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Specific investigations: other studies

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Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP study, no guideline available.

Data source

Reference
Reference Type:
publication
Title:
Species and strain sensitivity to the Induction of peroxisome proliferation by chloroacetic acids
Author:
DeAngelo AB et al
Year:
1989
Bibliographic source:
Toxicol. Appl. Pharmacol. 101, 285-298

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Species and strain sensitivity to the induction of peroxisome proliferation was investigated. B6C3F1 mice and Sprague-Dawley rats were provided drinking water containing 6-31 mM (1-5 g/L) trichloroacetic acid (TCA), 8-39 mM (1-5 g/L) dichloroacetic acid (DCA), or 11-32 mM (1-3 g/L) monochloroacetic acid (MCA) for 14 days. Thereafter, animals were killed by CO2 asphyxiation.
GLP compliance:
not specified
Type of method:
in vivo

Test material

Constituent 1
Chemical structure
Reference substance name:
Chloroacetic acid
EC Number:
201-178-4
EC Name:
Chloroacetic acid
Cas Number:
79-11-8
Molecular formula:
C2H3ClO2
IUPAC Name:
acetyl chloride
Details on test material:
Purchased from Aldrich Chemical Co., Inc. (Milwaukee, WI) (purity ≥ 99%). No further details specified.

Test animals

Species:
other: rat and mouse
Strain:
other: Rats: Sprague Dawley. Mice: B6C3F1
Sex:
male
Details on test animals or test system and environmental conditions:
Rats (weighing 225-275 g) and mice (weighing 20-25 g) were purchased from Charles River Laboratories (Portage, MI). The animals were maintained on Purina Laboratory Chow and water ad libitum at 22 ± 2°C and 40-60% humidity under a 12-hr light-

Administration / exposure

Route of administration:
oral: drinking water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Duration: 14 Days
The calculated average daily intakes in mg/kg bw/day for the B6C3F1 mouse over a 14-day period were:
265, 386, and 482 for drinking water containing 11, 21, and 32 mM MCA;
90,166, and 346 for 8, 16, and 39 mM DCA; and
131, 261, and 442 for 6, 12, and 31 mM TCA.
For the Sprague-Dawley rat the 14-day average daily intakes were:
170, 321, and 501 for 11, 21, and 32 mM MCA;
166, 294, and 666 for 8, 16, and 39 mM DCA; and
212, 327, and 719 for 6, 12, and 31 mM TCA.
Frequency of treatment:
Ad libitum
Post exposure period:
Not applicable.
Doses / concentrations
Remarks:
basis: nominal in water
Substances were dissolved in distilled water at concentrations 6-31 mM (1-5 g/L) trichloroacetic acid (TCA), 8-39 mM (1-5 g/L) dichloroacetic acid (DCA), or 11-32 mM (1-3 g/L) monochloroacetic acid (MCA), and the pH was adjusted to 6.8-7.2
No. of animals per sex per dose:
Not specified.
Control animals:
other: Control animals were given drinking water containing 34 mM sodium chloride.

Examinations

Examinations:
Body and liver liver weights; hepatic peroxisome proliferation by (I) palmitoyl-CoA oxidase and carnitine acetyl transferase activities, (2) appearance of a peroxisomeproliferation-associated protein, and (3) morphometric analysis of electron micrographs.
Positive control:
Not included.

Results and discussion

Details on results:
TCA and DCA, but not MCA, increased the mouse relative liver weight in a dose-dependent manner. Rat liver weights were not altered by TCA or DCA treatment, but were depressed by MCA. Hepatic peroxisome proliferation was demonstrated by (I) increased palmitoyl-CoA oxidase and carnitine acetyl transferase activities, (2) appearance of a peroxisome proliferation-associated protein, and (3) morphometric analysis of electron micrographs.
Mouse peroxisome proliferation was enhanced in a dose-dependent manner by both TCA and DCA, but only the high DCA concentration (39 mM) increased rat liver peroxisome proliferation. MCA was ineffective in both species.

Any other information on results incl. tables

Three other mouse strains (Swiss-Webster, C3H, and C57BL/6) and two strains of rat (F344 and Osborne-Mendel) were examined for sensitivity to TCA. TCA (12 and 31 mM) effectively enhanced peroxisome proliferation in all mouse strains, especially the C57BL/6. A more modest enhancement in the Osborne-Mendel (288%) and F344 rat (167%) was seen. Dosing F344 rats with 200 mg/kg TCA in water or com oil for 10 days increased peroxisome proliferation 179 and 278%, respectively, above the vehicle controls. Three other mouse strains (Swiss-Webster, C3H, and C57BL/6) and two strains of rat (F344 and Osborne-Mendel) were examined for sensitivity to TCA. TCA (12 and 31 mM) effectively enhanced peroxisome proliferation in all mouse strains, especially the C57BL/6. A more modest enhancement in the Osborne-Mendel (288%) and F344 rat (167%) was seen. Dosing F344 rats with 200 mg/kg TCA in water or com oil for 10 days increased peroxisome proliferation 179 and 278%, respectively, above the vehicle controls.

Applicant's summary and conclusion

Conclusions:
In a 14-D study, Sprague Dawley rats and B6C3F1 mice were exposed via drinking water to three types of acetic acids.
TCA and DCA, but not MCA, increased the mouse relative liver weight in a dose-dependent manner. Rat liver weights were not altered by TCA or DCA treatment, but were depressed by MCA. Hepatic peroxisome proliferation was demonstrated by by both TCA and DCA by (I) increased palmitoyl-CoA oxidase and carnitine acetyl transferase activities, (2) appearance of a peroxisome proliferation-associated protein, and (3) morphometric analysis of electron micrographs. Mouse peroxisome proliferation was enhanced in a dose-dependent manner by both TCA and DCA, but only the high DCA concentration (39 mM) increased rat liver peroxisome proliferation.
This study demonstrates that the mouse is more sensitive than the rat with respect to the enhancement of liver peroxisome proliferation by TCA and DCA and suggest that if peroxisome proliferation is critical for the induction of hepatic cancer by TCA and DCA, then the rat should be less sensitive or refractory to tumor induction. MCA was ineffective in both species.