Document rxBj6O4Ly0orGGBopgZYeBM4v
FEB-27-97 THU 02:09 PM HUNTINGDON LIFE SCIENCES FftX NO. 906 873 3992
P,01/18
TOTAL NUMBER OF PAGES INCLUDING THIS PAGE:
IB
Huntingdon
Life Sciences
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ATTENTION OF: Dr. 0. Knaak
COMPANY:
Occidental Chemical Corporation Dallas, TX 75244
CC: Dr. Hasmukh Shah Chemical Manufacturers Association Arlingon, VA 22209
FROM: DATE:
Raymond E. Schroeder 27 February 1997
MESSAGE:
Study No. 96-4080 - Vinyl Chloride Combined Inhalation Two-Generation Reproduction and Developmental Toxicity Study in CD Rats
This fasclmile includes the following summary data for the above referenced study for your review;
Tables
1. Summary of In-Life Physical Observations 2. Mean Body Weights 3. Percent Difference in Body Weight from Control 4. Mean Food Consumption
Appendix A. Methodology and References
Please contact me with any questions.
Best Regards,
Raymond E. Schroedfer Study Director
if. SJ--
CMA118813
FEB-27-9? THU 02:10 PH HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P. 02/18
n of animals examined
DRAFT
T 1-1
TABLE 1 VINYL CHLORIDE COMBINED INHALATION TWO*GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
96-4080
SUMMARY OF lN-UFE PHYSICAL OBSERVATIONS - MALES
WEEK: -1
1 2345 67
I 30 II 30 III 30 IV 30
30 30 3o 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
NORMAL WITHIN NORMAL LIMITS
DERMAL"GENERAL ULCERATION - CERVICAL
ALOPECIA EXTREMITIES/SNOUT
ALOPECIA - GENERAL
I JO II JO III jo IV 30
29 29 29 29 29 27 27 30 19 28 26 26 27 17
30 29 28 28 28 26 2A 30 30 29 28 27 27 27
I0 II 0 III 0 IV 0
I0 II 0 III 0 IV 0
I0 II 0 III 0 IV 0
O11 111 } 00OO0O0 OOO00O 0 00O0 0 o 0
00009 0 1 0 112 2 1 1 00000 00 09000 00
oooooo 0 0 0 1111 1 000000 0 000 000 0
LACRIMATJON - UNILATERAL
I0
II 0
III 0
IV 0
100001 0 000000 1 00 0000 0 0001 00 1
CMA118814
FEB-27-97 THU 02:10 PH HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P. 03/18
Of ANIMALS EXAMtNED
DRAFT
T 1-2
table 1 (com.) VINYL CHLORIDE COMBINED INHALATION TWO-GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
SUMMARY OP IN-LIFE PHYSICAL OBSERVATIONS MALES
WEEK: -1
I 30 n 30 m 30 IV 30
1 23A 56 7
30 So 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
96-40B0
CHROMOOACRYORftHEA
unilateral
CHROMOPACRY0RRHEA -
bilateral
oral/buccal INCISORS kalOCCLUDED
INCISORS BROKEN/MISSINO
I0 II 0 III 0 IV 0
I0 I! 0 Ill 0 IV 0
I0 11 0 III 0 IV 0
10 El Q III 0 IV 0
1 0000 \ o 0000 1 1 1 00000 02 00 1 21 1 1
0 0 0 0 0 o f] 0001 000 00000 1 0 00 00 000
00000 2 2 000 1 1 1 0 01 222A3 00 1 233 3
000000 1 00 0 000 0 0000003 000000 0
CMA 118815
FEB-27-97 THU 02:10 PM HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P. 04/18
* OF ANIMALS EXAMINED
DRAFT
TABLE T LOOflt.) VINYL CHLORIDE COWINEP INHALATION TUo-GENSRATION REPRODUCTION
ANO DEVELOPMENTAL TOXICITY STUDY IN CD RATS
SUMMARY OF JN-LIFE PHYSICAL OBSERVATIONS - FEMALES
WEEK) 1
1 234 S67
l 30 II 30 m 30 IV 30
30 30 30 30 30 30 30 30 30 30 30 30 30 30
30 30 30 30 30 30 30 30 30 30 30 30 30 30
NORMAL
WITHIN NORMAL LIMITS CENL APPEARANCE
I 30 It 30 111 30 IV 30
EARS SWOLLEN/SED BILATERAL
O-CULAR
!0
II 0 III 0
IV 0
LACRIMATION - UNILATERAL
I0
11 0
III 0
IV 0
CHROMOOACRTORRHEA UNILATERAL
I0 II 0 HI 0
IV 0
CHROMOOACRTORRHEA BILATERAL
I0 II 0 111 0 IV 0
ORAL/BUCCAL
INCISORS MALOCCIUOEO
10
II 0 lit 0
IV 0
30 30 30 29 29 28 28 30 30 30 30 30 30 30 30 30 30 29 29 28 28 30 2? 29 2B 27 25 28
000000 1 0000000 00 000 0 0 00000 1 1
0000 0 0 0 0000 0 0 0 000 \ 000 01 1 121 1
0000000 0000 00 0 0001 00 1 01 11221
0000 0 1 1 0000000 0000 000 0 000 0 00
0001 1 1 1 00 0 0 0 0 0 0001 1 22 000 2 3 4 3
P6-A080
CMA118816
FEB-27-97 THU 02:10 PH HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P, 05/18
# OF ANIMALS examined
DRAFT
T 1-4
TABLE i <eont.) VINYL CHLORIDE combined INHALATION TWQ-QEHERAT10N REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CO RATS
SUMMARY OP IN'LlPE PHYSICAL OBSERVATIONS - FEMALES
WEEK: -1
I 30 II 30 III 30 IV 30
1 2345
30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
96-4080
ORAL SORE INCISORS BROKEN/MISSINS
t0 II 0 Itt 0 IV 0
I0 II 0 III 0 IV 0
000 0 0 00000 0 0 00 0 a1 1 00
00000 00000 00 00 0 00 000
CMA 118817
FEB-27-97 THU 02=10 PM HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P. 06/18
T 2-1
94*4080
TABLE 2 VWl ChLO#tot COMBINED inhalation rwo*aeitATi(w REPRODUCTION
AW DEVELOPMENTAL TOXICITY STUOY IN CD RATS
draft
STAY SYMBOL:
um
8Y WEIGHT IN GRAMS
MALES DOSE LEVEL I PPM
0.0000
10.0000
100.0000 1100.0000
A-LA*L-
i MEAN ASS.9
S.D,
31.6
N 30
0 MEAN 233.3
S.D.
11.6
N 30
452.1 41.1 10
237.7 15.3 30
447.3 31.0 30
236.6 12.6 30
447.4 37.0 SO
234.3 14.0 30
A-L-
1 MEAN 274.5
S.D.
13.4
N 30
279.6 19. Q 30
277.8 14.5 30
272.4 16.6 30
A-L-
2 MEAN 314.2
S.O.
16.9
N 30
322.1 23.5 30
321.7 17.9 30
318.3 20.3 30
A-L-
3 MEAN 348.8
S.D.
16.0
N 30
357.7 27.2
30
357.2 20.4 30
348.0 25.3 30
A-L-
4 MEAN 375.3
S.D.
22.4
N 30
384.2 32.8 30
382.3 25.5 30
374.7 27,8 30
A-L-
5 MEAN 401.8
S.D.
23.1
N 30
412.1 36.2 30
409.2 28.0 30
405.5 30.1 30
a-l*
6 MEAN 417.1
S.O.
32.7
N 30
432.4 38.8 30
426.1 29.2 30
424.5 33.3 30
CMA 118818
FEB-27-97 THU 02:10 PH HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P. 07/18
96-4080 T 2-2 TABLE 2 leant.) VlHYl CHLORIDE CONSIKED INHALATION TWO*GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
STAY SYMBOL:
WEEK
body weight in grams
MALES DOSE LEVEL: PPM
0.0000
10.0000
100.0000 1100.0000
a-l-
7 MEAN 455.9
S.D.
31.6
N 30
*52.3 *1.1 30
4*7.3 31.0 30
447.6 37.0 30
draft
CMA 118819
FEB-27-97 THU 02M0 PM HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P. 08/18
T 2-3
96'4080
tails 2 (cent.) V14TL CHLORIDE COMBINED INHALATION TWO-GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
STAT SYMBOL:
WEEK
BOOT WEIGHT IN GRAMS FEMALES
DOS! LEVEL: PPM
0.0000
10.0000
100.0000 1100.0000
A'L' A-LA-L-
1 MEAN 258.5
S.D.
15.8
N 30
0 MEAN 15B.0
S.D.
7.5
N 30
1 MEAN 177.1
S.D.
9.7
N JO
253.4 14.3 30
158.5 9.1 30
173.8 9.5 30
259.6 20.7 30
156.3 9.3 30
178.1 12.1 30
253.1 14.2 30
157.0 7.7 30
175.8 9.3 30
A*lA-LA-LK-J-
2 MEAN 196.4
S.D.
11.9
N 30
3 MEAN 213.2
S,D.
12.3
N 30
4 MEAN 225.6
S.D.
15.3
N 30
5 MEAN 241.6
S.D,
14.7
N 30
197.3 10.4 30
209.8 10.5 30
222.0 10.7 30
236.6 10.5 30
199.1 14.1 30
214.4 16.6 30
226.7 17.4 30
241.5 19.4 30
197.1 11.7 30
212.2 12.7 30
225.0 13.1 30
236.4 13.0 30
A-L-
6 MEAN 250.7
S.D.
15.S
N 30
247.8 13.8 30
252.1 20.7 SO
247.5 13.8 30
CMA 118820
FEB-27' 97 THU 02:11 PM HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P, 09/18
>
TABLE VJNH CHLORIDE COMBIMED INHALATION TWO-GENERATION REPRODUCTION
AMO DEVELOPMENTAL TOXICITY STUDY IN CD RATS
DRAFTI
STAY SYMBOL;
WEEK
BODY WEIGHT IN GRAMS FEMALES
DOSE LEVEL; PPM
0.0000
10.0000
A-l-
7 MEAN
S.D. N
zse.s
15. S 30
3.< U.3 30
100.0000 1100.0000
59,6 20.7 30
53.1 H. 30
CMA 118821
FEB-27-97 THU 02:11 PH HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P. 10/18
T 3-1
96-4060
tabus 3
V1BYL CHLORIDE COMBINED INHALATION TWO-GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITT STUOT IN CD RATS
DRAFT
X DIFFERENCE IN BOOT WEIGHT MALES
DOSE LEVEL: PPM
WEEK
0.0000
10.0000
100.0000
-1 % DIFF
0.0
3.8
2.6
N 30 30 3o
0 X DIFF
0.0
1.9
1.4
N 30 30 30
1 X DIFF
0.0
1.9
1.2
N 30 30 30
2 x DIFF
0.0
2.5
2.4
N 30 3o 30
3 X DIFF
0.0
2.6
2.4
N 30 30 30
4 X DIFF
0.0
2.4
1.9
N 30 30 30
S X DIFF
0.0
2.6
1.8
H 30 30 30
6 X DIFF N
0.0 30
3.7 30
2.2 10
1100.0000
2.7 30
0.4 30
-0.8 30
1.3 30
-0.2 30
-0.2 30
0.9 30
1.8 30
CMA 118822
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P, 11/18
T 3-2
96-4080
TABLE 3 (cent.)
VINYL CHLORIDE COMBINED INHALATION TWO-GENERATION REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
draft
* DIFFERENCE IN BOOT WEIGHT
males
DOSE LEVEL! WH
WEEK
0.0000 10.0000 100,0000
7 X DIFF N
0.0 30
3.8 2.6 SO 30
1100.0000
l.r 30
CMA118823
FEB-27-97 THU 02:]] pm HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P, 12/18
t s-s
96*4080
TABLE 3 (cent.) VIJlyL CHLORIDE COMBINED INHALATION TIAD'GENBRATlON REPRODUCTION
AND DEVELOPMENTAL TOXICITY STUOT IN CD RATS
`A DIFFERENCE IN BODY WEIGHT FEMALES
DOSE LEVEL: PPM
0.0000
10.0000
100.0000 1100.0000
DIFF N
DIFF H
DIFF N
DIFF N
DIFF N
DIFF N
DIFF N
DIFF N
0.0 30
0.0 30
0.0 30
0.0 30
0.0 30
D.O 30
0.0 30
0.0 30
2.0 30
0.3 30
1.9 30
0.5 30
*1.6 30
*1.6 30
*2.1 30
-1.2 30
0.4 30
-1.1 30
0.6 30
1.4 30
0.6 30
O.S 30
0.0 30
0.6 30
-2,1 30
0.6 30
0.7 30
0.4 30
-O.S 30
-0.3 30
2.2 30
-1.3 30
.O
CMA118824
FEB-27-97 THU 02: PM HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P. 13/18
T 3-4
96-4060
VINYL CHLWIOE COMINEO lwALATJOH TWO-GENERATION REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDY JR CD RATS
draft
* DIFFERENCE )N SCOT WEIGHT FEMALES
DOSE LEVEL) PPM
WEEK
T X DIff N
0.0000
0.0 30
10.0000
2.0 30
100,0000
0.4 SO
1100.0000
-2.1 30
CMA 118825
FEB-27 -97 THU 02M1 PM HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P. 14/18
T 4-1 TABLZ 4
94-4060
VINYL CHLORIDE COHIINED INHALATION TWO-GENERATION REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
STAT SYMBOL;
WEEK
fOCO CONSUMPTION O/ltC/DAY PEMALES
DOSE LEVEL: PPM
0.0000
10.0000
100.0000 1100.0000
A-L-
0 MEAN S,D. N
131.8 5,9 29
133.S 9.4 29
134.9 7.8 28
134.9 8.0 26
AL-Q
1 MEAN 107,4
S.D.
5.2
N 30
104.3 5.4
28
109.2 8.7 29
105.4 6.7 27
K-J
2 MEAN 103.6
103.9
105.9
103.9
S.P.
10.3
5.5
9.5
8.6
N 30 30 30 30
A-L-
3 M$E.0AN.
N
94.3 5.2 30
94.7 6.2 30
96.9 5.8 30
96.9 6.3 29
A-L-
4 MEAN S.D. N
90.3
5.6 30
89.0
4,9 30
92.2 5.9 30
90.6 5.9 30
K-JA+L-O*
5 MEAN S.D. N
85.8 4.3
30
6 MEAN S.D. N
79.4 S.4 29
87.6 5.6 30
84.9 5.7 30
87.6 7.0 30
*
84.7 6.0 30
87.1 7.8 30
*
85.0 3.6 30
A-L-
7 MEAN S.O. N
77.6 5.9 30
76.5 5.7 30
76.5 5,0 30
77.7 6.1 30
CMA 11882f
FEB-27-97 THU 02:11 PM HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P. 15/18
>p 96-4060 TABLS 4 (COWT.)
VIWYL CHLORIDE COMBINED INHALATION TWO-GENERATION REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDY IN CD RATS
STAT SYMBOL:
Al-S
FOOD CONSUMPTION O/XO/DAY MALES
DOSE LEVEL! PPM
WEEK
0.0000
0 MEAN S.D, N
122.6 6.2 29
10.0000
125.1 4.4 30
100.0000
# 127,1
5.1 30
1100.0000
124.8 6.6 30
A-LA+L-8+ AL-0+
1 MEAN S.D. N
98.3 4.8 30
2 MEAN S.D. N
86.7 6,3 30
3 MEAN S.D. N
78.5 3.2 30
98.8 4.0 30
89.3 3.9 30
79.1 3.5 30
99,5 4.9 30
WW 91,2
4.3 30
** 82.1
3.8 30
97.0 4.8 30
89.1 4.7 SO
80.3 3.8 30
A-LAL* AL-Q AL-
4 MEAN S.D. N
72.7 3.1 30
5 MEAN S.D. N
68.6 2.7 30
& MEAN S.D. N
62.6 4.6 30
7 MIAN S.D. N
60.2 3.7 30
72.5 3.9 30
69.5 3.5 29
w 66.0
3.4 29
61.0 2.3 30
73.3 3.2 30
70.3 3.5 30
65.0 6.0 30
+ 62.4
3.5 30
73.2 3.5 30
* 71.4 3.8
30
# 65.6
3.9 30
* 62.3
3.5 30
CMA118827
FEB-27-97 THU 02:11 PH HUNTINGDON LIFE SCIENCES FAX NO. 908 873 3992
P.16/18
w DRAFT 96-4080
J,
Appendix A
Vinyl Chloride Combined Inhalation Two-Generation Reproduction
and Developmental Toxicity Study in CD Rats
Methodology and References - Statistical Analysis
Parameters analyzed statistically for this status report: body weights and food consumption
MULTIPLE GROUP ANALYSIS STAT SYMBOL
No Slq pao.05 pgQ.Ol Parametric
A-
A A+
L-
L L+ Q 0+
n **
STATISTICAL STATEMENT
No statistical differences among the means (parametric ANOVA). The means differ significantly (parametric ANOVA). The response is not linearly related to the dose levels. The response is linearly related to the dose levels. The response shows a lack of fit. Significantly different from control (Dunnett's).
CMA118828
FEB-27-97 THU 02:12 PN HUNTINGDON LIFE SCIENCES FAX NO, 908 873 3992
P, 17/18
A-2
Appendix A (cant.)
96-4080
Vinyl Chloride Combined Inhalation Two-Generation Reproduction
and Developmental Toxicity Study in CD Rats
Methodology and References Statistical Analysis
MULTIPLE GROUP ANALYSIS STAT SYMBOL
No Siq 0=0.05 p=&.01 tonparametric
K-
K
J
NT
STATISTICAL STATEMENT ""
No statistical differences among the means (Kruskal-Wallis, nonparametric). The means differ significantly (Kruskal-Wallis nonparametric). There is not an ordered response to dosage. There is an ordered response to dosage. Significantly different from control (Dunn's Rank Sum). Not tested due to lack of variance.
Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed. First, Bartlett's test was performed to determine if groups had equal variance. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. The parametric procedures were the standard one way AN0VA using the F distribution to assess significance. If significant differences among the means were indicated, Dunnett's test was used to determine which means were significantly different from the control. If a nonparametric procedure for testing equality of means was needed, the Kruskal-Wallis test was used, and if differences were indicated a summed rank test (Dunn) was used to determine which treatments differed from control.
CMA 118829
i ( FEB-27-97 THU 02:12 PM HUNT1NGD0M LIFE SCIENCES FAX NO. 908 873 3992
P. 18/18
A-3 DRAFT
Appendix A (cont.)
96-4080
Vinyl Chloride Combined Inhalation Two-Generation Reproduction
and Developmental Toxicity Study in CD Rats
Methodology and References - Statistical Analysis
A statistical test for trend in the dose levels was also performed. the parametric case (i.e., equal variance) standard regression techniques with a test for trend and lack of fit were used. In the nonparametrfc case Jonckheere's test for monotonic trend was used.
In
The test for equal variance (Bartlett's) was conducted at the 1%. two-sided risk level. All other statistical tests were conducted at the 5% and !*, two-sided risk level.
References for these techniques are Snedecor, G.W., and Cochran, W.G., Statistical Methods. 6th edition, Iowa State University Press (1967);
Hollander, M. and Wolfe, D.A., Nonporametric Statistical Methods. John Wiley and Sons, New York (1973); Dunnett, C.W., J. Am. Sta. Assn. Vol, 50 (1955) and Biometrics. Vol. 20 (1964).
Bartlett's Test
pp. 296-298
anova
pp. 277-279
Dunnett's
PP- 1096-1121
pp. 482-491
Kruskal-Wallis
pp. 114-116
Summed Rank Test (Dunn) P- 131 Regression Analysis
Trend Lack of Fit
PP- 135-153 pp. 456-459
Jonckheere's Statistic PP- 120-123
S&C S&C D Bio H&W H&W
S&C S&C H&W
CMA118830