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2,3,4,6-Tetrachlorophenol (CASRN 58-90-2)
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0108
2,3,4,6-Tetrachlorophenol;
CASRN 58-90-2
Health assessment information on a chemical substance is included in IRIS
only after a comprehensive review of chronic toxicity data by U.S. EPA
health scientists from several Program Offices and the Office of Research
and Development. The summaries presented in Sections I and II represent
a consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR 2,3,4,6-Tetrachlorophenol
File First On-Line 01/31/1987
Category (section) |
Status |
Last Revised |
|---|---|---|
| Oral RfD Assessment (I.A.) | on-line | 01/01/1992 |
| Inhalation RfC Assessment (I.B.) | no data | |
| Carcinogenicity Assessment (II.) | no data |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
Last Revised — 01/01/1992
The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.
__I.A.1. Oral RfD Summary
Critical Effect |
Experimental Doses* |
UF |
MF |
RfD |
|---|---|---|---|---|
|
Increased liver Rat oral subchronic U.S. EPA, 1986 |
NOAEL: 25 mg/kg/day LOAEL: 100 mg/kg/day |
1000
|
1
|
3E-2
mg/kg/day |
*Conversion Factors: none
__I.A.2. Principal and Supporting Studies (Oral RfD)
U.S. EPA. 1986. 2,3,4,6-Tetrachlorophenol. 90-Day subchronic oral toxicity
study in rats. Office of Solid Waste, Washington, DC.
Sprague-Dawley rats (30/sex/dose) were gavaged daily with 0, 25, 100 or 200
mg/kg/day 2,3,4,6-tetrachlorophenol in olive oil. Body weight gain, food
consumption, clinical signs of toxicity and mortality were recorded throughout
the study. Clinical pathology was performed on 10 rats/dose/sex both at 44-45
day interim sacrifice interval and after 90 days; gross pathology was
performed on all animals sacrificed at interim or final sacrifice and on all
animals found dead or sacrificed moribund. Histopathological evaluations were
also conducted in animals sacrificed at 90 days as well as in the cases of
unscheduled death. Results of this study indicated that at 200 mg/kg/day dose
male rats showed progressive depression of body weights 3 weeks after the
onset of dosing; these body weight depressions were significantly different
from controls during week 4, and weeks 8 through 12. No such difference was
observed in females. Liver and kidney weights and relative liver and kidney
weights (ratio to body and brain weight) were significantly higher than
controls both in males and females at the time of sacrifice. Centrilobular
hypertrophy was observed histopathologically in 15 males and 6 females at this
dose (200 mg/kg), compared with none seen in control. Females in the 200
mg/kg group had significantly reduced platelet count (increased alkaline
phosphatase levels), and increased BUN levels at 100 and 200 mg/kg; whereas
males in the high-dose group had increased SGPT levels and an A/G ratio. Both
males and females had significantly reduced Cl levels at 200 mg/kg, and
females (200 mg/kg) and males (100 and 200 mg/kg) had increased total protein
and albumin levels.
Rats administered 100 mg/kg/day tetrachlorophenol were found to have
statistically significant elevations in liver weights (net and relative) in
both males and females. In females, both absolute and relative kidney weights
were also elevated. Centrilobular hypertrophy in livers was seen (with lower
incidence than in the 200 mg/kg dosage group) in 12 males and 1 female. Based
on the results discussed above, the 25 mg/kg/day dosage represents the NOAEL
and the 100 mg/kg/day is the LOAEL for 2,3,4,6-tetrachlorophenol in this oral
subchronic study.
A reproductive study (Schwetz et al., 1974) and a 55-day oral gavage study
(Hattula et al., 1981) provided a NOEL of 10 mg/kg/day in rats; however,
inadequate study designs (few animals per group) and impurities associated
with the commercial grade tetrachlorophenol used in these studies raised some
concerns for the validity of the database to derive an RfD. These concerns
prompted the Office of Solid Waste to sponsor a 90-day oral study (U.S. EPA,
1986) and a teratology study (Research Triangle Institute, 1986) in rats.
Both the studies used purified 2,3,4,6-tetrachlorophenol (99% pure) suspended
in olive oil.
In the teratology study, pregnant rats were administered by gavage with 0, 25,
100 or 200 mg/kg/day 2,3,4,6-tetrachlorophenol in olive oil daily on days 6-15
of gestation. Body weight gain, food consumption and clinical signs of
toxicity were recorded during the gestation period. Rats were sacrificed on
gestation day 20; gross pathology, liver and gravid uterine weight and status
of uterine contents were recorded. Fetuses were removed, weighed and examined
for malformations.
Results of this study indicated the only statistically significant adverse
effect in the high-dose group (200 mg/kg/day): reduced maternal weight gain
(corrected to exclude weight of uterine contents) as contrasted with controls.
No significant maternal effects were noted at 25 or 100 mg/kg/day dosage
group. Embryo-fetal growth and prenatal viability were not adversely affected
by tetrachlorophenol exposure, nor was there any definitive evidence of an
effect of the compound on fetal morphological development.
Based on data presented above, the 25 mg/kg/day dosage represents the
subchronic NOAEL for 2,3,4,6-tetrachlorophenol; by applying an uncertainty
factor of 1000 to this NOAEL, an RfD of 0.025 mg/kg/day or 0.03 mg/kg/day can
be derived.
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF — 1000: 10 interspecies and 10 for intraspecies variability to the
toxicity of this chemical in lieu of specific data and 10 for extrapolation of
a subchronic effect level to its chronic equivalent.
MF — None
__I.A.4. Additional Studies/Comments (Oral RfD)
Previously an RfD of 0.01 mg/kg/day was verified on 7/8/85 based on a 55-day
oral study (Hattula et al., 1981) in which Wistar rats were administered daily
with 0, 10, 50 and 100 mg/kg/day 2,3,4,6-tetrachlorophenol by gavage (10
rats/group). This study reported body weight changes and organ histopathology
at doses higher than 10 mg/kg; the NOAEL identified in this study was 10
mg/kg/day. This study, however, used commercial grade compound which contains
substantial proportion of contaminants such as pentachlorophenol and dioxins.
Additionally, this study used few number of animals and the duration of the
study was only 55 days.
Schwetz et al. (1974) evaluated potential effects of both commercial grade and
purified 2,3,4,6-tetrachlorophenol on embryo-fetal development following
gavage dosing of pregnant Sprague-Dawley rats on gestational days 6 through
15. Based upon an earlier range finding study, doses of 10 and 30 mg/kg/day
of both grades of tetrachlorophenol were examined in this teratology study.
Administration of either grade of the compound resulted in no evidence of
maternal toxicity, resorptions, fetal body weight or fetal crown-rump length.
The only fetal anomaly that was increased at 30 mg/kg/day was delayed
ossification of the skull bones, an effect that was interpreted as a
developmental delay, not teratogenicity. The lower dose (10 mg/kg/day) in
this study produced subcutaneous edema in exposed fetuses that was considered
a chance alone incidence. The subcutaneous edema was not observed in the
high-dose group. The issues related to both these studies, discussed above,
call into question the validity of the data to derive an RfD.
__I.A.5. Confidence in the Oral RfD
Study — High
Database — Medium
RfD — Medium
The critical study is a very well-designed oral study with adequate toxicological endpoints and a higher than average number of animals/sex/dose; therefore, a high confidence was recommended. The database provided adequate supporting subchronic oral studies and reproductive studies; therefore, a medium confidence was recommended. The RfD was supported by subchronic toxicity and teratology studies; however, until additional chronic toxicity data are available a medium confidence is recommended.
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation — U.S. EPA, 1986
Agency Work Group Review — 07/08/1985, 08/13/1987
Verification Date — 08/13/1987
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for 2,3,4,6-Tetrachlorophenol conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
This substance/agent has not undergone a complete evaluation and determination under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. Bibliography
Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
Last Revised — 06/01/1991
_VI.A. Oral RfD References
Hattula, M.L., V.M. Wasenius, R. Krees, A.U. Arstila and M. Kihlstrom. 1981.
Acute and short-term toxicity of 2,3,4,6-tetrachlorophenol in rats. Bull.
Environ. Contam. Toxicol. 26: 795-800.
RTI (Research Triangle Institute). 1986. Teratologic evaluation of 2,3,4,6-
tetrachlorophenol (CAS No. 58-90-2) administered to CD rats on gestational
days 6 through 15. Chemistry and Life Sciences, RTI, Research Triangle Park,
NC.
Schwetz, B.A., P.A. Keeler and P.J. Gehring. 1974. Effect of purified and
commercial grade Tetrachlorophenol on rat embryonal and fetal development.
Toxicol. and Appl. Pharmacol. 28: 146-150.
U.S. EPA. 1986. 2,3,4,6-Tetrachlorophenol. 90-Day subchronic oral toxicity
study in rats. Office of Solid Waste, Washington, DC.
_VI.B. Inhalation RfC References
None
_VI.C. Carcinogenicity Assessment References
None
_VII. Revision History
Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
|
Date |
Section |
Description |
|---|---|---|
| 12/23/1987 | I.A. | RfD withdrawn pending further review |
| 03/01/1988 | I.A. | Revised Oral RfD summary added - RfD changed |
| 06/01/1991 | VI. | Bibliography on-line |
| 01/01/1992 | I.A.7. | Secondary contact changed |
| 01/01/1992 | IV. | Regulatory actions updated |
| 04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
| 12/03/2002 | I.A.6. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Substance Name — 2,3,4,6-Tetrachlorophenol
CASRN — 58-90-2
Last Revised — 01/31/1987
- 58-90-2
- DOWICIDE 6
- PHENOL, 2,3,4,6-TETRACHLORO-
- RCRA WASTE NUMBER U212
- TCP
- 2,3,4,6-Tetrachlorophenol
- 2,4,5,6-TETRACHLOROPHENOL
- Tetrachlorophenol, 2,3,4,6-