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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Cardiac teratogenicity of trichloroethylene metabolites
Author:
Johnson PD, Dawson BV, Goldberg SJ
Year:
1998
Bibliographic source:
JACC 32(2), 540-545
Reference Type:
review article or handbook
Title:
A review: Trichloroethylene metabolites: potential cardiac teratogens
Author:
Johnson PD, Dawson BV, Goldberg SJ
Year:
1998
Bibliographic source:
Environ. Health Perspect. 106, suppl. 4, 995-999

Materials and methods

Principles of method if other than guideline:
Pregnant rats were dosed via drinking water from 1 day of pregnancy throughout pregnancy (21 days).
GLP compliance:
not specified
Limit test:
yes

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:
chloroacetic acid
Specific details on test material used for the study:
Not provided

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
This study was conducted in Association for Assessment and Accreditation of Laboratory Animal Care accredited and Institutional Animal Care and Use Committee governed facilities at the University of Arizona Animal Care Center. Animals were quarantined for 7 days before study. Study groups consisted of virus free, young, sexually mature Hsd:Sprague Dawley SD rats (Harlan Sprague Dawley, Inc., Indianapolis, Indiana). Females, 225 +/- 30 g, were housed in pens of four, and the males, 300 +/- 50 g, were housed individually. All rats had access to water and Teklad 4% Mouse Rat diet (Teklad, Madison, Wisconsin) ad libitum. Each animal was identified by an ear notch code. The number of animals in each group was determined by a power calculation to detect a threefold increase in the malformations over controls.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Control animals for this study received distilled water throughout pregnancy. On day 1 of pregnancy, and continuing throughout pregnancy, their regular drinking water was replaced with treated water. Compounds tested included TCAA, MCAA, TCEth, CMC, TCAld, DCAld and DCVC. Solutions of the various compounds were prepared by dilution with distilled water and, if necessary, titrated with NaOH to a pH of approximately 7.0, a pH similar to that of the control water. Each water bottle was placed in a specially made metal casing to reduce light exposure and subsequent chemical breakdown. The amount of water consumed by each pen of animals (4 maximum) was monitored and recorded every 24 h. Bottles were cleaned and fresh solutions prepared daily. Levels of metabolites were based on the dosage equivalent to that expected if all of the high dose of TCE (1,100 ppm, the limit of solubility, and the maximal TCE dose tested) was to breakdown completely into that given metabolite. To achieve uniformity between the tri- and monochloroacetic acids, MCAA was also given at an equivalent dose.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Daily vaginal smears or impedance measurements (Estrous Impedance Monitor, Fine Scientific Instruments, Inc., Phoenix, Arizona) were obtained from all females to determine stages of the estrous cycle. When in proestrus, female rats were placed in a cage with one male overnight. The presence of a vaginal plug and/or spermatozoa in the vaginal smear the following morning was considered indicative of day 1 of pregnancy.
Duration of treatment / exposure:
Whole pregnancy period (21 days)
Frequency of treatment:
Continuously (via drinking water)
Duration of test:
Whole pregnancy period (21 days)
Doses / concentrations
Dose / conc.:
1 570 mg/L drinking water
Remarks:
corresponds to 193 mg/kg bw/day
No. of animals per sex per dose:
10 rats in test group, 55 rats in control group
Control animals:
yes, concurrent vehicle
Details on study design:
For all groups, on day 22 of gestation, approximately 1 day before parturition, each pregnant rat was weighed before euthanasia in a carbon dioxide chamber. An examination was then conducted for any abnormalities (external and internal) and the gravid uterus and ovaries removed. The uterus was opened, exposing all fetuses, implantation sites (sites where the embryo implanted in the uterus, but did not mature beyond implantation, leaving only a metrial gland) and resorption sites (sites where fetal development began, but stopped at some point during gestation with only decaying fetal tissue remaining). The position of each site was recorded. Fetuses and placentas were examined in situ, then removed and individually examined externally for any morphologic abnormalities. All fetal placements, weights, placental weights, crown rump (C/R) lengths and any gross fetal abnormalities were evaluated by an experienced veterinarian.

Examinations

Maternal examinations:
Each rat was carefully observed throughout pregnancy and weight gain was monitored and recorded daily.
Ovaries and uterine content:
The uterus was opened, exposing all fetuses, implantation sites (sites where the embryo implanted in the uterus, but did not mature beyond implantation, leaving only a metrial gland) and resorption sites (sites where fetal development began, but stopped at some point during gestation with only decaying fetal tissue remaining). The position of each site was recorded. Placentas were examined in situ. Pplacental weights were evaluated by an experienced veterinarian.
Fetal examinations:
Fetuses were examined in situ, then removed and individually examined externally for any morphologic abnormalities. All fetal placements, weights, crown rump (C/R) lengths and any gross fetal abnormalities were evaluated by an experienced veterinarian. Using an Optivisor (Donegan Optical Co., Inc., St. Lenexa, Kansas) for magnification, the thoracic and abdominal cavities were opened. All abdominal organs were inspected for any congenital abnormalities. Exposing the thoracic cavity allowed observation of the great arterial and venous connections to the heart in situ. Pulmonary and vena caval attachments were then incised, as distal to the heart as possible, and the heart removed. A 27-gauge needle was placed apically in the left
ventricle and the heart gently flushed with 2% glutaraldehyde solution. Each heart was then placed in an individual vial that was labeled with a seven digit code (for future “blind” assessment) and placed in the same solution for 24-h fixation. The
heart was then transferred to a 0.1 mol/L phosphate buffer solution for storage.
Individual hearts were dissected and evaluated using a Nikon SMZ-2T light microscope with an attached TV camera and monitor (Nikon, Chandler, Arizona). This allowed excellent visualization and manipulation. Initially, the heart was examined for any gross morphologic abnormalities from both dorsal and ventral aspects. The heart was then examined in a step by step protocol which is detailed by Dawson et al. (10). This method allows visualization of the atrial septum, aortic and pulmonary vessels, semi-lunar and atrioventricular valves and the ventricular septum. All confirmed abnormalities were agreed upon by the three investigators: a veterinarian, a pathologist and a pediatric cardiologist.
All abnormal specimens were then photographed using a Nikon N2020 camera mounted on the light microscope. Decoding of the hearts, with respect to treatment, occurred only after final examination of all hearts and fetuses.
Statistics:
For an effect size of a threefold increase over background heart defects, a power analysis of 90%, with an alpha error of 0.05 and a beta error of 0.1, determined that a sample size of 100 was needed for statistical significance.
Statistics for the individual fetal data were analyzed by using Fisher’s exact test. The Wilcoxon and exact permutation tests were used to determine the significance of the litter outcome.
Indices:
No info

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
All maternal rats were healthy throughout the study and without evidence of toxicity.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Steady weight gain occurred throughout pregnancy in bot the control and MCA group.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Average amount of the control group was 46 mL/day; for the MCA group it was 21 mL/day.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Ovaries had normal morphologic features. All uterine morphological examinations were normal.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
There were no pregnancy complications.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
One dead fetus in the MCA group, 3 dead fetuses in the control group.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
The uterus was examined for implantation sites, resorption sites, and live and dead fetuses. External inspection of live fetuses (n = 602 in control group and n = 131 in MCA group) and dead fetuses (n = 3 in control groups versus n = 1 in MCA group) demonstrated no gross morphologic congenital abnormalities in any group. No differences were found between the treated group and the control for the mean number of implantation sites and resorption sites using Fisher’s exact analysis.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 193 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: absence of maternal toxicity at this level (only level tested)

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
not examined
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
See below

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 193 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of increased incidence of heart malformations at this level (only level tested)

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Fetuses were analyzed by determining numbers of live or dead fetuses, fetal weight; placental weight, C/R length, and external morphology. No significant difference was found when comparing the treated and control fetal

group for these observations. There were no gross external or noncardiac internal congenital abnormalities found in the treated or control group.

Several different cardiac malformations were found and no one lesion or grouping predominated (see table attached). Variations of normal morphology similar to those found in humans were not classified as defects (for example, tricuspid valve leaflet contribution to complete coverage of a membranous ventricular defect). General types of cardiac defects were grouped in categories and listed by treatment in the table attached. Septation defects appeared to be more represented than a difference between lesions of the left and right sides of the heart.

When examining the fetuses on an individual basis the assumption was made that each fetus had an equal chance of developing a heart malformation independent of its litter mates. Because this may not be the correct assumption, fetal hearts were also evaluated on a per litter basis to determine the significance of any increase in number of cardiac abnormalities. The range of cardiac abnormalities in the MCA group was 4.55% with a control group value of 2.15% (not statistically significantly different).

Applicant's summary and conclusion

Conclusions:
MCA at 193 mg/kg bw did not appear to be a specific cardiac teratogen in the fetus when imbibed by the maternal rat.