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TOXICOLOGY RESEARCH LABORATORY
1.7,4 4,6 | 0, 7,1 ,0 ,0
A COMPARISON OF SINGLE-DOSE ORAL LDSO'S FOR SPB: (SPRAGUE-DAWLEY) RATS AND CD0F (FISCHER 344-DERIVED) RATS
>UTMO|*. J. W, Henck. C. N. Park and C. D. Blogq
L/THO|) ionatukc)*)
RUftDhllll't I1GN1TURE. a
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K. J. Olson and K. S. Rao 4 mW| ?V
DATA REFERENCES (book and page):
V/
INTERIM
0 FINAL
and mainly:
38
PAGES IN FULL HEPOR1
NEW 0 REVIEW
CRI NUMBER
(Rafer alto to aarliar related raporn and publications.I
PATENT STATUS: I I disclosure submitted I I
i filed
no patent action required
DESCRIPTIVE SUMMARY WITH CONCLUSIONS'.
Subchronic and chronic toxicity studies at the Toxicology Research Laboratory are currently conducted using CD't (Fischer 344-derived) rats. In contrast, acute oral toxicity tests are currently conducted using Spb: (Sprague-Dawley) rats.
In order to conform with repeated administration data, it has been suggested that acute oral toxicity tests should be conducted using CDF rats. This study was conducted to determine if strain differences in mortality, behavior, or pathology in response to single oral doses of a
given compound exist.
CDF rats (Charles River Breeding Laboratories, Portage, Michigan) and SpragueDawley rats (Spartan Research Animals, Inc., Haslett, Michigan), 7-8 weeks of age, received one of the following compounds: epichlorohydrin, 2,4,5-trichlorophenoxy acetic acid, ally! chloride, malathion, acrylic acid, or benzene. Five rats/sex/strain/dose level received doses of the chosen compound by single-dose oral gavage. Following dosage, body weights and behavioral signs of toxicity were monitored for 2 weeks. Survivors were submitted for gross pathological
examination 2 weeks post-treatment.
A 2-week single-dose oral LD50 for each sex and strain for each compound was calculated. Overall, a comparison of LD50 values revealed that CDF rats appeared to be at least as sensitive, if not slightly more sensitive, than Sprague-Dawley rats when dosed orally. Subtle differences in behavior also indicated that CDF rats may be slightly more sensitive to certain chemicals than Sprague-Dawley rats. Both strains were comparable with regard to body weight gain. With regard to gross pathology, Sprague-Dawley rats appeared to be slightly more sensitive than CDF rats when dosed with epichlorohydrin or benzene. In both instances Sprague-Dawley rats exhibited an increased incidence of gastric irritation when compared to CDF rats. For the remaining 4 compounds, both strains appeared to be equally sensitive, with regard to gross pathology data,
DISTRIBUTION: Sm B*ck Pag FORM C-4*4M
DO 136678 CONFIDENTIAL.
A COMPARISON OF SINGLE-DOSE ORAL LOGO'S FOR SPB: (SPRAGUE-DAWLEY) RATS AND CDF (FISCHER 344-DERIVED) RATS
Reported By. J. W. Henck, C. N. Park and C. D. Blogg
Reviewed By: K. J. Olson and K. S. Rao
Toxicology Research Laboratory Health and Environmental Sciences, U.S.A.
Dow Chemical, U.S.A. Midland, Michigan 48640
00 136679 CONFTOFNTTAl
These data indicate that CDF and Sprague-Dawley rats are essentially comparable in overall response to single oral doses of a given chemical. It is therefore conclude that the use of CDF rats in acute oral toxicity' studies is feasible and would not jeopardize the credibility of the existing Sprague-Dawley data base.
DO 136680 CONFIDENTIAL.
1- -
SUMMARY
Subchronic and chronic toxicity studies at the Toxicology Research Laboratory are currently being conducted using CDF (Fischer 344derived) rats. In contrast, acute oral toxicity tests are currently conducted using Spb: (Sprague-Dawley) rats. In order to conform with repeated administration data, it has been suggested that acute oral toxicity tests should be conducted using CDF rats. This study was conducted to determine if strain differences in mortality, behavior, or pathology in response to single oral doses of a given compound exist.
CDF rats (Charles River Breeding Laboratories, Portage, Michigan) and Sprague-Dawley rats (Spartan Research Animals, Inc., Haslett, Michigan), 7-8 weeks of age, received one of the following compounds: epichlorohydrin, 2,4,5-trichlorophenoxy acetic acid, ally! chloride, malathion, acrylic acid, or benzene. Five rats/sex/strain/dose level received doses of the chosen compound by single-dose oral gavage. Following dosage, body weights and behavioral signs of toxicity were monitored for 2 weeks. Survivors were submitted for gross pathological examination 2 weeks post-treatment.
A 2-week single-dose oral LD50 for each sex and strain for each compound was calculated. Overall, a comparison of LD50 values revealed that CDF rats appeared to be at least as sensitive, if not slightly more sensitive, than Sprague-Dawley rats when dosed orally. Subtle differences in behavior also indicated that CDF rats may be slightly more sensitive
oo OONF
i T
Dpt^TT
^
-2to certain chemicals than Sprague-Dawley rats. Both strains were comparable with regard to body weight gain. With regard to gross pathology, SpragueDawley rats appeared to be slightly more sensitive than CDF rats when dosed with epichlorohydrin or benzene. In both instances Sprague-Dawley rats exhibited an increased incidence of gastric irritation when compared to CDF rats. For the remaining 4 compounds, both strains appeared to be equally sensitive with regard to gross pathology data. These data indicate that CDF and Sprague-Dawley rats are essentially comparable in overall response to single oral doses of a given chemical. It is therefore concluded that the use of CDF rats in acute oral toxicity studies is feasible and would not jeopardize the credibility of the existing Sprague-Dawley data base.
DO 1.3668? CONFIDENTIAL
INTRODUCTION Subchronic and chronic toxicity studies at the Toxicology Research Laboratory are currently conducted using CDF (Fischer 344Derived) rats (Charles River Breeding Laboratories, Inc., Portage, Michigan) because of their survivability, low mammary tumor incidence, and low incidence of severe chronic renal disease. In contrast, acute oral toxicity tests are currently conducted using Spb: (SpragueDawley) rats (Spartan Research Animals, Inc., Haslett, Michigan). In order to conform with repeated administration data, it has been suggested that acute oral toxicity tests should be conducted using CDF rats The purpose of this study was to compare the single-dose oral LDSO's and slopes of the dose-response curves for given compounds using both CDF and Sprague-Dawley rats.
0 136683
CONFIDENT}At
-4-
EXPERIMENTAL
Test Articles Six test articles were chosen on the basis of differing chemical structures, universality, availability, and differing acute oral LDSO's for rats. The names of these test articles, structures, lot numbers or sources, analyses, and rat oral LDSO's obtained from the literature are given in Table 1.
Test Animals Acute oral toxicity tests were conducted on male and female Spb: (Sprague-Dawley) rats (Spartan Research Animals, Inc., Haslett, Michigan), 7-8 weeks of age, and male and female CDF (Fischer 344-Derived) rats (Charles River Breeding Laboratories, Inc., Portage, Michigan), 7-8 weeks of age. All rats were maintained on a 12-hour light and dark cycle in animal care facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care. The animal rooms are designed to maintain a temperature of 73F and relative humidity of 45%, and to provide an air change approximately every 5 minutes. All rats were acclimated to the laboratory environment at least 1 week prior to testing, and all were uniquely identified by an individual metal ear tag. Rats were housed 2 or 3/cage, and were maintained on a diet of commercial laboratory chow (Ralston Purina Company, St. Louis, Missouri) and water ad libitum.
Design Groups of rats, each consisting of 5 rats/sex/strain, initially received 4 dose levels of the selected test article by single-dose oral gavage. If
DO 136684 OONFTDFNTTAl.
these initial dose levels failed to cause mortality, or, if a partial effect level was not achieved, more dose levels were added to calculate an LD50. Table 2 gives the test article, vehicle, and dose levels which each strain and sex received. The maximum volume with which SpragueDawley rats were dosed was 4.7 ml, while that for CDF rats was 2.8 ml.
All rats were fasted 16-18 hours prior to dosing. Each rat was weighed immediately prior to treatment, and weekly thereafter for a 2-week post treatment observation period. The rats were observed each working day during this time for signs of toxicity. Survivors only were submitted for gross pathological examination (as described in the Pathology Group Standard Operating Procedures) 2 weeks post-treatment.
Statistics The acute oral median lethal dose, 95% confidence interval, and approximate slope of the dose-response curve for both strains for aI ll test articles were calculated by the moving average method of Thompson and Weil (1952), as implemented by a computer program (Stephan, 1978). The approximate slope was calculated as 1/2 1 og-jq (LD84/LD16). Because this computer program also computes LD50's, 95% confidence intervals, and slopes by probit analysis (Finney, 1972), the values obtained from both methods of analysis are reported to assess the comparability of the 2 procedures.
RESULTS AND DISCUSSION
Animal Observations
Mortality of test rats, including LD50 and slope determinations, is given in Tables 3-8. With regard to mortality data, male and female
oo co^F
CDF rats appeared to be slightly more sensitive than Sprague-Dawley rats to benzene. Although the mortality of female rats of both strains receiving acrylic acid was comparable, male CDF rats appeared to be more sensitive than male Sprague-Dawley rats. Female CDF rats receiving 2,4,5-trichlorophenoxy acetic acid were actually less sensitive with regard to mortality than female Sprague-Dawley rats; both strains of male rats receiving 2,4,5-trichlorophenoxy acetic acid were comparable with regard to mortality. Males and females of both strains appeared to be equally sensitive to oral doses of epichlorohydrin, ally! chloride, and malathion.
Behavioral observations made during the 2-week post-treatment observation
period are given in Tables 9-14. With regard to this parameter, no
basic differences were observed between the strains when dosed with
malathion. However, subtle behavioral differences between strains did
occur for all other compounds tested. Female CDF rats dosed with
398 and 795 mg/kg epichlorohydrin had diarrhea, whereas female Sprague-
Dawley rats did not; diarrhea was not observed in male rats of either
species at any dose level. Following dosage with 2,4,5-trichlorophenoxy
acetic acid, only CDF rats had piloerection. This observation may be
equivocal, as CDF rats initially have rougher haircoats than Sprague-
Dawley rats. Dosage with 795 mg/kg ally! chloride resulted in convulsions
in 1/5 male CDF rats and 1/5 female CDF rats; no convulsions were observed
in Sprague-Dawley rats. In general, CDF rats dosed with acrylic acid exhibited
signs of toxicity at lower dose levels than did Sprague-Dawley rats. Of
the rats receiving 2520 mg/kg benzene, only male Sprague-Dawley rats had
dark exudate around the nose. In addition, only 1 female Sprague-Dawley
rat of the 5000 mg/kg dose group had convulsions.
00 '1.36686
confidential
-7-
Mean (+ standard deviation) body weights of test rats are given in Tables 15-20. Male CDF rats dosed with 795 mg/kg and female SpragueDawley rats dosed with 398 mg/kg 2,4,5-trichlorophenoxy acetic acid exhibited a body weight loss during the 2-week post-treatment observation period. The body weights of these rats could not be compared to those of the opposite strain because they did not receive comparable doses. Individual male Sprague-Dawley rats of the 630, 1260 and 1580 mg/kg groups, female Sprague- Dawley rats of the 63, 126 and 158 mg/kg groups, male CDF rats of the 63, 126, 158 and 316 mg/kg groups, and female CDF rats of the 31.6, 63, 126, 158, 316 and 630 mg/kg groups exhibited a body weight loss 2 weeks after dosage with acrylic acid. Although a comparison of body weight loss is difficult due to the different doses received by each strain, the body weight losses of overlapping doses indicate that both strains were equally sensitive. Pathology Gross pathologic findings in both strains of rat for all test materials are presented in Tables 21-26. Comparison of both strains with regard to gross pathology was difficult because rats of each strain sometimes received different doses of the same compound. Of the rats which
DO 1366S7 CONFIDENTIAL
-8-
could be compared, those receiving 2,4,5-trichlorophenoxy acetic acid, ally! chloride, malathion, and acrylic acid exhibited no major strain differences. The majority of Sprague-Dawley rats dosed with 100 mg/kg of epichlorohydrin exhibited thickening and roughening of the squamous epithelium of the stomach. Only 1 of 5 male CDF rats of the 100 mg/kg dose group exhibited gastric irritation; this was not seen in female CDF rats of the same group. Signs of gastric irritation were observed in both Sprague-Dawley and CDF rats dosed with 200 mg/kg epichlorohydrin. Thickening and roughening of the squamous epithelium of the stomach was also observed in female Sprague-Dawley rats dosed with 398 mg/kg of 2,4,5-trichlorophenoxy acetic acid. This observation may be equivocal, however, as gastric irritation was not observed in female Sprague-Dawley rats dosed with higher or lower doses. Thickening and roughening of the squamous epithelium of the stomach was observed in male Sprague-Dawley rats dosed with 630, 1260 or 2520 mg/kg benzene. These rats also exhibited focal thickening of the nonglandular stomach wall and erosion of the nonglandular epithelium of the stomach at the 2520 mg/kg dose level. Female Sprague-Dawley rats and male and female CDF rats did not exhibit gastric irritation at the 630 mg/kg level, and the incidence of this irritation at higher doses was greatly reduced over that of male Sprague-Dawley rats. No gastric irritation was observed in CDF rats fed 2520 mg/kg.
DO 136688 CONF T DFNTI At..
SUMMARY AND CONCLUSIONS
The purpose of this study was to compare the single-dose oral LD50`s and slopes of the dose-response curves of CDF and Sprague-Dawley rats for each compound tested. Overall, a comparison of LD50 values revealed that CDF rats appeared to be at least as sensitive, if not slightly more sensitive, than Sprague-Dawley rats when dosed orally. LD50 values obtained by the moving average and probit methods of analysis correlated well. It is obvious, however, that the moving average method is more versatile than the probit method, as only 1 partial effect level is needed to estimate the LD^q.
The slope values obtained in this study were extremely variable, and it was concluded that more rats per dose would be needed to accurately determine a slope. Therefore, it was decided to eliminate slope values as a basis for comparing strains.
Subtle differences in behavior observed up to 2 weeks following dosage indicated that CDF rats may be slightly more sensitive than Sprague-Dawley rats. The behavioral responses of CDF rats appear to be slightly more obvious to the observer.
Body weight data indicated that both strains were essentially comparable.
With regard to gross pathology, Sprague-Dawley rats appeared to be slightly more sensitive than CDF rats when dosed with epichlorohydrin or benzene. In both instances Sprague-Dawley rats exhibited an increased incidence of gastric irritation when compared to CDF rats. For the remaining 4 compounds, both strains appeared to be equally sensitive.
00 136689 CONFTeNT'1
-10-
M
These data indicate that CDF and Sprague-Dawley rats are essentially comparable in overall response to oral doses of a given chemical. It is therefore concluded that the use of CDF rats in acute oral toxicity studies is feasible and would not jeopardize the credibility of the existing Sprague-Dawley data base.
Written By:
Research Biologist Study Director
C. N. Park, Ph.D. Research Specialist
Clinical Veterinarian
Checked By:
Associate Scientist
K. S. Rao7 D.V.M., Ph.D. Research Specialist
REFERENCES
Bailey, K. F. (1978). Personal communication with R. R. Miller (September 8), study file HET K 2585-(6).
Finney, D. J. (1972) Probit Analysis. Third Edition, Cambridge University Press, Cambridge, England.
Kociba, R. J., D. G. Keyes, R. W. Lisowe, R. P. Kalnins, D. D. Dittenber, S. J. Gorzinski, C. E. Wade, N. H. Mahle, and B. A. Schwetz (1978). Results of a two-year chronic toxicity and oncogenic study of rats ingesting diets containing 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Toxicology Research Laboratory report HET K-004568-(26).
Mensik, E. (1978). Personal communication with T. S. Lederer (July 11), study file HET K 1710-(14).
Mensik, E. (1979). Phone communication with M. M. Schlacter (January 24), study file HET K 1720-(8).
Rowe, V. K. (1945) Toxicity of (2,4,5-Trichlorophenoxy) Acetic Acid. Toxicology Research Laboratory Report #T23.14-23-1.
The Toxic Substances List: 1973 Edition, H. E. Christensen, Ed.; U. S. Department of Health, Education and Welfare; Public Health
, Service, National Institute for Occupational Safety and Health, i Rockville, Maryland. Thompson, W. R. and C. S. Weil, Biometrics, Vol. 8, No. 1, March, 1952,
pp. 51-54. As implemented in a computer program (Stephan, C., 1978, personal conmunication).
DO 1,30691. OONF TDFNTTAl..
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A Comparison of Single-Dose ORAL LDSO's For SPB: TITLE OF STUDY: (Sprague-Dawley) Rats and CD^F (Fischer 344-Derived) Rats
In compliance with Good Laboratory Practice Regulations, this study was inspected by the Quality Assurance Unit and the results of these inspections reported to Management and the Study Director on the dates listed below. The report accurately reflects the data generated in accordance with the regulations and standard operating procedures of the Laboratory. All data and the reports are located at the submitting laboratory.
Study Started: April 3, 1979 Dates of Inspection:^**-*-^ tf7?
7 ^ yt h'fa
Report Issued Date:_ Date of Report:
3.
?!
/? 7?
yo
7,1 S. 24
3/ Y*
W. E. Hoover
(Date)
Quality Assurance
Toxicology Research Laboratory
Health and Environmental Sciences, U.S.A.
1803 Building
Dow Chemical U.S.A.
Midland, MI 48640
00 13669?
conftdfntiai
TEST TEST ARTICLE
Epichlorohydrin
Table 1
wtmm&
A COMPARISON OF S1NGLF-OOSF. ORAL LOGO'S FOR SPD: (SPRAGVF-DAWLF.V) RATS AND CDF (FISCHER 14 4-DERIVED) RAT:
TEST ARTICLES USED
STRUCTURE
LOT NUMBER OR SOURCE
ANALYSIS
RAT ORAL L050
/\
CHj---------CNCHgCl
TB 10047-1
99.8K Eplchlorohydrin; 0.11% 2,3-dichloropropene; 0.031 cis-1,3-dlchloropropene; 0.01% B-chloroallyl alcohol (Hensik, 1978).
90 mg/kg (Christensen et al,
1973) ' ~
(2,4,5-trichlorophenoxy) acetic acid
JOkCIU-CrOOH
Cl
AGR 133711
99.1* (2,4,5-Trichlorophenoxy) acetic acid; 0.67% 2,5-dichloro-4-methoxyphenoxyacetic acid; + 2,4 ,-dichloro-5-methoxyphenoxyacetic acid; 0.34% 4,5-dichloro-2-methoxyphenoxyacetic acid; 0.12% 2,5-dichlorophenoxy acetic acid; 0.14% unknown; 0.02% 2,4-dichlorophenoxyacetlc acid; other impurities were below the detection limit of 0.02% (Kociba, e aK, 1978)
300-500 mg/kg (Rowe, 1945)
Allyl chloride
H2C = CHCH2C1
TB 06308-3
98.65 Allyl chloride; 0.741 isopropyl
chloride; 0.40% 1,5-hexadiene; 0.14% normal propyl chloride; 0.10% 2,2dichloropropane (Hensik, 1978)
700 mg/kg
(Christensen, et al 1973)
Malathion (diethyl mercaptosuccinate - 0,0-dimethyl diethiophosohate)
Acrylic acid
s
K (CHJ^OJ2-P-S-CIH-COO-C2-Kc5
O^-COO-CgHg
American Cyanamid Company
0 H,C-CH-C
2 ^OH
Vessel 547 (9/8/78)
96% 0,0-dimethylphosphorodlthioate of diethyl mercaptosuccinate; 4% inert ingredients (American Cyanamid Company)
99.7% Acrylic acid; 0.08% water; trace amounts of dimer, acetic acid, propionic acid; acrolein, ethyl acrylate, phenothla zine proto-anemonin, Furfural (Bailey, 1978)
1156 mg/kg (Christensen, et at
1973) --------
2590 mg/kg (Christensen, et a\
1973)
Benzene
J. T. Baker Chemical Co. *715990
Not available
3400 mg/kg (Christensen, et al,
1973)
-14-
TEST ARTICLEVEHICLE,POSE LEVELS (mg/fcp) Epichlorohydrin
Table 2 A COHiAMWN OF SINGLE-DOSE OHM LDbO'a FOR SVD: (SrRAOHE-PAWLEY) FATS AND ClTF (FISCHER 344-DERIVED) RATS
TEST ARTICLES, VEHICLES AND DOSAGES RECEIVED
Undiluted
| Hale Sprague-Dawley Rat Female Sprague-Dawley Rat Male CDF Rat Female CDF Rat
25, 50, 100, 200, 398, 795 25, 50, 100, 200, 398, 795 25, 50, 100, 200, 210, 225, 252, 398, 795 25, 50, 100, 200, 210, 225, 252, 398, 795
(2,4,5-Trichlorophenoxy) acetic acid
Acetone/corn oila (1:9)
Hale Sprague-Dawley Rat Female Sprague-Dawley Rat Hale CDF Rat Female CDF Rat
126, 252, 500, 1000, 1580 126, 252, 350, 398, 450, 500, 1000 126, 252, 500, 795, 1000, 2000 126, 252, 500, 1000. 2000
Allyl Chloride
Undiluted
Hale Sprague-Dawley Rat Female Sprague-Dawley Rat Hale CDF Rat Female CDF Rat
200, 39U, 795. ISUO 200 , 398 , 795, 1580 200. 398, 795, 1580 63, 126, 200, 398, 795, 1580
Halathlon
Undiluted
Male Sprague-Dawley Rat Female Sprague-Dawley Rat Hale CDF Rat Female CDF Rat
252, 252, 252, 252,
500, 1000, 2000, 2100, 2250, 2520, 3980 500, 1000, 2000, 3980 500, 1000, 2000, 2520, 39C0 500, 1000, 2000, 3980
Acrylic Acid
Undiluted
Male Sprague-Dawley Rat female Sprague-Dawley Rat Male CDF Rat Female CDF Rat
630, 1260, 1580, 2000, 2520, 5000 63, 126, 150, 316, 630, 1260, 2520, 5000 63, 126, 158, 316, 630, 1260, 2520, 5000 31.6, 63, 126, 158, 316, 630, 1260, 2520, 5000
Benzene
Undiluted
Hale Sprague-Dawley Rat Female Sorague-Dawley Rat Hale CDF Rat female CDF Rat
630, 1260, 2520, 3160, 5000 630, 1260, 2520, 5000, 10,000 316, 630, 1260, 2520, 5000, 10,000 316, 630. 1260. 2520, 5000
a)
O.
z
2 o
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Z O'
Corn oil - CX 1955 L543, Hatheson Coleman and Bell Manufacturing Chemists
p
m i
C3 gg
H* ITris SSE
WT ,
Dose (mq/kq)
25 50 100 200 210 225
252
398
795
-15-
Table 3
A COMPARISON OF SINGLE-DOSE ORAL LDi-Q's F.h SPt: (SPRAGUE-DAWLEY) RATS AND CDF (FISCHER 344-DERIVED) FATS
EPICHLOROHYDRIN: MORTALITY
Male Sprague-Dawley
# Dead/# Treated
Female Sprague-Dawley
Male CDF
Female CDF
0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 1/5 2/5 0/5 0/5
- 0/5 3/5
- 5/5 5/5
- 5/5 5/5
4/5 5/5 5/5 5/5
5/5 5/5 5/5 5/5
Single-dose Oral LD50 (mg/kg)
957 Confidence Interval (mg/kg)
Slope
Moving Averaqe Probit
282 282
117-448 162-490
3.91
6.04
Moving Average Probit
Moving Average;
175 183 ^218a ;
116-306 3.06
106-330 4.55
-
Moving13 Average
210
203-216 18.28
a) No partial-effect level could be achieved for male CDF rats. Therefore, the LD50 is estimated by the average of 210 mg/kg (07. kill) and 225 mq/kg (100'. kill).
b) Probit could not be computed because less than 2 concentrations at which the percent dead was between 0 and 100 were achieved. DO 136695 CONFIDENTIAL
Table 4
A COMPARISON OF SINGLE-DOSE ORAL LDSO'e FOR SPB: (SPRAGUE-DAWLEY) RATS AND ClPF (FISCHER 344-DERIVED) RATS
2,4,5-TRlCHLOROPHENOXY ACETIC ACID # Dead/# Treated
Dose (mg/kg)
126 252 350 398 450 500 795 1000 1580 2000
Male Sprague-Dawley
0/5 0/5
-
-
1/5
-
5/5 5/5
Female Sprague-Dawley
0/5 0/5 0/5 1/5 0/5 5/5
-
5/5
-
"
Male CDF
0/5 0/5
-
-
0/5 4/5 5/5
-
5/5
Female CDF
0/5 0/5
-
-
-
0/5 -
3/5
-
5/5
Moving9 Average
Moving3 Average
Moving3 Average
Moving3 Average
Single-dose Oral LD50 (mg/kg)
95% Confidence Interval (mg/kg)
Slope
588
428-906 4.82
474
442-568 12.46
692 950
557-811
650-1339
7.06
4.23
a) Probit could not be computed because less than 2 concentrations at which the percent
dead was between 0 and 100 were achieved.
do ^36696
CONFIDENTIAL
Table 5
A COMPARISON OF SINGLE-DOSE ORAL LD50's FOR SPB: (SPRAGUE-DAWLEY) RATS AND CDF (FISCHER 344-DERIVED) RATS
ALLYL CHLORIDE: MORTALITY # Dead/# Treated
Dose (mg/kg)
Male Sprague-Dawle.y
Female Sprague-Dawley
Male CDF
Female CDF
63 126 200 398 795 1580
1 1 1
Single-dose Oral LD50 (mg/kg)
*-
--
0/5 0/5 3/5 3/5 5/5 4/5 5/5 5/5
- 0/5 - 3/10 0/5 1/5 2/5 2/5 5/5 5/5 5/5 5/5
Moving3 Average i
i
379 :
Moving Averaqe Probit
Moving3 Average
455 435
419
Moving Average
Probit
275 293
95% Confidence Interval (mg/kg)
259-533
260-685 241-751 298-612
180-526 177-719
Slope |
i
4.64
3.44
4.56
4.25
2.18
2.54
a) Probit could not be computed because less than 2 concentrations at which the percent dead was between 0 and 100 were achieved.
DO 1.36697 CONFIDENTIAL
-18-
Table 6
A COMPARISON OF SINGLE-DOSE ORAL LDSO'b FOR SPB: (SPRAGUE-DAWLEY) RATS AND ClPF (FISCHER 344-DERIVED) RATS
MALATHION: MORTALITY
# Dead/# Treated
Dose (mg/kg)
Male Spraque-Dawlev
Female Spraque-Dawlev
Male CDF
Female CDF
252 500 1000 2000 2100 2250 2520 3980
0/5 0/5
0/5 0/5
0/5 0/5
0/5 0/5
0/5 0/5
0/5 0/5
0/5 2/5
1/5 3/5
3/5 -
--
5/5 -
--
5/5
-
10/10
-
5/5 5/5
4/4 5/5
Single-dose Oral LD50 (mg/kg)
95% Confidence Interval (mg/kg)
Slope
Moving3 Average
2101
2035-2164 '18.28
Moving3 Average
2102
1493-3068 4.63
Moving3 Average
1875
Moving3 Average
1898
1578-2191 7.49
1300-2671 4.24
a) Probit could not be computed because less than 2 concentrations at which the percent dead was between 0 and 100 were achieved.
136698 CONFIDENT TAI.
Dose (mg/kg) 31.6 63
126 158 316 630 1260 1580 2000 2520 5000
Table 7
A COMPARISON OF F^riF-^OSE ORAL LD&C'a FOR SPB: (SPRAGUE-DAWLEY) RATS hND CD^F (FISCHER 344-DERIVED) RATS
ACRYLIC ACID: MORTALITY
__ ___________________________ # Dead/# Treated___________________
Male Spraque-Dawlev
Female Spraque-Dawlev
Male CDF
Female CDF
- - - 0/5 - 0/5 0/5 3/9a
-
3/1C
2/5 0/5
-
l/9a
4/5 2/5
-
2/5
3/4
l/4a
0/5 1/5 5/5 2/5 1/5 3/5 5/5 6/9a
4/5
-
--
5/5 -
--
5/5 5/5 5/5 5/5
5/5 5/5 5/5 5/5
Single-dose Oral LD50 (mg/kg)
Moving Averaqe Probit
1337
1409
Moving Averaqe Probit
Moving
Moving
Averaqe Probit Averaqe Probit
718 617
151
146 526
468
95% Confidence
Interval
(mg/kg)
936-1680 1030-1750
Slope
7.82
17.79
408-1567 323-2120
1.50
1.52
94-227 3.18
84-255 3.91
308-979 211-1497
1.23
1.21
a) Because the test material was deposited into the lungs of 1 rat of this test group, this rat was not considered in LD50 calculations.
00 1
OONf
se (mq/kq) 316 630
1260 2520 3160 5000 10,000
-20-
m.cmrkrnil
Table 8
A COMPARISON OF SINGLE-DOSE ORAL LDSO'a FOR SPB: (SPRAGUE-DAWLEY) RATS ARE CE&F (FISCHER 344-DERIVED) RATS
BENZENE: MORTALITY
Male Spraque-Dawley
0/5 1/5 0/5 4/5 5/5
-
# Dead/# Treated
Female Spraque-Dawley
Male CDF
- 0/5
0/5 3/10
1/5 1/5
3/5 4/5
--
2/5 4/5 5/5 5/5
Female CDF 0/5 2/10 1/5 3/5
-
5/5
-
Single-dose Oral LD50 (mg/kg)
Moving Averaqe Probit
3093
2654
Moving Average Probit
Moving Averaqe
Probit
Moving Averaqe
Probit
2951
3123
1618
1527
1606
1659
95% Confidence
Interval (mg/kg)
2495-3621 1582-4074
1790-5458 1606-6830
369-2856 855-2982
1047-2902 1012-:
Slope
6.86
4.71
2.19
2.54
2.01
2.26
2.65
2.E
O 0 136700 CONFIDENTIAL.
-21-
Table 9
A COMPARISON OF SINGLE-DOSE ORAL LDLO'a FOP SPb:
(SPRAGUE-DAWLEI) RATS AND CDF (FISCHER S44-DERIVED, RATS EPICHLOROHYDRIN: BEHAVIORAL SIGNS OF TOXICITY
Dose (mg/kg) 200 210 225 252
398
795
Signs of Toxicity
Slight lethargy
Slight lethargy Piloerection
Lethargy Piloerection
Extreme Lethargy Piloerection Shallow breathing Darkened extremities
Lethargy Hyperactivity Watery eyes Diarrhea
Lethargy Severe diarrhea
# Affected/# Treated
Male
Female
Male
Spraque-Dawley Spraque-Dawley CDF
5/5 5/5 5/5
_ _ 5/5 5/5
_ 5/5 5/5
5/5 5/5 5/5 5/5
5/5 5/5 5/5 1/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5
5/5 5/5 5/5 0/5 0/5 0/5
Female CDF
0/5
5/5 5/5
5/5 5/5
5/5 0/5 5/5 0/5
5/5 0/5 5/5 5/5
5/5 5/5
a) No signs of toxicity were observed in rats of the 25, 50, or 100 mg/kg dose groups
no I367cn OQNFtOFNTTAL
-22-
Table 10
A COMPARISON OF SINGLE-DOSE ORAL LDSO'e FOR SPB: (SPRAGUE-DAVLEY) RATS AND CD*F (FISCHER 344-DERIVED) RATS
2,4,5-TRICHL0R0PHEN0XY ACETIC ACID: BEHAVIORAL SIGNS OF TOXICITY
if Affected/# Treated
(mq/kq) 252
Siqns of Toxicity Slight lethargy
Male Spraque-Dawley
5/5
Female Spraque-Dawley
0/5
Male CDF
5/5
Female CDF
0/5
350 None
-
5/5
--
398 Slight lethargy
-
3/5
--
450 None
500 Lethargy Piloerection
-
5/5
--
5/5 5/5 5/5 5/5 0/5 0/5 5/5 5/5
795 Lethargy Piloerection
- - 5/5 5/5
1000
Lethargy Piloerection Diarrhea
5/5 5/5 5/5 5/5 0/5 0/5 5/5 5/5
0/5 0/5 0/5 3/5
1580 2000
Lethargy
Lethargy Piloerection Diarrhea
5/5
- --
- - 5/5 5/5 5/5 0/5 0/5 3/5
No signs of toxicity were observed in rats of the 126 mg/kg dose group.
36702
in-23-
Table 11
A COMPARISON OF SINGLE-DOSE ORAL LD50'a FOR SPB: (SPRAGUE-DAWLEY) RATS AND CD^F (FISCHER 344-DERIVED) RATS
ALLYL CHLORIDE: BEHAVIORAL SIGNS OF TOXICITY
Dose (mg/kg) 63
126 200 398
795
1580
Signs of Toxicity
Slight lethargy
Slight lethargy
Lethargy Piloerection
Lethargy Diarrhea Piloerection
Extreme lethargy Diarrhea Piloerection Convulsions
Extreme lethargy Severe diarrhea
# Affected/# Treated
Male
Female
Male
Sprague-Dawley Sprague-Dawley
CDF
- --
- --
5/5 5/5 5/5 0/5 0/5 5/5
5/5 5/5 5/5 3/5 3/5 2/5 0/5 5/5 5/5
5/5 5/5 5/5 5/5 4/5 5/5 0/5 0/5 0/5 0/5 0/5 1/5
5/5 5/5 5/5 5/5 5/5 5/5
Female CDF
5/5
io/ir
5/5 5/5
5/5 2/5 5/5
5/5 5/5 0/5 1/5
5/5 5/5
00 136703 CONFTOFNTTAL.
-24- OGW-CQtifilRfc
Table 12
A COMPARISON OF SINGLE-DOSE ORAL LDSO'e FOR SPB: (SPRAGUE-DAWLEY) RATS AND CD(FISCHER 344-DERIVED) RATS
MALATHION: BEHAVIORAL SIGNS OF TOXICITY # Affected/# Treated
! (mq/kq) 500
1000
2000
2100
2250
Signs of Toxicity
Male Sprague-Dawley
None Slight lethargy
5/5 0/5
None Total body tremors Bluish face Slight lethargy
5/5 0/5 0/5 0/5
Total body temors Piloerection Heightened tail color Slight lethargy Bluish face
5/5 5/5 5/5 5/5 0/5
Total body tremors Lethargy Piloerection Convulsions
Total body tremors Dark exudate around eyes
5/5 5/5 1/5 5/5
3/3^ 1/1D
Female Sprague-Dawley
5/5 0/5
0/5 5/5 5/5 0/5
5/5 0/5 0/5 0/5 5/5
-
Male CDF
2/5 3/5
0/5 0/5 0/5 5/5
5/5 5/5 0/5 5/5 0/5
-
Female CDF
5/5 0/5
0/5 5/5 0/5 5/5
5/5 0/5 0/5 5/5 0/5
2520
Total body tremors Slight lethargy
5/5 0/5
0/5 5/5
3980
Lethargy Gasping None Total body tremors
Z/2h 2/2 0/2
0/5
0/5 3/5 0/5 0/5 0/5 0/5 5/5 4/5 5/5 0/5 1/5 0/5
a) No signs of toxicity were observed in rats of the 252 mg/kg dose group. b) The number affected given is per number of survivors.
DO 136704 CONFIDENTIAL
Table 13
A COMPARISON OF SINOLE-UuSE URAl LD;0's F\-' SIR:
(SPRAGUE-PAWLED RATS AND Cl'**? (FISCHER 344-DERiVED: RATS
ACRYLIC ACID: BEHAVIORAL SIGNS OF TOXICITY
Dose (mg/kq) 31.6
Signs of Toxicitv None
63 Lethargy Piloerection Dark exudate around nose and mouth
126 Slight lethargy Piloerection None
158 None Lethargy Piloerection
316 Lethargy Piloerection
630 Lethargy
Piloerection Dark exudate around
nose and mouth
1260
Lethargy
Piloerection Dark exudate around
nose and mouth
1580
Lethargy
2000
Lethargy
2520
Lethargy
5000
Lethargy
# Affected/# Treated
Male
Female
Male
Spraque-Dawlev Spraque-Dawlev CDF
- --
0/5 5/5 0/5 5/5 0/5 0/5
Femal CDF
5/5
5/5 5/5 j/5
3/10 0/10 0/10
9/9b 0/9 0/9
5/5 0/5
5/5 5/5 0/5
0/5 5/5 3/3a
4/4b 4/4
0/5 0/5 5/5
0/5 5/5 0/5
4/41 4/4
5/5 5/5 5/5 5/5
5/5 0/5 5/5 5/5 0/5 0/5 5/5 0/5
5/5 5/5 5/5 9/91
5/5 5/5 5/5 9/9 0/5 0/5 5/5 4/9
5/5
- --
5/5
- --
5/5 5/5 5/5 5/5
5/5 5/5 5/5 5/5
a) The number affected given is per number of survivors.
b) Because the test material was deposited into the lungs of 1 rat of this test group, this rat was not considered in the observation.
QO 1 36705 CONFTClFNTTAl.
T.M. 14
' i.RRll
Dose (mq/kq) 316 630
1260
2520
3160
5000
10,000
A COMPARISON OF SINGLE-DOSE ORAL LDSO'e FOR SPB: (SPRAGUE-DAWLEY) RATS AND CDF (FISCHER 344-DERIVED) RATS
BENZENE: BEHAVIORAL SIGNS OF TOXICITY
# Affected/# Treated
Signs of Toxicity
None Slight lethargy
Male Sprague-Dawle.y
Female Sprague-Dawley
.
Male CDF
5/5 0/5
Female CDF
0/5 5/5
Lethargy
5/5 5/5 10/10 10/10
Total body tremors Lethargy Hyperventilation Dark exudate around
the nose Severe diarrhea
Total body tremors Lethargy Hyperventilation Dark exudate around nose
Total bcdy tremors Lethargy Piloerection Hyperventilation
Total body tremors Lethargy Hyperventilation Convulsions
Lethargy Labored breathing
5/5 5/5 5/5 5/5
0/5
5/5 5/5 5/5 5/5
l/la 1/1 1/1 1/1
5/5 5/5 0/5 0/5
-
5/5 5/5 5/5 5/5 5/5 5/5 5/5 0/5 0/5 0/5 0/5 0/5
1/5 0/5 0/5
5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 0/5 0/5 0/5
_ --
5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 1/5 0/5 0/5
0/5
2/2a
-
0/5 2/2
a) The number affected given is per number of survivors.
OO 13670ft CONFTDFNTTAL
-27
Dose (mg/kg) 25 50 100
200 210 225 252 398 795
TABLE 15 A COM!'AlaCOtt or SINGIE-DOSE OHAL LDIO'a FOR SVB: (SPRAGVE-DAWI.EY) HATS AND CD^F (F1SCRER hi-derived) rats
EPICHL0R0HVDR1N: MEAN ( + STANDARD DEVIATION} INITIAL (FASTED) AND FINAL BOOT HEIGHTS
Male
Spraque-Dawley
Initial
Final
n Weight (q) n Weight (q)
Female
Sprague-Dawley
Initial
Final
n Weight (g) n Weight (g)
Male
CDF
Initial
Final
n Height (q) n Height (q)
Female
CDF
Initial
Final
n Heiqht ill " Weight (q)
5 269*11 5 381+16
5 192+3
5 248+7
5
109 + 5
5 200+4
5 91 + 2 5 139 + 4
5 265+11 5 . 366+17 5 262+.18 5 370+21
5 197+11 5 251+16
5 194+9
4 246+20
5
111+3
5 199+13
5
109+4
5 194+10
5 92+5 5 139+8 5 89+3 5 135+6
5 274+13 4 374+20
5 193+7
3 239+3
5
108+5
5 193+5
5 88+5 5 135+5
- -- ---
---
---
5
167+9
5 217+16
5 111+8
2 139+4
--- ---
---
---
5 161+6 a --
5 131+5
a--
----
5 320+22 a 5 325+13 a
-- -- --
---
-
5 208+4
a
5 199+13 a
-- -- --
5 185+3 a -- 5 104+4 a --
5 103+8 a --
5 118+7 5 81+7 5 79+5
a -a -a --
a) No survivors
DO 1 3 6 7 0 7 CO NFIDENTIAL
*3*
3 33 try'll *IS;a-*--'
-28-
Dose (mg/kg) 126
table 16 A COMPARISON OF SINdf-DOSE ORAL LUSO'a FOR SPB: (SPRAGUE-DAWLEY) RATS AND Clf"F (FISCHER 344-UERTVED) RATS
2,4,5-TRICHLOROPHENOXY ACETIC ACID: MEAN (_+ STANDARD DEVIATION) INITIAL (FASTED) AND FINAL BODY WEIGHS
Male
Female
Sprague-Dawley
Sprague-Dawley
Initial
Final
Initial
Final
n Weight (g) n Weight (g) rt Weight (g) n Weight (g) n
Male
CDF
Initial
Final
Height (g) n Weight (g)
Female CDF
Initial Weight (g) n
F inal Weight (g)
5 322+15 5 424+26 5 201+9
5
253+7 5
141+9
5 226+10
5 90+4 5 137+7
252
5 313+26 5 405+37 5 195+2
5
240+3 5
141+12 5 219+16
5 92+5 5 140+3
350 - --
-- 5 200+13 5 233+14 - --
---
- -- ---
398 - -- 450 - --
--
5 208+9
4
163+8 -
--
-- 5 203+15 5 235+16 - --
--- ---
- -- --- - -- ---
500 795 1000
5 311+15 4 380+18 5 196+5
---
-----
5 306+12 a -- 5 190+4
a a
-- 5 144+9 5 221+9 -- 5 156+8 1 124 -- 5 144+4 a --
5 95+4 5 144+5 - -- - -5 94+3 2 139+2
1580 2000
5 289+7
a
--
---
.--
_
---
--
---
5 129+9 a __
- -- --- 5 90+4 a
O o z-n
o o
o LJ
rrt O'
Z-1 ^O ,-i 3> >
f
TABLE 17 A COMPARISON OF SINOPE-DOSE ORAL RVSO'o FOR SIR: (SPRACIIF-PAULF.K) RATS AND CPPF {FISCHER 344-DERIVED) RATS
ALLYL CHLORIDE: MEAN ( + STANDARD DEVIATION) INITIAL (FASTEO) AND FINAL BODY HEIGHTS
Dose (roq/kq) 63
Male,
Spraque-Dawlev
Initial
Final
n Height (q) n Height (q)
- --
-
126 - --
- --
200
5 308+13
5 403+22
Female --------
Spraque-Dawlev
Initial
Final
n Weight (q) n Height (q)
---
--
---
--
5 193+6
5 236 + 8
Male
COF
Initial
Final
n Weight (q) n Weight (q)
---
---
---
---
6 139+7 5 214+7
Female CDF
Initial n Height (q) n
5 82+5
5
Final
Weight In)
133+2
5 83+5 3 133+8
5 92+1 4 143j_7
398
5 296+12
2 284+10
5 191+3
2 238+6
5 335+7 3 136+9
5 91+4 3 143+3
795
5 308+8
a--
5 189+4
1 250
5 136.216 a --
5 94+2
a
1580
5 318+13
a
--
5 196+12
a
--
5
135+6
a
5 88+4
a
a) No survivors
30-
table 18
A COMPARISON OF SINGLE-VOSE ORAL LVbO's FOR SPB: (SPRAGUE-DAWLEY) RATS AND CE^T (FISCHER 344-DERIVED) RATS
Cose (roq/kq) 252 500
1000 2000 2100 2250 2520 3980
HALATHION: MEAN (+ STANDARD DEVIATION) INITIAL (FASTED) AND FINAL BODY WEIGHTS
*
Hale
Spraque-Dawley
Initial
Final
n Weiqht (q) n Weiqht (q)
5 231*22 5 349+
Female
Spraque-Dawley
Initial
Final
n Weiqht (q) n Weiqht (q)
5 171+5
5 224+12
Hale
CDF
Initial
Final
n Weiqht (q) n Weiqht (q)
5
144+3
5 222+6
Female
CDF
Initial
Final
n Weiqht (q) n Weiqht (q)
5
100+3
5 140+3
5 229+3
5 343+7
5 180+7
5 242+10
5
148+4
5 219+5
5
100+3
5 138+4
5 220+6
5 337+16
5 176+6
5 224+8
5 149+10 5 227+13
5
98+4
5 138+2
5 235+8
5 350+15
5 179+11
3 232+21
5
150+1
4 226+7
5
100+6
2 121+5
5 244+5
2 348+6
---
---
- -- ---
5 357+9 a --
---
---
- -- ---
5 296+21 a
--
---
---
10
185+30 a
--
- -- - --
5 274+11 a
--
5 200+7 a --
5 185+7 a --
5 92+5 a --
O oo zo n
--s
O G)
rri O'
Z Si -i -1 -+ O 1>
-31-
table 19 A COMPARISON OF SINGLE-DOSE ORAL LOSS'a FOR SPB: (SPRAGUE-CAWLEY) RATS AND Clf'JF (FISCHER 344-DERIVhV) RATS
ACRVLIC ACID: MEAN ( + STANDARD DEVIATION) INITIAL (FASTED) AND FINAL BODY WEIGHTS
Dose (mq/kg)
waie
Spraque-Dawley
Initial
Final
n Weiqht (q) n Weight (q)
31.6 63 126 I SB 316 630 1260 1580 2000 2520 5000
_
__
__ __
--- * - -_
5 279+13 5 279+74
5 275+10 4 215+74
5 328+20 1 213
5 311+9
4--
5 258+18 a --
5 274+11 a --
Sprague-Oawley
Initial
Final
n Weight (g) n Weight (g)
- -5 219+7 5 221+9 5 217+8 5 195+4 5 191+6 5 194+6 --- --- 5 197+11 5 188+7
--- 5 230+35 4 227+32 4 225+26 2 236+18 4 211+31 2 224+20 --- - -a-- a --
CPF
Initial
Final
Weiqht (g) n Weiqht (q)
--- 5 178+6 5 189+4 5 101+8 5 104+3 5 115+5 5 114+3 - ---- 5 114+6 5 101+5
--- 5 193+46 3 209+61 1 70 1 98 a-- a-- - -a-- a--
CDF
Initial
Final
n Weight (g) n Weight (g
5
120+6
5 142+29
10 122+11 6 105+21
5
114+9
5 104+30
5
114+2
3 119+47
5
120+2
3 109+20
5
92+2
3 107+24
10 114+21 3 112+16
"-- " 5 94+4 a -* 5 93+3 a --
32-
Dose (mg/kg) 316 630
1250 2520 3160 5000 10,000
TABLE 20
A COMPARISON OF SINGLE-DOSE ORAL LDtO'a FOR SPB: (SPRAGUE-RAWLSY) RATS AND Clf'F (FISCHER HI-DERIVED) MTS
BENZENE: MEAN (+ STANDARD DEVIATION) INITIAL (FASTED) AND FINAL BODY WEIGHTS
Hale
Spraque-Oawlev
Initial
Final
n Welqht (q) n Welqht (q)
Female
Sprague--Dawlev
Initial
Final
n Weight (g) IL Weight (g)
Hale
CDF
Initial
Final
n Weiqht (g) n Weiqht (q)
Female
CDF
Initial
Final
Weight (g) n Weight (g)
---
---
---
---
5
134+3
5 225+2
5
118+3
5 156+3
5 314+9
5 405+22
5 195+8
5 244+14
10 118+16 7 210+23 10 100+19 8 143+17
5 327+9
4 434+10
5 201+5
5 256+9
5
100+3
4 179+10
5
81+b
4 125+3
5 312+8
5 418+15
5 196+4
2 248+7
5
101+_3
1 157
5
82+7
2 136+1
5 276+15 1 5 311+11 a
341 --
--- 5 197+7
--- 3 256+6
- -- - --
5
103+4
1 172
- -- --- 5 81+7 a --
5 194+7
a
5
125+7
a
a) No survivors
n ozT* oo
i-H
o lj
ti cr-
z-) ^ -i \> >
-33-
Table 21
a rtmiwnnw of mmis-p r? m. uc.o'a tm ;tr:
(SrRACUh-DAWWY) HATS ANP CD'T' (FISCHER A44-PEH1VEP) RATS
f
EP1CHL0R0HY0R1N: GROSS PATHOLOGIC FINDINGS
Gross Observations3
Dose mg/kg
25 50 100 200 210 398
Hale Female Hale Female Hale Female Hale Female Hale Female Hale Female Male Female Hale Female Hale Female Kale
S.D. S.O.
CDF CDF S.D. S.D.
CDF CDF S.O. S.D.
CDF CDF S.D. S.D. CDF CDF CDF CDF S.D.
General
Ilo visible lesions Focal corneal
cloudiness Accumulation of
exudate around eyes
A/S 1/5 0/5
5/5 0/5 0/5
3/5 5/5 3/5 5/5 2/5 0/5 1/5 0/5 0/5 0/5 2/5 0/5
5/5 5/5 0/5 1/A 0/5 0/5 1/5 0/4 0/6 0/5 1/5 0/4
4/5 3/5 0/5 2/5 0/5 0/5
0/4 1/3 1/4 0/3 1/4 0/3
2/5 1/5 0/5 2/2 2/5 2/5 3/5 0/2 0/5 0/5 0/5 0/2
1/1 0/1 0/1
Gastrointestinal System Stomach
OO 20
OW m O' 2 ^ {j
X>
c
Thickening and roughing of
squamous epithelium Focal thickening of
nonglandular stomach wal1 Erosion of nonglandular
epithelium Healed perforated
ulcer Fibrous adhesions
between stomach and abdominal musculature
0/5 0/5 0/6 0/5
0/5
0/5 0/5 0/5 0/5 `
0/5
0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5
0/5 0/5 0/5 0/5
0/5 0/5 5/5 3/4 1/5 0/5
0/5 0/5 0/5 0/4 0/5 0/5
0/5 0/5 0/5 0/4 0/5 0/5 0/5 0/4
0/5 0/5 0/5 0/5
0/5 0/5 0/5 0/4 0/5 0/5
4/4 2/3 2/5 4/5 4/5 0/2 0/1
0/4 1/3
0/5 0/5 0/5 0/2
0/1
0/4 1/3 1/4 0/3
0/5 0/5 0/5 0/2 0/5 0/5 0/5 0/2
0/1 0/1
1/4 0/ 3 0/5 0/5 0/5 0/2 0/1
Liver Diaphragmatic hernia 0/5 0/5
0/5 0/5 0/5 0/5
0/5 0/5 0/5 0/4
0/5 0/5
0/4 0/ 3 0/5 0/5 1/5 0/2 0/1
a) Data presented as number affected/number examined.
-34-
Table 22 A COMPARISON OF SJNGLE-WSE ORAL LDRO'b FOR SFB: tSPRAGUE-PAULEY) RATS AND CD``F (FISCHER 344-DERIVED) RATS 2,4,5-TRlCHLOROPHENOXT ACETIC ACID: GROSS PATHOLOGIC FINDINGS
Gross Observations9
General
No visible lesion Focal corneal
cloudiness Accumulation of exudate
around eyes
Respiratory System
Lunqs
Multiple pinpoint gray Foci scattered throughout all lobes
tinal System
126
Male Female S.D. s.o.
Male Female COF CDF
Dose (mg/kg)
252 350
Male Female S.D. S.O.
Male Female CDF CDF
Female S.D.
398
Female S.D.
450
Female S.D.
Male S.O.
500 795
Male Female! Male CDF CDF COF
3/5 4/5 2/5 1/5 1/5 0/5
4/5 5/5 1/5 0/5 0/5 0/5
2/5 4/5 0/5 0/5 2/5 1/5
4/5 4/5 0/5 1/5 1/5 0/5
4/5 0/4 3/5 2/4 3/5 5/5 0/1
1/5 0/4
1/5 0/4 2/5 0/5 1/1
0/5 0/4 0/5 2/4 0/5 0/5 0/'
0/5 0/5
0/5 0/5
1/5 0/5
0/5 0/5
0/5 0/4 1/5 0/4 0/5 0/5 0/1
1 "/s
0/5
0/5 0/5
0/5 0/5
0/5 0/5
0/5 4/4 0/5 0/4 0/5 0/5 1/1
imined.
.4:=-*
no 1.06715
CONFTDFNTTAI.
Gross Observations3
General
Ho visible lesion Focal corneal cloudiness Accumulation of exudate
around eyes
63 Female
CDF
2/5 3/5 0/5
Respiratory System
Lungs
Multiple pinpoint gray Foci scattered throughout all lobes
0/5
Gastrointestinal System
Stomach
Thickening and roughening of nonglandular squamous epithelium
Focal thickening of nonglandular stomach wall
Erosion of nonglandular epithelium
Firm, nodular-like Foci throughout epithelial surface
Perforated Ulcer Fibrous adhesions between
stomach ar.d 1 iver, spleen, or diaphragm
0/5 0/5 0/5
0/5 0/5
0/5
-35-
Table 23
a omi'AVAr,(iu or .:t:.<;:.E-'ur<F. oi<al une'c rou :;rn: <SPRAGUE-PAWLEY) HATS A!,'D CD*F (FISCHER J44-(ERIVED) RATS
ALLYL CHLORIDE: _GROSS PATHOLOGIC FINDINGS Dose (mg/kg)
126 200
398
Female CDF
Male Female Male Female
S.D.
S.D.
CDF CDF
Male Female Male
S.D.
S.D.
CDF
Female CDF
1/7
0/5 0/5 1/5 3/4
0/2 0/3
0/3 1/3
0/7
0/5 0/5 1/5 0/4
0/2 1/3
1/3 0/3
0/7
0/5 0/5 0/5 0/4
1/2 0/3
1/3 0/3
0/7
0/5 1/5 0/5 0/4
0/2 0/3
0/3 0/3
5/7
5/5 5/5 4/5 1/4
1/2 2/3
3/3 2/3
0/7
1/5 3/5 0/5 0/4
0/2 0/3
0/3 0/3
0/7 0/5 0/5 0/5 0/4
1/2 2/3
2/3 0/3
0/7
0/5 0/5 0/5 0/4
0/2 0/3
1/3 0/3
0/7
0/5 0/5 0/5 0/4
0/2 1/3
0/3 0/3
0/7 0/5 0/5 0/5 0/4
1/2 2/3
1/3 0/3
a) Oata presented as number affected/number examined.
IF*
-36-
Gross Observations3
Genera 1 No visible lesion Focal corneal cloudiness
Table 24
A am'ARTCON OF SINGLE-POSE OliAI., fJfRO'e FOR PVB: (SPRAGUE-PAWLEY) RATS AND CDk,F (FISCHER 344-l'EHlVED) RATS
MALATHION: GROSS PATHOLOGIC FINDINGS Dose (mg/kg)
252 500 1000
2000
[ 2100
Male Female Male Female Male Female Male Female Male Female Male Female Hale Female Male Female Male
S.D. S.D.
COF CDF S.D. S.D.
CDF CDF S.D. S.D.
CDF CDF S.D. S.D. CDF CDF S.O.
5/5 5/5
3/5 5/5
5/5 5/5
1/5 5/5
5/5 4/5 4/5 4/5
5/5 2/3 3/4 2/2
2/2
0/5 0/5
2/5 0/5
0/5 0/5
4/5 0/5
0/5 1/5
1/5 1/5
0/5 1/3 1/4 0/2
0/2
a) Data presented as number affected/number examined .
-37
Table 25
Gross Observations* General
1.316
male CDF
a co:fpap:r,r;/ of
ofai ltlj'c top cn:
(SFRACUZ-ZfWLS?) IATS A'.D Ch F (Fir.'rE.-.
PATS
ACRYLIC ACID: GROSS PATHOLOGIC FINDINGS
Dole (mg/kg)
63 126 158 316
Female Male Female Femelt Hele Femtle Female Mele Female Female Male Female S.D. CDF CDF S.D. CDF C0F S.D. CDF CDF S.D. CDF CDF
f----- 530 126C
Male S.D.
FemaleFemale S.D. CCF
1 fie 1 e |5.;.
Ft.Tiale c2
.
'VjV
15 3
v-oIf :-
1
No visible
lesion Focal comcal
1/5 3/b 2/5 1/5 5/7 1/3 1/5 6/8 0/1 2/3 3/3 0/1 0/3 1/5 0/4 0 `i ou 0/2
cloudiness
3/5
Secretory material
Z/S
2/5 1/5
1/7
1/3 1/5
0/C
0/1 0/3
0/3
0/1 0/3
1/5 1/4
0/J 0/4 0/2
around mouth
and nose Depletion of
0/5 0/5 0/5 1/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 0 3 0/4 0/2
body fat and
muscular atrophy 1/5 0/5 1/5 5/6 0/7 1/3 3/5 1/E 0/1 0/3 0/3 0/1 0/3 0/5 0/4 1/3 ;) /4 0/2 LOSS Cf body
condition
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 1/1 1/3 0/3 1/1 3/3 0/5 0/4 0/3 j 0/4 0/2
C/3 0/1 o/2 m
/3 on
r/3 1 1 1 0/3 0/1
lesoiratory Svstem ungs
Multiple pinpoint Foci scattered
through'/.*. .1!
lobes Pulmonary
(1/5 0/5 0/5 0/6 1/7 0/3 0/5 1/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 0/3 0/4 0/2
aT#^Ftf ti
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 (i/i 0/' 1/5 n/4 (1'3 0/4 O'?
astrointestinal '.utr1
0-J 0/1 or*. 'i
toraach
Thickening anu
roughening of
squamous
eounel i;;m
0/5 0/5 0/5 1/6 1/7 1/3 1/5 0/8 0/1 0/3 0/3 1/1 2/3 4/5 4/4 3/3 4/4 2/2
Focal tn1c ten jug
Of nonglandular
Stor-ach wall
0/5 0/5 0/5 1/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 1/3 0/4 0/2
Hemolyzed blood
in glandular I
portion
10/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 1/1 1/3 0/3 0/1 0/3 0/5 0/4 0/3 0/4 0/2
Thickened area
-1 at .junction of
glardular and nonglandular
mucosa Distention of
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 1/4 0/7 0/4 0/2
Stomach by
muCus
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 0/3 1/4 0/2
Gaseous distention
of stomach and/or
intestinal tract 0/s 0/S 0/s 0/6 0/7 0/3 0/S u/8 O/l 0/3 U/J 0/1 0/3 0/S 0/4 U/J H 4 0/2
Fibrous adhesions
between stomach
1
and liver
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 0/J 1/4 0/2
3 ` i/: fD ; i/i 0/'; 0/1
0/7 0/1 0/3 0/1 U/J o/l 0 j i)M
ntestinal tract
Presence of
mucoid, yellow
bile-liin fluid
in intestinal j
tract
0/5 0/5 0/5 0/6
HwrhaqK
j
appearance of
cecum
0/5 0/5 0/5 0/6
0/7 0/3 0/5 0/8 0/1 0/7 0/3 0/5 0/8 0/1
0/3 0/3 0/3 0/3
1/1 1/3
4 0/5 0/4 0/J 2/4 f'
0/1 0/3 0/5 0/4 0/ * 'l/4 i
JI./: l( 0/i './I
symuS decreased size
0/5 0/5 0/5 0/6 0/7 0/3 0/5 0/8 0/1 0/3 0/3 0/1 0/3 0/5 0/4 0/3 0/4 0/2 -i 0/3 1/1
1
__ Li
_|
) Gala prcsnniio . number af fccted/nuinbcr examined.
DO 1.36717 CONFIDENT! AD
-38-
Table 26
a nwAitisox or
r-iort ohm, wuo'n ran sin:
(Sl'KAGlir-PAW'KV) HATH AS,I i.V'".1' (ftSCIIkii API-Lft-.HIVkD) RATS
BENZENE: GROSS PATHOLOGIC FINDINGS
Gross Observations3
0. 116
Hale Female CDF CDF
0.63
Male Female Hale Female S.D. S.D. CDF CDF
1.26
Hale Female Male Female
S.D. S.D.
CDF CDF
2. 52
Hale Female Hale Female S.D. S.D. CDF C0F
3.16
Hale S.D.
5.0
Female Hale
S.D.
CDF
General
Ho visible lesion A/5 4/5* 1/5 5/5
Focal corneal
cloudiness
1/5 1/5 1/5 0/5
5/7 4/8 2/7 4/8
1/4 3/4 1/4 0/4
1/4 3/4 2/4 1/4
1/5 1/2 0/1 2/2 1/1 0/5 0/2 1/1 0/2 0/1
2/3 1/1 0/3 0/1
Gastrointestinal System
Stomach
Thickening and
roughening of
nonglandular
squanous
epithelium
0/S 0/5 3/5 0/5
Focal thickening
of nonglandular
stomach wall
0/5 0/5 0/5 0/5
Erosion of
nonglandular
epithelium
0/5 0/5 0/6 0/5
0/7 0/8 0/7 0/8 0/7 0/8
3/4 1/4 0/4 0/4 0/4 0/4
1/4 0/4 0/4 0/4 0/4 0/4
4/5 1/2 0/1 0/2 0/1
1/3 0/1
1/5 0/2 0/1 0/2 0/1 0/3 0/1
1/5 0/2 0/1 0/2 0/1 0/3 0/1
a) Data presented as number affected/number examined.
n oo zo Ti
zj m o'
Z vi -A r-"
i--i 3) 3>