Document 8R5X9R895YB1285Gp2jYdOVQ5
R&S 112381
bio-medical.research DOCUMENT DESCRIPTION POEM
63
Duplicate.in all cards:--> year as-1961-
File number [Right justify [Numeric only]
Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space
1 Cti/0
20 21
40 41
77 78
Sub-Index Code
60 61 62 11 12 13
Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms,
separated from each other with comma-space. Avoid other punctuation;
do not abbreviate..
12
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Source (Journal, Vol., Number, Pages, Date )
12
61 62
Brief Summary
12
10
SUMMARY:
61 62
61 62 63 64
R&S 112382
UUJ CENTRAAL INSTITUUT VOOR VOEDINGSONDERZOEIC
Utrachueweg 48 Zelft
ONTHAL WfTTTVTl PO NUTRITION ANO ROOO MSSARCH INCTTTUT CSNTRAL D LA NUTRITION IT DC L'AUMCNTATION ZINTRAUNTTTTUT K)R IRNAHRUNGttORSCHUNG
Chronic (two-year) oral toxicity study with vinyl chloride in
(Interim information III) 1. Conduct of the study
0000372
See Interim Information of 15th December 1975, given in Enclosure I.
Vinyl chloride-treatment by gavage was discontinued in week 84 be
cause the condition of the rats given 300 mg vinylchloride/kg body weight
was rapidly declining and mortality in this group was high (55 Z). More
over, most of the rats of this group that died or were killed in extremis
showed extensive liver damage (haemorrhages, focal necrosis), liver tumours
or tumours at other sites.
2. Results available after a test period of 90 weeks
2.1.Body weights
Not affected.
2.2. Food consumption
Not distinctly affected.
2.3. Mortality
VCM (mg/kg body wt)
Total number of deaths*) at week 90
males
females
02
13
36
lU
9 300 (by gavage)
20 _ 46
-
Qoco - i
*) Initial number of rats: 60 animals/sex/group
Zb -MVl'
2.4.Haematology
5 4 16 40__ 44
Slightly decreased haemoglobin values in males of the 9 mg/kg group after 78 weeks.
2.5.Blood biochemistry
No indications of an adverse effect of vinyl chloride. See also Interim information II, given in enclosure 2, S 2.5.
<mM of fadoaicaUjka pubMod* van 4k rapport to node rahrtfcd|lra aoaattmMtng vartooSan. Tool or partial pvbliroilun of ttoto rapora wdthooc nrluaa anani la not dlmaag.
R&S 112383
CiNTMAAL INSTITUUT V * V CDINGSONOERZOEK
uCD -2-
2.6.Liver function See Interim information II, given in enclosure 2, $ 2.6.
2.7.Urine analyses No indications of an adverse effect of vinyl chloride. See also Interim information II, given in enclosure 2, S 2.7.
2.8.Liver and kidney weights See Interim information II, given in enclosure 2, S2.8.
2.9. Pathology 2.9.1.Rats_kille after 26_and_5 weeks
See. Interim information II, given in enclosure 2, S 2.9.1 2.9.2.Rats_found_dea<i or_kille<i vhen_moribund
See above table for mortality figures.
Gross autopsy findings allow the following preliminary information on both the occurrence of presumable tumours and the number of rats bearing these lesions (in some cases the gross diagnosis was confirmed by histo logical examination):
Control group:
Thymic tumour Mammary tumour Leukaemia Cervix tumour
1
I mg/kg group:
Thymic tumour Uterus tumour Lymphoreticular tumour Mamnary tumour Abdominal tumour .
--, f
3 mg/kg group:
Liver nodules (tumours ?) Subcutaneous tumour Uterus tumour Pituitary tumour Mammary tumour Ovarian tumour
7 I
2
3-
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CINTRAAL INSTITUUT V A V EDINGSONOERZOCK
CCD
-3-
I
9 mg/kg group: 300 mg/kg group:
Liver nodules (tumours ?) Pancreas tumour Thymic tumour Lymphoreticular tumour Mannary tumour Pituitary tumour Subcutaneous tumour
^ c>
4( I 1 2 2 I I
Liver nodules/haemorrhagic cysts (tumours ??)
40
Pancreas tumour
3
Pituitary tumour
I
Lymphoreticular tumour
4
Pulmonary nodules/haemorrhagic lesions (tumours ?) 9
Nodules aer-duct area
2
Abdominal tumour
I
Manmary tumour
10
Kidney mass (tumour ?)
*
3. Preliminary conclusion
From the results so far available it appears that the administration of
vinyl chloride monomer to.rats at levels of 9 (as PVC-povder in diet) and
300 mg/kg body weight (in soyaoil by gavage) resulted in obvious liver changes
which in many cases seem to be neoplastic in nature. Moreover, 'there are in
dications that similar lesions also occur at the 3 mg/kg level, but so far
are absent at the 1 mg/kg level. --
--
19 October 1976
R&S 112385
BIO-MEDICAL RESEARCH
DOCUMENT DESCRIPTION FORM 63
68 69
76
Duplicate.in all cards: -P
kj?J 1 nnnxL37-a
year as-1961- FUe number
[Right justify
[Numeric only]
Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space
1 a/t/t
20 2140 4160 61 62 T7U'#
77 78
II
Sub-Index Code
Title of Report: end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation;
Source (Journal, Vol., Number, Pages, Date )
12_____________________
C/M
7~A/<?
Brief Summary
12
10
SUMMARY:
61 62
nn
32
61 62 61 62 63 64
Attachment Nr. 1 CENTRAL INSTITUTE FOR NUTRITION AND FOOD RESEARCH TNO
Chronic oral toxicity study with vinyl chloride in rats (Interim information IV)
C i3 H -.
V. cr.
R&S 112386
l. Conduct of the study
0000373
Six hundred weanling albino rats (Uistar strain from the SPF-
colony of the Central Institute for the Breeding of Laboratory Animals
TNO, Zeist, The Netherlands) were divided into five groups of 60 males
and 60 females each. The control group is fed a diet containing I0Z
PVC-powder free from vinyl chloride monomer (VCM). Three of the test
groups are fed increasing levels of VCM-containing PVC, which is added
to the diet at the expense of VCM-free PVC et levels resulting in a
daily intake of approximately 1, 3, and 9mg VCM/kg body weight.
The diets are freshly prepared daily just prior to use and the animals
are allowed to eat them during a period of four hours each day.
The fourth test group fed on etock diet received VCM in soya bean oil
by gavage at a relatively high level (300mg VQl/kg body weight) once a
day, five day* a week* This group was merely added to find out whether
oral administration of VCM at a high laval results in tumours.
For this group a real control group is not svsilable. Nevertheless,
a number of criteria studied in the other groups are also examined in
this high-dose group.
Both the control group end the 9 and 300mg VCM/kg body weight
groups were extended with 20 male end 20 female rats, of which ten
males and ten females are killed for interim information after six
and twelve months respectively.
Body weights, food consumption, haesiatology, urine analyses,
biochemistry of the blood, organ weights, gross pathology, extensive
histopathology, enzyme histochemistry and electron microscopy are
used as criteria to disclose possible harmful effects.
An extra control group of 60 males and 60 females was added.
This group is fed on stock diet containing 10Z PVC-powder without VCM.
The animals are housed in a room separate from that used for the other
rats in the VCM experiment, thus preventing any contact of the rats
with VCM. Moreover, these rats are fed the PVC diet ad libitum.
Organs and tissues of all animals are preserved in formalin, and
examined histologically only if necessary.
-2-
Treatment by gavage with vinyl chloride was discontinued in week 84 because the condition of the rats given 300mg vinyl chloride/kg body weight was rapidly declining and mortality in this group was high (55Z). Moreover, most of the rats of this group that died or were killed in extremis showed extensive liver damage (haemorrhages, focal necrosis), liver tumours or tumours at other sites.
Results available after 104 weeks 1. Body weights
R&S 112387
VCM (mg/kg body wc)
0 1 3 9
Average body weights (g) at week 104
stales
Females
380 231 399 231 395 238 381 224
300 (by gavage) 0 (extra group)
458 568
/
Food consumption
Not distinctly affected in main study,
270 352
Mortality
VCM (mg/kg body wt)
36
00 10 30 9l
300
(by
*) gavage)
6
0 (extra group) 0
Total number of deaths
60 80 104 males
36
007 1 16 I 2 13 5 9 40
0 0 1 0
at week 60 80 females
01 I2 27 27
1C4
7 13***) 31 60
8 21 53 0 1 19
4 8 24 56 0 3 4 20
*) Initial number of rats: 60/sex/group **) Treatment discontinued in week 84
-3-
2.4.
Haematology Slightly decreased haemoglobin values in males of Che 9mg/kg group
after 78 and 94 weeks. Decreased packed cell volume, increased number of white blood
cells, decreased Z of lymphocytes and increased Z of neutrophils in males of the 9mg/kg group after 94 weeks.
2.5.
Blood biochemiscry
No indications of an adverse effect of VCM (the results of several enzyme activity determinations after 104 weeks were not yet available).
2.6. Liver function (determined in rats killed after 26 and 52 weeks) Slightly decreased clotting time and BSP-retention at the-
9mg/kg level both after 26 and 52 weeks.
2.7.
Urine analyses
Slightly increased UGOT-values were found in females of the 3 and 9mg/kg groups after 13 weeks, and in females of the 9mg/kg group after 52 and 94 weeks, but not after 26 and 78 weeks.
After 78 and 94 weeks the pH of the urine was slightly lower and the number of bacteria in the urine was slightly higher in the 9mg/kg group chan in controls and lower-dose anistals.
2.8.
Liver and kidney weights (determined in rats killed after 26 and 52 weeks) Liver-to-body weight ratios were slightly increased in males
and females of the 9mg/kg group both after 26 and 52 weeks. Relative kidney weights were not affected after 26 weeks, but were slightly increased in females of the 9mg/kg group after 52 weeks.
2.9. 2.9.1.
Pathology
Rats killed after 26 and 52 weeks The livers of several male and female rats of the 9 and 300mg/kg
groups killed after 26 and 52 weeks showed one or a few foci of cellular
R&S 112388
4-
alteration mainly being'blear cell foci". Degree and incidence of these liver changes were slightly higher a) after 52 than after 26 weeks, and b) in animals of the 9mg/kg group than in those of the 300mg/kg group (receiving VCM in oil by stomach tube!). In addition, after 52 weeks one male and one female of the 9mg/kg group had a hepatocellular carcinoma. Moreover, several females of the 9mg/kg group showed focal cystic hyperplasia of bile ducts (cystadenomas or adenofibrosis?).
Rats found dead or killed when moribund
CROSS PATHOLOGY (at 110 weeks)
Preliminary information on gross autopsy findings concerning the
occurrence of presumable tumours ("t). Numbers of rats examined are
given in parencheses.
Control group
Males (8):
Thymic t
I
Lymphoreticular lung t
Females (7): Lymphoreticular abd. t
Subcutaneous t
l
Uterine t
1
Cervix t
2
Mammary t
2
Enlarged adrenals
Img/kg group
Males (7):
Thymic t
1
Subcutaneous t
Females (13): Liver nodules (tumours ?)
Pancreas t
Mammary t
5
Uterine t
3
Cervix t
Thymic t
Lymphoreticular abd. t
Enlarged adrenals
3
R&S 112389
3mg/kg group
Males (14): Liver nodules (tumours?)
Leukaemia
Subcutaneous t
Thyroid t
Zymbal gland t
Females (31): Liver nodules (tumours?)
Pituitary t
Cervix t
Mammary t
Subcutaneous t
Ovarian t
Zymbal gland t
Uterine t
9mg/kg group
Males (41): Liver nodules (tumours?)
Pulmonary nodules
Lymphoreticular abd.t
Thymic t
Zymbal gland t
Pancreas t
Mammary t
Subcutaneous t '
Females (60): Liver nodules (tumours?)
Pituitary t
Mammary t
Pulmonary nodules
Subcutaneous t
----
f
- Uterine t . --- ---- Abdominal t Pancreas t
I 2 I 1 I 20 1 1 6 1 1 1 3
25 6 4 1 1 1 1 1
56 4 13 5 1
-63 2
Bo
CO
6 Z ll
0)
112391
300mg/kg group
Hales (60): Liver nodules (tusiours?)
Pulmonary nodules
Subcutaneous t Zymbal gland t
Mansary t
Kidney t (?)
Abdominal t
Thymic t
Pituary t
Enlarged thyroid
Females (60): Liver nodules (tumours?)
Pulmonary nodules
Pituitary t Mannary t
Pancreas t Kidney t
Zymbal gland t
Uterine t Abdominal t
Subcutaneous t
Enlarged adrenals
Extra control group
'
Males (13): Leukaemia
Abscess in Liver (?)
Lymphoreticular abd. t
Enlarged adrenals
Enlarged thyroid
TM Females (16): Mammary t
Pituitary t
Uterine t
Lymphoreticular lung t
Enlarged adrenals
32 20
1 1 2 2 3 1 1 6 31 16 7 14 1 1 3 2 1 1 6
2 1 1 2 I **4 3 3 1 1
JJ (/) io w
CroO
j
<
i
A
-7-
MICROSCOPIC PATHOLOGY Preliminary information on histological examination of several
tumours of animals of various groups. Number of animals examined are given in parentheses. Control group
No microscopic examination.
1mg/kg group Males (1): Females (1):
Thymic fibrosarcoma Uterine adenocarcinoma
3mg/kg group
Males (2):
Leukaemia
Females (5): Uterine leiomyosarcoma
Hyperplastic liver cell nodule
with atypia
Reticular -cell sarcoma
Pituitary carcinoma
9mg/kg group Males (8):
Hyperplastic liver cell nodule with atypia
Angiosarcoma in liver/pancreas
Subcutaneous sarcoma
/
Abdominal sarcoma
Females (21); Hyperplastic liver cell nodule
with atypia Hepatocellular carcinoma
Hepatic angiosarcoma
Pituitary adenoma "* "" Mammary adenocarcinoma
Mammary fibroadenoma
Mammary adenoma
Uterine adenocarcinoma
Uterine polyp
Adrenocortical adenoma
Mesothelioma
300mg/kg group Males (16):
Hyperplastic liver cell nodule with atypia
Hepatic angiosarcoma
Leukaemia
6 8 5 3
T
2 1 1 2
I
8-
Females (20): Hepatic angiosarcoma Pulmonary angiosarcoma Mammary adenocarcinoma Mammary fibroadenoma Uterine polyp Abdominal lymphoreticular malignancy
Extra control group
No microscopic examination.
8 1 2 1 1 1
Remark: Many of the hepatic angiosarcomas had metastasized to the lungs. Occasionally it was difficult to discriminate between primary pulmonary angiosarcoma and metastasis from hepatic angiosarcoma.
3. Preliminary conclusion From the results so far available it appears that the administration
of vinyl chloride monomer to rats at levels of 9 (as PVC-powder in diet) and 300mg/kg body weight (in soya oil by gavage) resulted in obvious liver changes including hepatocellular carcinomas and angiosarcomas. Similar lesions are, very probably, also present in rats of the 3mg/kg
/ group. Whether this type of hepatic changes also occurs at the lmg/kg . level is not yet clear.
CIVO-TNO 4.2.1977JF
R&S 112393
<>
Attachment Nr. 2
t
EEDCENTRAAL INSTITUUT VOOR VOtDINGSONDERZOEK
CENTRAL INSTITUTE FOR NUTRITION ANO FOOD RESEARCH
lltrachuewet 48-ZEIST The Netherlands Telefoon (03404) 16411 Pojtjiro no. 271906
POSTB'JSoAO
P.0. B0X-'ow
Verbend Kunscstofferzeugende Industrie e.V z.H. Herrn Dr. H. Bornemann 6 Frankfurt om Main Karlstrasse 21 (Chemie-Rsus) Deutschland.
uw Mr:
uw DATUM: 21,12.1977 <>**= 7383 VF/F
18th January, 1977
R&S 112394
Dear Dr Bornemann,
Chronic oral toxicity atudy with VCM
Thank you for your letter of 21st December, 1976 authorizing us to continue the long-term oral study with VCM.
After discussions at CXVO and following contacts, by telephone with Dr Weigand (Boechst), Dr Jager (Shell) and Drs van Each (RIV) I should like to mention the following points:
1. Shell will continue to provide us with PVC powder.
2. The study will be terminated and the remaining animals killed and au-
copsied either, when only 25Z of the controls are still alive, or when all
test animals are dead. If there is an appreciable difference in mortality
between males and females, the experiment will be stopped for males and
females at different points of time. A complete histopathological examina
tion is done on 20 males and 20 females of the control and two highest dose
groups. The rats to be used for this examination are survivors and/or
animals killed at a late stage of the experimental period. Histological
examinations of the other animals are carried out according to the original
plan.
cont..........
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M udi wMUk tat Wqavat .W ladara MntankalaMi*'*
dartia. aaa M *t*nr M4jM ***** a* vaar wa ***** ***** M/a( art* -a**I alwaM.
Warfc lar aa* taaatar 4 afaia* eat aalr an candiuoa tint Ufa..........ir c*np*rni* fMaaatat ill m** t* Ml* tfc* tafaawi ***** Bfafa. --4 MMfaaeaaaaka t* M tha laar bttatfatt fra* an, tufalnr taetr* <*** anfa. Naanar tan*imn lAaR tatty a. in* * tn. aatett fan. efcara aa a* Mae* ta MM aaaa atfflcaaaa aaa/ar *4fal raraat
CIVO-TNO; 7383 VF/F; 18.1.1977.
2- -
The additional costs are Ofl 30.-/rat/month. For the first month (10th Jan. to 10th Feb. 1977) the cost is estimated to be about Dfl 9,500.- . Bills covering the extra costs are sent once every three months.
3. Because many of the test animals still alive are expected to have liver nodules (tumours?), it might be important to determine once or twice (e.g. after 25 and 28 months) the a fetoprotein content of the blood serum.
The costs are at most Dfl 2,500.- for one determination in all rats and Dfl 4,500<- for two determinations in all rats. 'J
4. Persorption of PVC particles has been reported to occur in rats, chickens, dogs, and pigs (Volkheimer, Ann. N.Y. Acad. Sci., 246, 1975, 164-171) following oral administration of PVC powder. We feel that it might be of interest to do some observations on possible persorption of the PVC powder used in our long-term study. Therefore, we propose to make an attempt to trace PVC particles in the blood and several other organs of a few rats given PVC powder suspended in soya been oil by gavage.
The costs are at most Dfl 2,500.-,
'
5. With reference to our letter of 24th April, 1975 (8875 FE/WW) I should like to bring to your attention the additional control group fed on stock
3 diet containing 10Z PVC powder without VCM and housed in a room separate
from that used for the other rata in the long-term VCM experiment. So far, --=* VKI and the other participating industries have not been charged for costs
attached to the keeping of this group of rats. Therefore, we hope you have no objections to CIV0 shortly sending bills together amounting to 1Dfl 19,200.-. This amount represents 407 of the maximum total costs going with the maintenance and complete examination of this extra group (see also the above mentioned letter). The mortality in this group is low, after
cont
R&S 112395
CIVO-TNOj 7383 VF/F; 13.1.1977.
-3-
an experimental period of two years, and ue propose, therefore, to continue this group also. The additional costs are Dfl 20.-/rat/month. For the first month the costs are estimated to be Dfl 2,100.-.
We should highly appreciate your informing us at short notice whether you can agree to the above suggestions.
With kind regards.
Yours sincerely,
CENTRAL INSTITUTE FOR NUTRITION
Dept Biological Toxicology
R&S
IO CO CO