Document 0gROm3RrEwgXxrDdLrkBB7Dvk
CHEMICAL MANUFACTURERS ASSOCIATION
December 17, 1981
Environmar.ts! Affairs
TO: EDC Program Panel and Toxicology
After continued persistence and another letter from CMA's legal department, Montedison finally responded to the deficiencies identified in Dr. Shah's letter of July 2, 1981. A copy of the response is enclosed along with a ballot for you to indicate whether the information provided is sufficient to warrant making the final payment of $19,500 to Dr. Maltoni.
If the enclosed submission from Dr. Maltoni is acceptable, CMA will compile, for your review and approval, all information received from Dr. Maltoni since our earlier submission to the Government Agencies prior to sending a final package to government agencies.
Yours truly.
Robert J. Fensterheim Administrator Ethylene Dichloride Program
Enclosures: 12/1/81 letter from Luigi Chiechi to Patrick Joyce 11/5/81 letter from Patrick C. Joyce to Luigi Chiechi 7/2/81 letter from Hasmukh C. Shah to Luigi Chiechi
Formerly Manufacturing Chemists Association --Serving the Chemical industry Since 1872 ?5Ci M S^ee* NW Wasmngfnr* DC 2003" * Telephone 202 887-1 IOC Telex 896''"' fCMA W5H
SL 080595
CHEMICAL MANUFACTURERS ASSOCIATION
July 2,- 1981
Luigi Chiechi Coordinamento Kedicina e Ambiente
Montedison Via Appiani, 12 20120 Milano
Italy
Re: Ethylene Dichloride Bioassay EDO l.O-TOX-MA/SP
Dear Mr. Chiechi:
CMA's panel of scientific experts has examined your
correspondence of March 10, 1981. The information provided by Dr. Maltonl has aided CMA's scientific panel's under
standing of the long term inhalation study on rats and mice with ethylenedichloride. However, there are still two
items which require further attention.
Dr. Maltoni stated that the treatment period.for both
rats and mice was 78 weeks. Furthermore, his response
indicates that the rats and mice were held'and observed until IbS and 119 weeks, respectively (end of experiment).
The tables in the final report do not state the duration of the study. All the tables in the final report must be
replaced by corrected ones which agree with those presented in the Banberry Report. Since the method section also in
correctly describes the treatment and duration, this must
be corrected. A statement of the actual exposure levels (including
standard deviation) is important. A statistical analysis
Including the "T" test must also be conducted to verify that each exposure level was significantly different.
Upon receipt of this supplemental information, CMA will make the final payment on the contract.
Sincerely,
i~l CLsrm
^
H. Shah, Ph. D. Director, Special Programs
Forme rly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 7501 M Street NW Washington. DC 20037 Telephone 202/687-1100 Tele* B9617 (CMA WSH)
SL 080596--
CHEMICAL MANUFACTURERS ASSOCIATION
* * .. / .
November 5, 1981
Luigi Chiechi Coordinamento Medicine e Ambiente Montedision Via Appiani, 12 20120 Milano Italy
RE: Ethylene Dichloride Bioassay EDC 1.O-TOX-MA/SP
Dear Mr. Chiechi:
On July 2, 1981, Dr. Hasmukh Shah of CMA wrote you the attached letter. As explained in that letter, and previous correspondence, CMA is withholding the final payment of $19,500 until several deficiencies in the final report are corrected.
If Montedison does not respond within thirty days (30), CMA will terminate the contract. We are under no-obligation to wait any longer for the completion of the report which is long overdue. The repeated failure of MorilSdison to complete the Agreement constitutes a material breach of the contract.
Sincerely
i Patrick C. Joyce Staff Attorney
Enclosure
cc: Cesare Maltoni Bolgna Tumour Centre 40138 Bologna, Italy
Professor Puglialunga Medicina e Ingiene del Lauoro Tossicolgia Industriale Montedison Via Appiana, 12 20121 Milano, Italy
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Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872.
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SL 080597
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Chemical Manufacturers Association 2501 M Street, N.W. WASHINGTON, D.C. 20037 U.S.A.
DATA 1.12.1981
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RACCOMANDATA-ESFRESSO
Att.: Mr. Patrick Joyce Staff Attorney
Dr. H. Shah, Ph. D. Director, Special Program
Re.: Ethylene Dichloride Bioassay.
Our telex of December 1, 1981, has already given some of the results concerning the actual concentrations of the above mentioned study (enclosure).
Attached you will find the report with the complete set of actual concentration data, statistically eva luated, and some amendments to the Final Report. These two items are in answer to the last questions that had not yet been clarified concerning the Ethylene Dichlo ride Final Report, as per Dr. Shah's letter of July 2,
1981 .
Concerning the Final Report Tables (to be replaced ac cording to Shah's request), Prof. Maltoni saw that the tables in the Bambury report are the same as in the Final Report.
The only point which could be misunderstood is the du ration of the study defined in the tables as end of experiment.
SL 080598-
f monTEoison 2.
/. . / ..
Therefore he decided to remove the possible misundertanding by amending the sections Materials and Methods (1.2) and Results (1*3) of the Final Report (enclosure). Prof. Maltoni has assured us that the raw data are readily available for inspection at his Institute, if required, and has pointed out that to furnish the last set of information he had to re-examine the raw data, which consist of miles of gas chromatographic tracings. Best regards
l__ . CsCu '*
Luigi Chiechi
Enel./
SL 080599*-
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APPENDIX
Mad. S. C. 3
dies on long-term effects on rats and mice of Ethylene Dioride, administered by inhalation.
Dose levels /
Tables 1 and 2 report the nominal and the actual concentra
tions used for the EDC inhalation study.
I The actual concentrations represent the average of the ana
lyses performed for 78 weeks of the inhalation period.
Each concentration was analysed by G.C. in 2 minutes every
12 minutes, i.e. 35 times per day of treatment.
The concentrations were statistically evaluated by "t test"
(l). Each concentration was significantly different (p<O.Ol).
A^lso reported are the coefficients of variation (CV) for each
concentration used. The CV represent the percentage of varia
tion of the actual concentration for the total period of inhji
lation. CV was calculated from 6/ji , where
is the Standard
Deviation of the Mean ( ji) .
Tables 3 and 4 report the actual concentrations, at monthly
intervals, of the EDC analyses performed during l8 months of
inhalation.
(l)
Snedecor, G.W. and Cochran, W.G. - Statistical Methods The Iowa State University Press - Ames, Iowa, U.S.A. Sixth Ed. - 1067 - p. 59-
SL 080600
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B. Amendments to the Final Report.
1. In the Final Report p. 2 Section 1.2, line 13 for: "The pe riod of treatment was 24 months for rats and 18 months for mice", read: "The period of treatment was 7? weeks for rats and mice".
2. In the Final Report p. 2 Section 1.2, line 18, 8th paragraph after: "All the animals were kept under observation until spontaneous death." add: "The spontaneous death of the last animal is the end of the experiment, i.e., duration of th study".
3. In the Final Report p. 3 Section 1.3, after 1st line: "The entire project lasted 148 weeks." add: "All mice were dead
v within 119 weeks while rats were dead within 148 weeks." These time periods are defined in the tables as "end of experiment".
SL 080601--
1
TABLE
1
Nominal and actual concentrations (ppm)-, difference and coefficient of variation (C.V.) of dose levels used in the rat study (BT 501)
Group
Nominal
Concentration (ppm)
Actual (M ^ S.D.*)
Difference (50
C.V. (%)
I **
II III IV
250' 150
50 10
5
233.9 + 15.4 148.3 + 5-0
49.9 + 2.3 10.1+ 0.5
5-1 1 0.6
6.-44 1.14 0.20 1.00 2.00
6.58 3.38 4.60 4.90 11.63
* ^ Z. S.D. Mean +_ Standard Deviation
2 50 ppm was reduced to 150 ppm due to signs of toxicity: ruffling of hair, hypomotility and loss of muscular tone.
SL 080602
\
TABLE
2
* ,. / . ,
Nominal and actual concentrations (ppm), difference and coefficient
of variation (C.V.) of dose levels used in the mouse study (BT 502)
Group il
N'ominal
Concentration (ppm)
Actual (M * S.D.*)
Difference (56)
C.V. (56)
I ##
11
III IV
250 150
50 10
5
255-0 *** 149.5 + 4.8
50.0 + 1.5 10.2 + 0.4
5.0 + 0.4
0.34 0.00 2.00 0.00
3-22 3-06 3.71 8.47
* M ^ S.D. Mean
Standard Deviation
*" 2.50 ppm was reduced to ISO ppm due to signs of toxicity: ruffling of hair, hypomoti1 ity and loss of muscular tone, showed by mice after two days of exposure.
Mean of two days of exposure.
SL 080603
TABLE .3
Monthly mean chamber concentrations of 1,2-Dichioroethane in the rat study (Mean *_ Standard Deviation) (BT 501)
Mont h
2 53 0'/ 1 50 *
PF m 50
10
5
1 O !
3
4 5 6
7 8
9 10 11 12 1* 14 15 16
17 18
234.8 + 19.4
231.3 + 12.4
235.4 + 13.9
151 *3 +, 151.3+ 151-3 i
2.2 2.2 2.2
147.5 + 2.5 140.0 +_ 14.6
140.0 _+ 2.0
145*0 +_ 3-5
1 51 . 3 +. 150.0 <
2.2 n.3
151.3 i 2.2
147.0 ^ 5.9
150.0 +_ 3.5
147.5 z 2,5 143.8 + 4*2
148.8 i 2.2
54.5 + 3-0 50.4 + 0.8 52..0 + 1.4 50.5 + 0.5 51.2 + 0.8 50.0 + 0.6 49.8 + 0.4 49*8 + 0.4 50.0 + 2.1 51.0 + 0.7 49.5 1 2.1 4`.0 3.1 49-5 +, 0.9 51.0 + 0.7 47.8 + 7-5 50.3 1 0.4 48.5* 1-7 44.5 1 3-2
. 9.5 0.5 10.3 i 15 11.5 1 1.1 10.0 + 0.2 10.1 + 0.6 10.1 +.0.3 10.2 + 0.2 10.0 + 0.1 10.0 + 0.1 10.0 + 0.2
9.9 +_ 0.3 10.0 +_ 0.4 10.3 +, 0.3 10.1 _+ 0.3 10.1 +0.1 10.2 +_ 0.1 10.0 + 0-2 10.1 +_ 0.2
5-8 + 1.3 6.5 _+ 1.5 5.0 + 0.0 ^> * 0 t 0.0 4.9 + 0.5 5.5 + 0.5 5.2 j+ 0.6 5.3 1 0.4 4.3 + 0.4 4.6 + 0.6 5.2 +, 0.6 5.1 +. 0.4 4*6 + 0*4 5.0 .+ 0.2 4.8 + 0.3 4.9 ^ 0.2 5.0 +_ 0.2 5.0 j+ 0.0
* 2 50 ppm was reduced to 150 ppm due to signs of toxicity (ruffling of hair, hvpomotility and loss of muscular tone).
SL 080604
TABLE
4
Monthly mean chamber concentrations of. 1,2-Dichloroethane in the mouse study (Mean + Standard Deviation) (BT 502)
'
Mont h
250/,1 so
PP m 50 10
1 * 255-0
50.3 + o.S
JO.3 2 -7
n
155.5 i 2.4
51.0 +_ 2.2
10.3 + 0.4
*
146-5 2. 4-2
49.5 1 1.5
10.6 2 .3
4
151.3 + 2.2
50.0 2 07
10.1 + 0.1
5
150.0 + 0.0
50.6 + 1.2
10.1 1 0.2
6
152.5 + 2.5
47.8 + 4-5
9.9 +0.1
7
150.0
5-5
49.3 1 0.8
9.9 1 0.1
S
150.0 0.0
50.5 - 1.1
10.3 + 0.2
9
145-0 +_ 6.1
51.3 1 o.s
10.4 + 0.4
10
151 -3 * 4-2
49.2 2 1-9
10.3 1 0.2
11
155-0 * 9.9
50.3 1 0.4
9-9 + 0.3
12
146.5 2. 3 S
51.3 1 0.4
10.1 + 0.3
15
151.3 2. 2 2
50.0 2 0.0
10.4 + 0-3
14
151.5 2. 2 2
50.0 + 1.4
9-9 1 0.4
15
147.5 2 5.0
50.5 * 0.0
10.5 2 09
10
150.0 ^ 0.1
50.0 0.0
10.5 1 0.5
17
151.5 ^ 7*4
50.8 z o.S
10.1 2 0.4
IS
143.8-1 5*6
48.0 2 1.4
10.3 + 0.3
5
6.0 + 1.1 4.9 + 0.3
4-8 2 0* 7
5-1 + 0.5 5-2 + 0.4 5.0 + 0.4 5.1 1 0.3 5.0 + 0.1 4.8 +_ 0.4 5.0 + 0.1 4.9 1 0.5 5.1 1 0.2
4.7 2 0.4
4-9 + 0.2
4.9 2 *3 5-1 2 *1
5.2 _+ 0.4 5.2 0.1
* Mean of two days' exposure. 250 ppm was reduced to 150 ppm due to signs of toxicity (ruffling of hair, hypomotility and loss of mu scular tone).
SL 080605"
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riSTA'CZXE .....MR .PATRICK ..,10VCl' ....................................................................................................
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.....RF.: F THVt n.VF 01 CHI ORI.DE...BIOAFSAY........................__......................_.........................................
r i i -wing dr. shuts it-titr or .July :sd iqSi ke.have..asked..prof.
..........................MALrOS'X . IO SPEED UP...THE RETRIVAL... OF.. THE.Kh'fcjwi-si ED BATA-. MEANWHILE WE HAVE RECEIVED YOUR LETTER OF NOVEMBER 5TH!
...................THE DATA... JUST RECEIVED, FROM PROF,.....MALTONI....ARE...BEING FORWARDED____
............BY MAIL...TO YOU.
...................... .............................................................................................................
............SOME OF THOSE DATA ARE;.:....................._...........................................................................................
ACTUAL CONCFNTRAI ION (ppm), MEAN +. STANDARD DEVIATION.............. ......................... ppm J SO- l 50................ ppm 50 ......... ppm 10..............ppm-5------
-... RAIS . ......... 233. o_i 5.4............... 49.9^2.3.............10.1^0. S..... S^.lr.0.6.... ........ i4s.;--s.o
MICE
-.i-).'1 ^ 141tS^4.S
___
50.Otl.5
_____ 10.4^0.4 5.0^0.4
..... "i !<1 !'F THE M A I i FD RESULTS WILL FINALLY.. SATlsr.Y ALL..C.0MMIIIE2.
_____oiesiions. ............ ... ...................................................................................................................................
BFST REGARDS.-........................................... ........................... ........................................................
....L . CHIECHI_ L^.LLU.d^i
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SL 080606
