholinesterase, ornithine carbamyl transferase, sorbitol dehydrogenase, triiodothyronine and thryoxin

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 4, 8 and at end study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: assumed yes (animals for clin chem were fasted)
- Parameters examined: color, appearance, specific gravity, pH, protein, glucose, occult blood, nitrites, urobilinogen, ketones, and bilirubin

NEUROBEHAVIOURAL EXAMINATION: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
necropsy on all animals not killed at 4 or 8 weeks for evaluation of haematologic and clinical chemistry parmaters. organ weights of brain, heart, liver, lungs, right kidney, adrenal gland, right testis and thymus were reorded for all animals surviving until the end of the study.
HISTOPATHOLOGY: Yes
Complete evaluation of all animals that died before termination and on all survivors in control, 60, 90, 120 and 150 mg/kg group. Heart, lungs, bronchi and liver were examined for rats in the 30 mg/kg group.
Tissues examined microscopically: adrenal gland, aorta, brain, cecum, colon, duodenum, esophagus, gross lesions, heart, jejunum, ileum, kidney, liver, lungs and bronchi, lymph nodes, mammary gland, nose, ovaries, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, rectum, salivary gland, spleen, sternum with marrow, stomach, testis, thymus, thyroid gland, trachea, tissue masses, urinary bladder and uterus.
Other examinations:
Electron microscopy to detect peroxisome proliferation, performed in selected animals
Statistics:
Body weight, organ weights: Dunn's or Shirley's test
haematology, clinical chemistry, urinalysis: Dunn's or Shirley's test; Jonckheere trend 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:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats in the 120 and 150 mg/kg bw/day group, 19/20 in the 90 mg/kg bw/day group, and
2 males and 1 female in the 60 mg/kg bw/day group died before the end of the study.
Given the high mortality in the highest dose groups, the results are mainly reported for the 0, 30,
and 60 mg/kg bw/day groups. No clinical findings noted
HAEMATOLOGY
Hematocrit,
hemoglobin, and erythrocyte counts were increased in male rats receiving 150 mg/kg bw/day for
4 weeks. Neutrophil counts were increased in males given 90, 120, and 150 mg/kg bw/day for
4 weeks. After 8 weeks ofMCAA administration, lymphocyte counts were decreased in males of
the 30, 60, 90, and 120 mg/kg bw/day groups.
CLINICAL CHEMISTRY
Blood urea nitrogen was doserelated increased at 90 to 150 mg/kg bw/day in males and at 60 to 150 mg/kg bw/day in females.
There was a dose-related increase in ASAT and ALAT in males and females at 60 to 150 mg/kg bw/day. The increases were not statistically significant at all dose levels and all time points.
Thyroxin (T4) levels were increased in male rats at 90, 120, and 150 mg/kg bw/day in week 4
and at 90 mg/kg bw/day in week 8. Serum cholinesterase activity was decreased in males at 30
and 60 mg/kg bw/day after 13 weeks, in all female dose groups after 4 and 8 weeks, and in
females of the 60 mg/kg bw/day group after 13 weeks. The decreased serum cholinesterase
activity may have been a result of liver toxicity, or direct inhibition of this enzyme by MCAA or its metabolites. In addition, females showed decreased plasma levels of total protein (from
30 mg/kg bw/day), albumin (at 60 mg/kg bw/day), calcium (30 and 60 mg/kg bw/day), and
sodium (from 30 mg/kg bw/day) after 8 and/or 13 weeks. Plasma potassium was increased after
13 weeks at 60 mg/kg bw/day in females and at 30 and 60 mg/kg bw/day in males.
ORGAN WEIGHTS
Absolute heart weight was decreased at 60 mg/kg bw/day in
both sexes, while relative heart weight was decreased at 60 mg/kg bw/day in males and at 30 and
60 mg/kg bw/day (dose-related) in females. Absolute liver weight was increased at
60 mg/kg bw/day in males and relative liver weight was increased at 30 and 60 mg/kg bw/day
(dose-related) in males and at 60 mg/kg bw/day in females. Relative kidney weight was
increased at 30 and 60 mg/kg bw/day (dose-related) in males.
GROSS PATHOLOGY
rats that died in the study showed blood or clear red fluid in thoracic cavity and congestion of lungs was observed.
HISTOPATHOLOGY
Treatment-related and dose-related cardiomyopathy (acute or subacute) was considered the cause of death in the decedents. Degenerative and inflammatory changes (cardiomyopathy) noted in hearts of mae and female rats receiving 60, 90, 120 or 150 mg/kg. Lesions occurred primaily in the myocardium of the left ventricular wall and interventricular septum.
EM examination on selected animals revealed no evidence of peroxisome proliferation.




Effect levels

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Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: LOAEL at 30 mg/kg, which is lowest dose tested. At 30 mg/kg changes in heart, liver and kidney weights and clinical chemistry values (LOAEL not specified in NTP TR 396, but taken from results and Final EU Risk Assessment Report (2005))
Dose descriptor:
NOAEL
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

Not applicable

Applicant's summary and conclusion

Conclusions:
LOAEL is 30 mg/kg bw/day