Commission of the European Communities

food-science and techniques

REPORTS OF THE SCIENTIFIC COMMITTEE FOR FOOD

(Eleventh series)

Commission of the European Communities

food-science and techniques

REPORTS OF THE SCIENTIFIC COMMITTEE FOR FOOD

(Eleventh series)

EUR 7421 EN

Published by the COMMISSION OF THE EUROPEAN COMMUNITIES

Directorate-General Information Market and Innovation

Batiment Jean Monnet LUXEMBOURG

LEGAL NOTICE

Neither the Commission of the European Communities nor any person acting on behalf of the Commission is responsible for the use which might

be made of the following information

This publication is also available in the following languages: DA ISBN 92-825-2555-4 DE ISBN 92-825-2556-2 FR ISBN 92-825-2558-9 IT ISBN 92-825-2559-7 NL ISBN 92-825-2560-0

Cataloguing data can be found at the end of this publication

Luxembourg: Office for Official Publications of the European Communities, 1981

© ECSC — EEC — EAEC, Brussels • Luxembourg, 1981

Printed in Belgium

ISBN 92-825-2557-0 Catalogue number: CD-NR-81-001-EN-C

SUMMARY

age

Report of the Scientific Committee for Pood on extraction solvents (opinion expressed 15 January 198l) . . . .

Report of the Scientific Committee for Food on sulphiting agents (opinion expressed 15 January 198l) 47

Composition of the S c i ^ f ^ C o m m i t s m, ^

Messrs P . E l i a s (vice-chairman) F . Fa i rweather R. Franck F . H i l l A. Lafontaine A. Mariani K. Ne t t e r

E. Poulsen (chairman) J» Rey V. S i lano

R. Truhaut (v ice-chairman) G.J. Van Esch B. Weedon R. Wennig

REPORT OF THE SCIENTIFIC COMMITTEE FOR FOOD ON EXTRACTION SOLVENTS (Opinion expressed 15 January 198l)

TERMS OF REFERENCE To advise primarily on extraction solvents, tut where information on the use of a particular extraction solvent as a carrier solvent is provided, to take this into consideration in the safety assessment.

BACKGROUND The Community's programme for harmonization of lawn on food additives includes extraction solvents as a subject on which the Commission is requested to make proposals. Carrier solvents have "been included already in a number of food additive Directives, but the provisions in these Directives are not always alike. As some carrier solvents may also "be used as extrac­tion solvents, and in order to align more closely the texts of the various Directives, the' Commission has decided to review the whole question of solvents used for whatever purpose.

TECHNOLOGICAL CONSIDERATIONS Solvents are used in food technology for a variety of purposes. For some solvents the pattern of use is clear cut, "because they are used solely as extraction solvents or solely as carrier solvents. However, a large number of solvents do not have exclusively either one or other usage "but serve dual functions. Solvents used for extraction purposes only are typified by the chlorinated hydrocarbons such as dichloromethane. They find their main application in the extraction of fats and oils, for defattening fish and other meals, and for the decaffeination of coffee and tea. They are chosen principally for their ability to dissolve selectively the desired food constitutents, and their volatility, which promotes easier separation from the extracted material. Their presence in food is considered undesirable and they are removed from food, as far as is practicable, once they have fulfilled their function.

Carrier solvents have the potential to be used as extraction solvents since they are capable of dissolving food or some component of food. Their exclusive use extends to dissolving and dispersing a wide variety of food ingredients, for example nutrients, flavourings, anti­oxidants, emulsifiers, and other additives. Carrier solvents may occur at higher levels in food for two reasons; frequently no attempt is made to remove them, and some of these solvents are relatively non—volatile. Examples of carrier solvents are low-molecular aliphatic alcohols and certain esters.

The majority of solvents serve dual functions. For example, propan-2-ol is used as an extraction folvent in the preparation of fish protein concentrate and as a carrier solvent for food colours. Such dual function solvents may be used also in a consecutive fashion with the same food. A natural flavouring might be extracted into a solvent and the resulting extract, which includes the solvent, is then added to food. An example of such a process is the extraction of vanilla flavouring in propane—1,2—diol and the incorporation of the solution of the extract into food.

A number of solvents occur naturally in a wide variety of foods. Some others are foodstuffs which possess solvent properties, for example, water, fat and edible oils, wines and spirits.

SPECIFICATIONS Criteria in a specification of purity of a solvent fall into two broad groups; those measuring properties inherent in the solvent and those specifically measuring impurities in the solvent. Solubility, relative density and distillation range are inherent physical characteristics, whereas residue on evaporation, lead, arsenic and acidity are examples of impurities. Where possible, quantitative limits should be specified.

Industrial grades and food grades of solvents often vary widely in the content of impurities. Food use is frequently a minor application, and food grade requirements may be given insufficient attention before use of a solvent in food processing and in selecting material for toxicological testing. Impurities and additives may not have the same volatility as the solvent, and may be retained in the extracted food after removal of the solvent. The possibility of reaction with food components needs consideration and evidence covering this possibility is needed where there is either data or other reasons to suspect such reaction.

For meaningful evaluation of the safety of the use of solvents in food information is required on (a) identity and content of the impurities, including those formed, acquired or concentrated on re-use, (b) the identity and content of stabilisers or other additives, and (c) residues of the solvent or of additives and impurities left in food as a result of its use.

Pood grade specifications are available for most solvents considered in this report. Details are referenced in the data sheets which summarize the toxicological studies, oral as well as inhalational, requested by the Committee. Data sheets have not been published but have been made available to Government Departments and the EEC Advisory Committee for Foodstuffs. The references on which the data sheets were prepared for each individual substance are annexed to this report.

STABILISERS IN SOLVENTS

Several of the solvents, particularly the chlorinated hydrocarbons, contain stabilisers. The function of a stabiliser is essentially to ensure that the solvent does not undergo chemical change during storage and shipment, so that it reaches the user while still complying with the manufacturer's specification. Stabilisers are also added to prevent the formation of dangerous substances. For example, stabilisers prevent in chloroform oxidation to phosgene, and in diethylether the production of unstable and explosive peroxides. All stabilisers are believed to exert an antioxidant effect. However those in chlorinated hydrocarbon solvents also function as acid acceptors to prevent corrosion of equipment and storage vessels by any acids formed on storage.

If the difference between the boiling points of the stabiliser and solvent is large, with the stabiliser having the higher boiling point (e.g. thymol b.p. 280°C in trichlorethylene b.p. 87°C) then the stabiliser will concentrate in the food during evaporation of the solvent. In processes using recycling of solvents concentration of non-volatile impurities from solvent in the extract will only be of concern when a completely fresh batch of solvent is used.

Stabilisers used in solvents can be considered from the toxicological point of view to fall into two broad groups, substances currently permitted for food use as additives and those not previously considered. The first group includes citric acid, ethanol, methanol and butylated hydroxytoluene. There is no need to object to the use of these substances on the grounds of safety.

The second group of stabilisers includes thymol, triethylamine, pyrogallol and 2-methylbut-2-ene (amylene) but others might possibly be used by manufacturers in different countries. The use of these materials is likely to result in small residues in food but the implications of their presence require toxicological evaluation. Hence toxicological testing should be carried out on solvents containing these stabilisers. In general it is recommended that stabilisers from the first group of substances should be used as far as is possible in solvents for food use. The Committee recommends that a list of acceptable stabilisers be established and revised periodically.

TOXICOLOGICAL CONSIDERATIONS

The toxicological issues raised by the use of solvents in food are threefold:

1. the toxicity of the solvent residues themselves;

2. the toxicity of impurities, additives and stabilisers, which may be left behind prefer­entially after removal of the solvent;

3. the potential for interaction of the solvent with food constituents.

As proposed by the Commission data from occupational or inhalational observations have been taken into consideration, where appropriate, by the Committee in arriving at its assessments. Where biological or toxicological data provide a more than ample margin of safety, or where considerations of the points listed above raise no concern, limitation of residues to the minimum levels attainable with appropriate technology appears to be an adequate safeguard for the health of the consumer. Where the toxicological data dictate limitations for reasons of safety, it is appropriate to establish an acceptable daily intake (ADl) or

discourage the use of the material. In those cases where the available information was adequate to support the conclusion of the continued use in food on a temporary basis, no hazard to health was considered to arise from this use, but during this time additional studies have been requested to permit a more precise re—evaluation to be made in the light of the forthcoming information. The Committee's assessments "acceptable", "temporarily acceptable" or "not acceptable" are to be regarded as toxicological evaluations and do not take into consideration other factors which might affect the ultimate legislative decision.

For the safety evaluation of some of the solvents e.g. propane, butane, isobutane, carbon dioxide and nitrous oxide the Committee did not require the provision of the whole spectrum of studies normally demanded for the safety assessment of food additives, set out in the Committee's guidelines of February I98O*

The Committee was aware of reports on the chemical reaction of solvents with nutrient components, on the possible loss of nutrients due to solvent extraction and on the reactions of solvents with food components giving rise to toxic compounds. Where such information was available, it was taken into consideration in the evaluation of the acceptability of the solvent.

The Committee has been asked to evaluate the safety of a number of fluorinated hydrocarbons. In the assessment of these compounds the Committee has not considered the environmental implications of the use of these solvents in food technology, but recognises that environmental considerations should take precedence over its own evaluations on this occasion.

A large number of solvents considered are esters of acids and alcohols which are common constituents of the body or known non—toxic metabolites. An important point in evaluating their safety was the availability of evidence of rapid and complete hydrolysis under in-vitro and in-vivo conditions simulating human digestion. In these cases the Committee evaluated the safety of these solvents without necessarily requiring the provision of all studies normally demanded for the evaluation of the safety of food additive (see guidelines).

The Committee draws attention to the use of foods possessing solvent properties as extraction solvents e.g. vegetable oils and fats. Since this particular application involves the continuous use of food as part of a recycling procedure, it is necessary to ensure that these foods do not as a result of processing technology accumulate impurities giving rise to adverse toxicological considerations. Any proposals for a Directive should take into account the need for controls to ensure that this usage does not result in consumption of unsafe foods e.g. due to the presence of peroxides and polymers in recycled fats.

For solvents whose use was considered temporarily acceptable by the Committee the stated residue limits are not based entirely on the toxicological data but on actual analytical data. The Committee considers it advisable to retain these residue limits in view of the temporary nature of the acceptance.

The Committee has been requested to evaluate the safety of a number of acids and bases, although these compounds are not used as extraction solvents in the sense of the report. The Committee has no objections to this use of acetic acid, lactic acid and sodium hydroxide.

The Committee has been requested to evaluate the safety of the following compounds on which, however, no data were submitted to enable this to be done: n-methyl pyrrolidone, methyl isobutylketone, di-isopropyl ether.

*Reports of the Scientific Committee for Food, Tenth Series, I98O (EUR 6892)

5

ASSESSMENT OF INDIVIDUAL SOLVENTS

GASES USED AS EXTRACTION SOLVENTS

Propane

Although the level of propane residues in food as consumed were claimed to be less than 1 mg/kg, no analytical results were presented to the Committee. Toxicological data appropriate for establishing an ADI are absent but an ADI is unnecessary for this gas. A specification for foodgrade quality and residue data are needed. Meanwhile the Committee considers the use of this compound acceptable as extraction solvent.

Butane

Although the level of butane residues in food as consumed were claimed to be less than 1 mg/kg, no analytical results were presented to the Committee. Toxicological data appropriate for establishing an ADI are absent but an ADI is unnecessary for this gas. A specification for food grade quality and residue data are needed. Meanwhile the Committee considers the use of this compound acceptable as extraction solvent.

Isobutane

Although the level of isobutane residues in food as consumed are claimed to be less than 1 mg/kg, no analytical results were presented to the Committee. Toxicological data appropriate for establishing an ADI are absent but an ADI is unnecessary for this gas. A specification for food grade quality and residue data are needed. Meanwhile the Committee considers the use of this compound acceptable as extraction solvent.

Carbon dioxide (liquid and supercritical gas)

This compound is a natural metabolite and man is permanently exposed to carbon dioxide from the atmosphere, food and drink. Compared to this exposure the residues from its use as extraction solvent are insignificant. The establishment of an ADI for this compound is unnecessary. A specification for food grade material already exists. The Committee considers this compound acceptable as extraction solvent. The setting of residue levels is unnecessary.

Nitrous oxide

The pharmacological and pharmacokinetic properties of this gas are known from its large established use as anaesthetic. Although no residue data are available, these are likely to be so low as to present no hazard to the consumer. The Committee considers the establishment of an ADI unnecessary and its use as extraction solvent acceptable. The specification should exclude the presence of other oxides of nitrogen.

ALCOHOLS

Methanol

The available toxicological data are insufficient to establish an ADI but the Committee considers an ADI unnecessary because residues from its use as extraction solvent are minimal. The Committee was informed that residues of methanol from use as extraction solvent are of the order of 5-10 mg/kg food. Knowledge of its biochemical and metabolic behaviour in man permits the conclusion that no safety problems are likely to arise from its use as extraction solvent. The Committee recognizes that the natural occurrence of methanol may create difficulties in the analytical determination of methanol residues. The Committee considers the use of methanol acceptable as extraction solvent.

Ethanol

In evaluating the safety of this compound the Committee considered its use as extraction and as a carrier solvent. On the basis of the large amount of toxicological information available the Committee did not consider it necessary to specify an ADI. A food grade specification for ethanol is available. The Committee considered it unnecessary to set residue levels in food where ethanol is used as extraction or carrier solvent. The use of this compound as extraction solvent is acceptable to the Committee.

Propan-1—ol

The available toxicological information r e l a t e s to metabolism s tud ies , acute t ox i c i t y s tud ies , and one short-term oral t ox ic i ty study in r a t s in which the l i ve r was the only organ studied. The reported adverse effects in the long—term study in r a t s are not in terpre table in the absence of essent ia l d e t a i l s . The data are insuff icient to es tabl ish a formal ADI.r The Committee considers the use of t h i s compound temporarily acceptable as extract ion solvent, if residues from t h i s use in food as consumed do not exceed 5 mg/kg. The Committee requires the r e s u l t s of an adequately performed 90—day study by the end of 1983. If t h i s substance i s to be used as a ca r r ie r solvent with residues in food great ly exceeding 5 mg/kg the Committee would require in accordance with i t s report on the general pr inciples (see guidelines) the r e s u l t s of a long-term study in a rodent species to assess the safety of t h i s use.

Propan-2—ol (isopropanol)

The available toxicological information r e l a t e s to metabolism, acute, short—term and reproduction oral s tudies in r a t s and a long—term oral study in ra tB. Another recent oral reproduction study of unusual design claimed to show adverse effects at low levels but the lack of speci f ica t ion of the compound tes ted makes t h i s study d i f f i cu l t to i n t e r p r e t . The Committee established a temporary ADI of 1.5 mg/kg b.w. and wishes to see the r e s u l t s of an adequate single generation reproduction study by 1983. Meanwhile i t considers the use of t h i s compound temporarily acceptable as an extract ion solvent.

Butan-1-ol

The avai lable toxicological data r e l a t e to metabolism and short—term oral studies in r a t s . No long-term oral s tudies are ava i lab le . The Committee was therefore unable to es tabl ish an ADI. Residues occur in food from use as extract ion and ca r r i e r solvent as well as from natural occurrence, but adequate residue data are not ava i lab le . The Committee considers the use of t h i s compound temporarily acceptable as an extract ion solvent provided the residues are l imited to 30 mg/kg food. The Committee requires the provision of an adequate 90 day oral study in r a t s as well as information on residue levels by 1983.

Butan-2-ol

There are insufficient data to establish an ADI but the available two—generation reproduction study shows a definite no—adverse—effect level. No residue data are provided. The Committee considers the use of this compound temporarily acceptable as an extraction solvent provided residues from use as an extraction solvent in food as consumed do not exceed 30 mg/kg food. The provision of an adequate 90-day feeding study in rats as well as information on residue levels is required by 1983.

Tertiary butanol

The available data are insufficient to establish an ADI. Biochemically this Bolvent will behave like other tertiary carbinols which are generally not very reactive. The residues in food are minimal and are not a hazard to health. The Committee considers the use of this compound temporarily acceptable as an extraction solvent provided residues from use as an extraction Bolvent in food as consumed do not exceed 10 mg/kg food. The provision of an adequate 90-day feeding study in a rodent species is required by I983.

12)

Benzyl alcohol

The metabolism by man is well established. Although no specific toxicological studies are available it is acceptable to include benzyl alcohol in the group ADI of 5 mg/kg b.w. established for benzoic acid (representing total benzoates) by JECFA (1973). The Committee considers the use of this extraction solvent acceptable.

Glycerol

This substance occurs naturally in fats and lipid complexes. The available toxicological evidence includes short— and long-term studies in rats as well as metabolic studies showing that glycerol participates in the normal carbohydrate metabolism. No essential toxicological difference exists between naturally derived and synthetically made glycerol. The specification of synthetic glycerols should contain a limit for the contamination by butanetriols. The Committee agrees with the JECFA evaluation (1976) that an ADI for man need not be specified. The Committee considers this substance acceptable for use as solvent for food.

Pr opan-1,2-di ol

There a r e s u f f i c i e n t d a t a a v a i l a b l e from o r a l t o x i c i t y s t u d i e s , i n c l u d i n g long- te rm s t u d i e s i n r a t s and dogs , t o e s t a b l i s h an ADI of 0-25 rag/kg b .w . (JECFA 1973) . The Committee ag rees wi th t h e ADI e s t a b l i s h e d by JECPA and cons ide r s t h e use of t h i s subs tance a c c e p t a b l e a s so lven t f o r food . Because of t h e i n fo rma t ion submit ted on t h e e x t e n s i v e use of t h i s subs tance i n food technology t h e Committee recommended t h a t t h e i n t a k e from a l l sources should be reviewed i n r e l a t i o n t o t h e e s t a b l i s h e d ADI.

HYDROCARBON SOLVENTS

Cyclohexane

Although t h e a v a i l a b l e t o x i c o l o g i c a l d a t a r e l a t i n g t o prolonged o r a l exposure of animals or man a r e s c a n t y , t h e me tabo l i c and o t h e r d a t a po in t t o a low t o x i c p o t e n t i a l . The e a r l y l i t e r a t u r e r e p o r t s of haemato log ica l i n j u r y were a t t r i b u t a b l e t o benzene as con taminant . No r e s i d u e d a t a were p rov ided . Any s p e c i f i c a t i o n f o r t h i s compound should i n c l u d e a l i m i t f o r benzene and p o l y c y c l i c a romat ic hydroca rbons . The a v a i l a b l e d a t a do not permi t t h e e s t ab l i shmen t of a formal ADI. The Committee c o n s i d e r s t h e use of t h i s subs tance t e m p o r a r i l y a c c e p t a b l e a s an e x t r a c t i o n so lven t bu t r e q u i r e s t h e p r o v i s i o n of an adequate long—term study i n a roden t and in fo rma t ion on r e s i d u e l e v e l s by 1985*

L igh t petroleum

This m a t e r i a l i s d i f f i c u l t t o spec i fy but comprises a mix tu re of s a t u r a t e d a l i p h a t i c hydrocarbons wi th a s p e c i f i e d d i s t i l l a t i o n r a n g e , c o n t a i n i n g up t o 50fo hexane and v a r i a b l e amounts of h e p t a n e . The metabolism of hexane may l e a d t o n e u r o t o x i c d e r i v a t i v e s . The a v a i l a b l e short—term o r a l s t u d i e s i n r a t s and dogs showed no d e l e t e r i o u s e f f e c t s . Hexane i s modera te ly h e p a t o t o x i c on i n h a l a t i o n a l exposure . No d a t a a r e a v a i l a b l e t o e s t a b l i s h an ADI. The Committee c o n s i d e r s t h e use of t h i s m a t e r i a l t e m p o r a r i l y a c c e p t a b l e f o r use a s e x t r a c t i o n so lven t when used under c o n d i t i o n s r e s u l t i n g i n minimal r e s i d u e s provided t h e r e s u l t s of a long—term study on a s p e c i f i e d l i g h t petroleum a r e a v a i l a b l e by 1985« A s p e c i f i c a t i o n i s needed wi th l i m i t s f o r u n s a t u r a t e d a l i p h a t i c hydrocarbons and p o l y c y c l i c a romat i c hydroca rbons .

2 - n i t ropropane

Appropr ia te metabol i sm, s h o r t - t e r m and long- te rm o r a l t o x i c i t y s t u d i e s a r e a b r e n t . Ra ts developed h e p a t o c e l l u l a r carc inomata when exposed f o r 6 months by i n h a l a t i o n and observed f o r ano the r 6 months . Rabb i t s and c a t s showed haema to log i ca l damage f o l l o w i n g i n h a l a t i o n due t o conver s ion of t h e compound t o n i t r a t e , whi le l i v e r damage a f t e r i n h a l a t i o n of h igh l e v e l s h a s been r e p o r t e d i n r a t s , c a t s and men. The Committee c o n s i d e r s t h i s compound u n a c c e p t a b l e a s e x t r a c t i o n so lven t f o r food .

Toluene

Almost all available toxicological data refer to exposure by routes other than oral and are therefore of little relevance for a meaningful evaluation of this compound. No residue data were available. The existing data do not allow the establishment of an ADI. The Committee considers this compound unacceptable as extraction solvent for food.

ETHERS_

Die thy l e t h e r

Most of t h e a v a i l a b l e t o x i c o l o g i c a l d a t a r e f e r t o i n h a l a t i o n a l exposure and t h e r e i s long expe r i ence from use i n human a n a e s t h e s i a . No o r a l t o x i c o l o g i c a l d a t a e x i s t which would permit e s t a b l i s h i n g an ADI. The s p e c i f i c a t i o n should c o n t a i n l i m i t s f o r named s t a b i l i s e r s . In view of t h e small r e s i d u e s l i k e l y t o remain i n food from t h e use of t h i s subs tance a s ' e x t r a c t i o n so lven t t h e Committee c o n s i d e r s i t unnecessa ry t o e s t a b l i s h an ADI and c o n s i d e r s t h e use a s e x t r a c t i o n so lven t a c c e p t a b l e .

D i - b u t y l e t h e r

No r e l e v a n t o r a l t o x i c o l o g i c a l d a t a a r e a v a i l a b l e on t h i s compound nor any r e s i d u e f i g u r e s . The e x i s t i n g t o x i c o l o g i c a l i n fo rma t ion i s i n s u f f i c i e n t f o r a meaningful e v a l u a t i o n or e s t a b l i s h m e n t of an ADI. The Committee c o n s i d e r s t h a t t h i s compound i s not a c c e p t a b l e f o r use as e x t r a c t i o n so lven t f o r f o o d s .

ALDEHYDES

F u r f u r a l

The l i m i t e d t o x i c o l o g i c a l d a t a i n d i c a t e t h a t t h e compound i s p o t e n t i a l l y h e p a t o t o x i c . The a v a i l a b l e i n fo rma t ion i s i n s u f f i c i e n t t o e s t a b l i s h an ADI. The Committee does not c o n s i d e r t h i s compound a c c e p t a b l e f o r use a s e x t r a c t i o n so lven t f o r food u n t i l t h e r e s u l t of a f u l l t o x i c o l o g i c a l examinat ion becomes a v a i l a b l e ( see g u i d e l i n e s ) .

KETONES

Acetone

Oral a d m i n i s t r a t i o n of massive doses t o dogs and r a b b i t s sugges t s nephro tox ic e f f e c t s and t h e r e i s some evidence of h e p t o t o x i c and nephro tox ic e f f e c t s i n man fo l l owing massive i n t o x i c a t i o n . The metabolism i n man i s we l l known. No t o x i c o l o g i c a l d a t a on o r a l a d m i n i s t r a t i o n a r e a v a i l a b l e t o e s t a b l i s h an ADI. The a v a i l a b l e o r a l short—term s tudy i n r a t s and m u t a g e n i c i t y s t u d i e s have shown no adverse e f f e c t s . The Committee recommends t h a t t h e s p e c i f i c a t i o n should i n c l u d e a l i m i t of 10 ppm f o r m e s i t y l o x i d e . The Committee c o n s i d e r s t h e use of t h i s subs tance a c c e p t a b l e a s e x t r a c t i o n so lven t f o r food provided r e s i d u e s a r e kep t t o 5 mg/kg food a s consumed.

Methyl e t h y l ke tone

Methyl e t h y l ke tone (MEK) occurs i n t r a c e s i n normal human u r i n e . I t s metabolism has been we l l s t u d i e d and i t has a low o r a l t o x i c i t y . There a r e no adequate o r a l long- te rm s t u d i e s a v a i l a b l e f o r e s t a b l i s h i n g an ADI. The compound appears t o have no n e u r o p a t h i c p r o p e r t i e s bu t enhances n e u r o t o x i c i t y of o t h e r subs t ances such a s me thy lbu ty lke tone (MBK) or n -hexane t i f combined wi th t h e l a t t e r . The Committee c o n s i d e r s t h e use of t h i s subs tance t e m p o r a r i l y a c c e p t a b l e as e x t r a c t i o n s o l v e n t , p rovided t h e r e s u l t s of adequate long- te rm s t u d i e s , r e p r o d u c t i o n s t u d i e s , i n c l u d i n g embryo tox ic i ty and m u t a g e n i c i t y s t u d i e s a r e a v a i l a b l e by 1985. Spec ia l emphasis should be p laced i n animal s t u d i e s on p o s s i b l e n e u r o t o x i c i t y a s p e c t s . The Committee recommends t h a t t h e s p e c i f i c a t i o n should l i m i t t h e amount of hexane i n MEK t o 50 mg/kg. The combined use of MEK wi th MBK or n-hexane should be avo ided .

Di-isopropyl ketone

No "toxicological data are available on this compound nor any information on residues or specification. No meaningful evaluation is therefore possible. The Committee considers this compound not acceptable for use as extraction solvent for food.

HALOGENATED HYDROCARBON SOLVENTS^

Chloroform

A large amount of data relating to several routes of exposure is available which shows that the compound is hepatotoxic and nephrotoxic to rodents at high levels of exposure. However a no-effect level for these toxic effects can be determined. There is also sufficient evidence that chloroform is carcinogenic in mice and one strain of rats following oral exposure. However, the neoplastic changes reported only occurred when excessive doses were used causing initial toxic damage. Chloroform is foetotoxic and not mutagenic in the bacterial systems tested. The Committee considers this substance unacceptable for use as extraction solvent in food.

Dichloromethane

The available data on metabolism indicate similarity of pattern whatever the route of administration. Both man and animals excrete most of the administered dose unchanged in the expired air, a small percentage being converted to carbon monoxide which binds to haemoglobin. A few short—term experiments on foods extracted with this solvent showed no toxicity from the minute residues of the solvent or from any potential reaction products with food components. The available short—term test using drinking water as vehicle showed hepatotoxicity in rats and mice at practically all levels tested. Cell transformation studies were negative but in—vitro mutagenicity tests in bacteria were positive. Inhalation studies showed questionable teratogenic effects in rats and mice. The available long-term studies in rats by inhalation were inadequate for meaningful evaluation but raised suspicions because of increased mammary tumour incidence. A long—term study in mice using i.p. administration pointed to a possible increase in lung adenomas. Long—term studies by gavage and in drinking water are either in progress or planned in rats and mice as well as repeat long—term inhalation studies in rats and mice.

The Committee considered that the available toxicological evidence was insufficient to establish an ADI but that meanwhile the use of this solvent was temporarily acceptable. In addition use should be such as to result in minimum residues and in any case not exceeding 10 mg/kg food as consumed, whatever the application, and provided material complying with a food grade specification and stated stabilisers is used. The Committee wishes to review the situation when the results of ongoing studies are available but not later than the end of 1983.

Trichloroethylene

There is a wealth of data on metabolism as well as short—term, long—term and mutagenicity studies. The substance has also been used for many years in human anaesthesia. Only the oral carcinogenicity study in mice in which large doses were used produced hepatocellular carcinoma and lung tumours in both sexes. Both oral carcinogenicity studies in rats are considered not adequate. Other more recent studies have identified carcinogenic/mutagenic stabilisers present in the samples tested which make the carcinogenicity findings questionable. Furthermore, additional inhalation studies in rats and mice and feeding studies using low levels have not shown any evidence- of carcinogenicity.

The Committee considers the use of this substance temporarily acceptable as extraction solvent for food. The results of well conducted oral carcinogenicity studies are needed by 1985 as well as data on the levels and nature of residues present in extracted foods.

10

1,2-Dichloroethane

A considerable amount of data on the metabolism and oral short—term and long-term studies are ava i lab le . The ra t and mouse studies showing a carcinogenic effect were performed on technical grade mater ia l , in which any contaminants present were not determined. Another oral long-term study has not shown any carcinogenic effects and long-term inhalat ion studies in mice and r a t s were equally negative as regards carcinogenici ty. The substance i s mutagenic in the bac te r i a l systems tes ted but a reproduction study showed no effects on offspring. No data on t i s sue accumulation are ava i lab le . The evidence on carcinogenicity i s conf l ic t ing . There i s some evidence of in te r reac t ion with cer ta in food const i tuents to form toxic compounds, however under excessively severe condit ions. The Committee considers t h i s substance not acceptable for use as extract ion solvent for food unless the r e su l t s of well conducted carcinogenicity studies on food grade material become available for evaluation.

Carbon t e t rach lo r ide

The available data show that t h i s substance i s rapidly absorbed and has considerable hepatotoxic i ty . The avai lable studies are not adequate for es tabl ishing an ADI. The oral long-term studies in r a t s , mice and hamsters, although not a l l adequate, show clear ly that the substance produces benign l i ve r tumours and hepatocel lular carcinomas. The compound i s also foetotoxic but non-mutagenic for bac te r i a . The Committee considers t h i s substance unacceptable for use as extract ion solvent for food.

Cis—1,2-dichloroethylene (acetylene dichloride)

No toxicological data are avai lable but oral long-term studies in r a t s and mice are planned. No food grade specif icat ion of t h i s solvent i s ava i lab le . The Committee considers t h i s compound unacceptable for use as extract ion solvent for food.

Trans-1,2-dichloroethylene (acetylene dichloride)

The avai lable toxicological s tudies are scanty and include only one short—term inhalat ion study in r a t s . Oral long—term studies in r a t s and mice are planned. No food grade specif icat ion of t h i s solvent i s ava i lab le . The Committee considers t h i s compound unacceptable for use as extract ion solvent for food.

Dichlorofluoromethane

No data are avai lable on the effects of oral administration of t h i s compound. A meaningful evaluation i s therefore not possible nor can an ADI be establ ished. The Committee considers t h i s compound not acceptable for use as extract ion solvent for foods.

Dichlorodifluoromethane

Data on the effect of oral administration are available from short-term s tudies in r a t s and dogs as well as from a long-term study in r a t s . Reproduction, te ra togenic i ty and mutagenicity has also been invest igated without revealing any adverse e f fec t s . Almost a l l of the ingested compound i s excreted unchanged in expired a i r . The cardiovascular effects noted af ter inhalat ion exposure in various species are of no significance in r e l a t ion to the safety of residues of the compound when used as extract ion solvent for foods. An ADI of 0-15 mg/kg bodyweight for man was established by JECPA (1975) and the Committee agrees with t h i s evaluation. The Committee considers t h i s compound acceptable for use as solvent for food.

see "Toxicological considerations'

I I

Di c h l o r o t e t r a f l u o r o e t h a n e

The a v a i l a b l e d a t a on t h e e f f e c t s of o r a l a d m i n i s t r a t i o n of t h i s compound do not permit a meaningful e v a l u a t i o n of t h e es t ab l i shmen t of an ADI. The a c u t e t o x i c i t y of t h i s compound appears t o "be low but t h e i n h a l a t i o n t o x i c i t y i s g r e a t e r t h a n t h a t of o t h e r h a l o c a r b o n s . The Committee c o n s i d e r s t h i s compound not a c c e p t a b l e f o r use as e x t r a c t i o n so lven t of food .

1 , 1 , 2 - t r i c h l o r o t r i f l u o r e t h a n e

No d a t a a r e a v a i l a b l e on t h e e f f e c t s of o r a l a d m i n i s t r a t i o n and t h e r e f o r e no meaningful . e v a l u a t i o n of t h e s a f e t y of t h e compound can be made. The Committee c o n s i d e r s t h i s compound not a c c e p t a b l e f o r use a s e x t r a c t i o n so lven t of food .

JDSTERS

Methyl a c e t a t e ( o p i n i o n expressed i n March 198l )

This so lven t i s t e m p o r a r i l y a c c e p t a b l e as an e x t r a c t i o n s o l v e n t . An i n v ivo h y d r o l y s i s s tudy should be provided by t h e end of I 9 8 I . Residues i n food should not be h i g h e r , i n molar t e r m s , t h a n t h o s e e s t a b l i s h e d f o r methanol .

E t h y l a c e t a t e

A m e t a b o l i c s tudy u s i n g C l a b e l l e d subs tance has shown t h a t t h e compound i s r a p i d l y hydro lysed i n - v i v o a f t e r o r a l a d m i n i s t r a t i o n i n t o t h e c o n s t i t u e n t a c i d and a l c o h o l which have w e l l known metabo l i c f a t e s . I n - v i t r o h y d r o l y s i s has been demonstra ted s a t i s f a c t o r i l y . The observed dermal i r r i t a n c y and p o s s i b l e a l l e r g e n i c i t y i s not r e l e v a n t t o t h e e v a l u a t i o n as an e x t r a c t i o n s o l v e n t . No t o x i c o l o g i c a l s t u d i e s e x i s t t o e s t a b l i s h an ADI but t h e m e t a b o l i c d a t a make i t unnecessa ry f o r an ADI t o be s p e c i f i e d . The Committee c o n s i d e r s t h i s so lven t a c c e p t a b l e f o r use i n food .

Butyl a c e t a t e

A m e t a b o l i c s tudy u s i n g ■ C l a b e l l e d subs tance has shown r a p i d h y d r o l y s i s in—vivo a f t e r o r a l a d m i n i s t r a t i o n and e l i m i n a t i o n of t h e a c i d and a l coho l by w e l l known m e t a b o l i c pathways. I n - y i t r o h y d r o l y s i s was shown t o be compara t ive ly s low. Severa l s h o r t - t e r m o r a l s t u d i e s i n r a t s a r e a v a i l a b l e p o i n t i n g t o a no—adverse-effect l e v e l of 600 mg/kg b .w. Oral s h o r t - t e r m s t u d i e s i n mice p o i n t t o a n o - a d v e r s e - e f f e c t l e v e l of 1,000 mg/kg b . w . No t o x i c e f f e c t s were seen i n r e p r o d u c t i o n and t e r a t o l o g y t e s t s i n r a t s and mice . The Committee e s t a b l i s h e d a temporary ADI of 0-6 mg/kg b . w . The Committee c o n s i d e r s t h i s subs tance t e m p o r a r i l y a c c e p t a b l e f o r use as so lven t f o r food and r e q u i r e s i n fo rma t ion on t h e l e v e l s of r e s i d u e s p r e s e n t i n e x t r a c t e d food by I 9 8 3 .

Ethy l l a c t a t e

Only an i n - v i t r o h y d r o l y s i s s tudy i s a v a i l a b l e and t h e r e a r e no o t h e r o r a l s t u d i e s i n e x i s t e n c e from which an ADI could be e s t a b l i s h e d . I t i s v e r y l i k e l y t h a t t h i s subs tance w i l l hydro lyse in-^vivo s i m i l a r t o o t h e r c l o s e l y r e l a t e d e s t e r s and on t h i s assumption t h e c o n s t i t u e n t a c i d and a l c o h o l would fo l low wel l e s t a b l i s h e d m e t a b o l i c pathways . The a v a i l a b l e s h o r t - t e r m s tudy i n r a t s was j u s t s u f f i c i e n t t o i n d i c a t e t h e absence of any a c u t e t o x i c i t y a t t h e h igh dose l e v e l t e s t e d . The Committee c o n s i d e r s t h e subs tance as t e m p o r a r i l y i nc luded i n t h e ADI f o r l a c t i c a c i d provided adequate evidence of i n - v i v o h y d r o l y s i s becomes a v a i l a b l e by t h e end of 1981 . On t h i s b a s i s t h e Committee c o n s i d e r s t h i s subs tance t e m p o r a r i l y a c c e p t a b l e as so lven t f o r food .

see "Tox ico log ica l c o n s i d e r a t i o n s '

12

Benzyl benzoate

No oral toxicological data are available on t h i s compound and in-vivo hydrolysis in to i t s const i tuents has been proposed. The metabolic fa te of both benzyl alcohol and benzoic acid i s well established in man. The Committee has temporarily included t h i s substance in the ADI of 0-5 mg/kg b.w. established in 1973 (JECPA) for a l l benzoate derived from food addit ive use, subject to provision of adequate confirmation of the in—vivo hydrolysis by the end of 1981. The Committee meanwhile considers t h i s substance temporarily acceptable for use as solvent for food.

Triethyl c i t r a t e

This compound i s hydrolysed i n -v i t r o into i t s acid and alcohol moieties of well known metabolic fa te in man. The avai lable short—term studies in r a t , cat and dog and one long—term study in r a t , although not ful ly adequate by present day standards, allowed the establishment of a temporary ADI of 10 mg/kg b.w. by JECPA with which the Committee agrees. The compound was non-mutagenic in the microbial systems t e s t e d . The Committee considers t h i s substance temporarily acceptable for use as solvent for food provided adequate evidence of in—vivo hydrolysis i s furnished by the end of I98I .

Diethyl t a r t r a t e

No toxicological data are ava i lab le . However, in the l ight of exis t ing knowledge on the biological propert ies of t a r t r a t e e s t e r s , the Committee considers t h i s compound temporarily acceptable for use as an extract ion solvent for food but requires adequate data to be submitted by the end of 1983 on in-vivo hydroljrsis as well as the r e s u l t s of a 90-day oral feeding study in r a t s . Because of the existence of an ADI for t a r t a r i c acid t o t a l residues of t h i s compound from a l l uses should not exceed 100 mg/kg food.

Isopropyl myristate

There are no oral tox ic i ty data available to make a meaningful evaluation or es tabl ish an ADI. The Committee considers t h i s compound not acceptable for use as extract ion solvent for foods.

Glycerol mono—, d i - and t r i - a c e t a t e

These glycerol e s t e r s , except for the tr i—acetate, occur always as a mixture with glycerol . No biochemical or formal feeding studies are available on the glycerol mono— and di—acetates but the t r i - a c e t a t e i s rapidly hydrolysed i n - v i t r o . The tri—acetate i s metabolised ef f ic ient ly by known metabolic pathways. No formal shor t - or long-term studies exist for the t r i - a c e t a t e . Nevertheless the metabolic data permit the reasonable conclusion that a l l three aceta tes are l ike ly to be readi ly hydrolysed in to const i tuents of well known metabolic f a t e . The Committee agrees with the evaluation by JECFA (1979) that an ADI need not be specified and considers these compounds acceptable for use as solvents for food.

Glycerol tripropionatc

There are no oral t ox ic i ty data available to make a meaningful evaluation to es tabl ish an ADI. The Committee considers t h i s compound temporarily acceptable for use as solvent for the extract ion of food provided adequate information on in-vivo hydrolysis i s submitted by the end of I98I .

Glycerol t r i bu ty ra t e

There are no oral t ox ic i ty data available to make a meaningful evaluation to es tabl ish an ADI. However t h i s compound occurs natural ly as a consti tuent of milk f a t . The Committee considers the use of t h i s compound acceptable as a solvent for the extract ion of food provided the leve ls of residues comply with good manufacturing p rac t i ce .

13

Diethylene glycol monoethyl ether (DCME)

A considerable amount of toxicological data is available on this compound. However, only the short—term studies are adequate and were carried out in several species. The long-term studies are not suitable for establishing an ADI and the available reproduction study is inadequate for meaningful evaluation. Since the evaluation by JECPA (1976) the additional data requested to permit meaningful evaluation have not been presented. The uncertainties regarding a no—effect level for nephrotoxicity and hepatotoxicity as well as effects on reproduction including teratogenicity and carcinogenicity remain unanswered. The Committee considers this compound not acceptable for use as extraction solvent for food, particularly as its non-volatility makes comparatively high levels of residues likely.

Acknowledgement The Committee is grateful for the assistance given by:

Prof. P. Marquardt, D 7800 FREIBURG/BR. Laufenerstrasse 9, Deutschland

14

REFERENCES

P r o p a n e

1. P a t t y , F . A . , 1963, " I n d u s t r i a l Hygiene a n d Tox ico logy" , Vol. I I , I n t e r -s c i e n c e , New York. p . 1 1 9 8 .

Butane

1. P a t t y , F . A . , 1963, " I n d u s t r i a l Hygiene a n d Tox ico logy" Vol. I I , I n t e r s c i e n c e , New York. p . 1 1 9 8 .

2. S h u g a e v , B . B . , 1969, A r c h s . e n v i r . H l t h . , J_8, p . 8 7 8 .

I s o b u t a n e

1. F r i e d m a n , S .A. , C a m m a r a t o , M. a n d Av iado , D .M. , 1973, Tox ico logy , J_, p . 345-

Carbon Dioxide ( l i q u i d and s u p e r c r i t i c a l g a s )

1. E u r o p e a n P h a r m a c o p o e i a , 1971, p .175 -

2 . H u b e r t , P . and Vi t z thum, O.G. , 1978, Angew. Chem. I n t . Ed. E n g l . , 17, p . 7 1 0 .

Ni t rous Oxide

1. FAO, 1979, Food a n d Nu t r i t i on P a p e r No. 7, p . 4 6 .

Methanol

1. DeFe l i ce , A . , Wilson, W. a n d Ambre, J . , 1976, Toxico l , a p p l . P h a r m a c o l . , 38, p . 6 3 1 .

2. DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. A s s . J . , 35 , p . 2 1 .

3 . Henson, E . V . , I960, J. Occup . Medic ine , p . 4 9 7 .

4 . K imura , E . T . , E b e r t , D.M. a n d Dodge, P . W . , 1971, Tox ico l . a p p l . P h a r m a c o l . , _19, p . 6 9 9 -

5. M a k a r , A.B. a n d T e p h l y , T . R . , 1976, N a t u r e , 261 , p . 7 1 5 -

6. M a r d o r e s , J . , 1963, P h y s i o l o g i c a l P h a r m a c o l o g y , Vol. 1, Academic P r e s s , New York, 1963.

7. McMart in , K . E . , M a k a r , A . B . , M a r t i n , A .G . , P a l e s c , M. a n d T e p h l y , T . R . , 1975, Biochem. Med . , _13, p . 3 1 9 .

8. Rushmer , R. , Van L i t t e r s , R. a n d F r a n k l i n , D . , 1963, C i r c u l a t i o n , 27, p . 1 1 8 .

9 . S i e g e r s , C . - P . , S t r u b e l t , O. a n d B r e i n i n g , H. , 1974, P h a r m a c o l o g y , 12, p . 2 9 6 .

10. T o x i c o l o g i c a l M o n o g r a p h s , F o u r t e e n t h Report of t h e Join t FAO/WHO Exper t Committee on Food A d d i t i v e s ; FAO Nut r i t ion Meet ings Report Ser ies No. 48A; WHO/Food A d d . / 7 0 - 3 9 , 1970, p . 1 0 5 -

E t h a n o l

1. B a d r , F.M. a n d B a d r , R . S . , 1975, N a t u r e , 253, p . 1 3 4 .

2 . C h a u h a n , P . S . , A r a v i n d a k s h a n , M., Kumar , N.S . a n d S u n d a r a m , K., 1980, Muta t ion R e s . , 79, p . 2 6 3 -

3 . Conn, R . A . , Jones , R.A. , J e n k i n s , L . J . j r . a n d S ieg e l , J . , 1970,Toxicol . Appl . P h a r m a c o l . , 16, p . 6 4 6 .

4 . Di Luz io , N . R . , 1961, Am. J. C l i n . N u t r i t i o n , 9, p . 4 4 2 .

5 . G a i l l a r d , D . , C h a m o i s e a u , G. a n d S u s c h e t e t , M., 1976, Fd . Cosmet. T o x i c o l . , 14, p . 1 2 3 .

6. G r i f f a t a , G. , Baron , P. a n d Lowy, R. , 1970, In fo rma t ion B u l l e t i n , B . I . B . R . A . , 9, p . 3 1 7 . -. .

7. Kimura , E . T . , E b e r t , D.M. a n d Dodge, P . W . , 1971, Toxico l . a p p l . P h a r m a c o l . , 19, p .699-

8. Kors t en , M.A. , M a t s u z a k i , S. , F e i n m a n , L. a n d L i e b e r , C . S . , 1975, New E n g l . J. Med. , 292, p . 3 8 6 .

9^ L o c k n e r , D. a n d E r i c s o n , U. , 1973, Acta Haemat . , 49, p . 2 4 2 .

10. Mann , L . I . , B h a k t h a v a t h s a l a n , A., Liu , M. a n d Makowski , P . , 1975, Am. J. O b s t e t . , 122 , p . 8 3 7 .

11 . Mann , L . I . , B h a k t h a v a t h s a l a n , A. , Liu , M. a n d • M a k o w s k i , P . , 1975, Am. J. O b s t e t . , 122, p . 8 4 5 .

12. Mul le r , G., S p a s s o w s k i , M. a n d H e n s c h l e r , D . , 1975, Arch . T o x . , 33 , p .173- '

13. Nomiyama, K. a n d Nomiyama, U. , 1974, I n t . Arch . A r b e i t s m e d . , 32, p . 7 5 .

14. Osz tov i c s , M., I g a l i , S . , A n t a l , A. a n d V e g h e l y i , P . , 1980, Muta t ion R e s . , 74 ( 3 ) , p . 2 4 7 . • ■

15. P i e p e r , W.A. a n d Skeen , M . J . , 1973,- Biochem. P h a r m a c y , 22, p . 1 6 3 .

16. S a r d e s a i , V.M. a n d Thomas , C . C . , E d s . , 1969, Biochemica l a n d C l i n i c a l Aspects of Alcohol Metabo l i sm; S p r i n g f i e l d , I l l i n o i s , p<93.

17. T o x i c o l o g i c a l M o n o g r a p h s , F o u r t e e n t h Report of the' Jo in t FAG/ WHO Expe r t Committee on Food A d d i t i v e s ; FAQ Nut r i t i on Meet ings Report Ser ies No. 48A;

> ■ WHO/Food Add. 70 /39 , 1970, p i 9 9 . • ■ - . . . . ' •)

18. Tze , V.J . a n d Lee, M., 1975, N a t u r e , 257 , p . 4 7 9 .

P r o p a n - 1 - o l

1. A b b o n d a n d o l o , A. et a l . , in p r e s s .

2 . Beaud , '?. " a n d Ramuz, A . , 1978, Mit. fur Lebensm. H y g . , 69, p . 4 2 3 .

3 . B e a u g e , F . , Clement , M., Nordmann , J . a n d Nordmann , R. , 1979, Chem. Biol. I n t e r a c t . , 26, p . 1 5 5 .

4. Bikfalvi, I. and Pasztor, L. , 1977, Szeszipar, 25. p.96.

5. Birkett, D.J., 1974, Clin. Exp. Pharm. Phys., _1, p.415.

6. Bonte, W., 1978, Blutalk., _15, p.392.

7. Bonte, W., 1979, Blutalk., _16, p.108.

8. DeFe l i ce , A . , Wilson, W. a n d Ambre, J . , 1976, Tox. Appl . P h a r m . , 36, p . 595 -

9. D u r w a l d , W. a n d Degen , W., 1956, Arch . T o x i c o l . , J_6, p . 8 4 .

10. E l h a r d t , W . P . , 1931, Am. J. P h y s i o l . , 100, p . 7 4 .

1 1 . I v a n e t i c h , K.M. , L u c a s , S . , M a r s h , J .A. a n d Z iman , M.R. , 1978, D r u g . M e t a b . D i s p o s . , 6, p . 2 1 8 .

12. J a d d o u , H .A. , P a v e y , J .A . a n d l a n n i n g , D . J . , 1978, J. D a i r y R e s . , 45 , p . 3 9 1 .

13. McCrery , M.J. a n d Hunt , W.A., 1978, Neuroph . , J/7, p . 4 5 1 .

14. Monick, J . A . , 1968, Alcohols , Chapman & R e i n h o l d , N.Y.

15. M u r p h r e e , H . B . , G r e e n b e r g , L.A. a n d C a r r o l , R . B . , 1967, F e d . P r o c , 26, p . 1 4 6 8 . —

16. Obe, G. a n d Ris tow, H . J . , 1977, Muta t . R e s . , 56, p . 2 1 1 .

17. Obe, G. , Ristow, H.J . a n d He rha , J . , 1977, Adv. E x p . Med. B i o l . , 85A, p . 4 7 .

18. O t s u k a , K., I k i , 1. a n d Y a m a s h i t a , T . , 1979, Hakko Kogaku K a i s h r i , 57, p . 2 0 . —

19. P e s t e l , W. a n d Adam, H. , 1978, B r a n n t w . , 118, p . 4 0 4 .

20. P u r c h a s e , I . F . H . , 1969, S.A. Med. J . , 43 , p . 7 9 5 .

2 1 . R a p p , A. a n d Avramov , I . , 1977, J. V i n o g r a d . V i n a r . , 11 , p . 5 .

S c h r e i e r , P . , D r a w e r t , F . a n d Wink le r , F . , 1979, J. A e r i e . Food Chem. , 27, p . 3 6 5 . —

22.

23 . S h e h a t a , M. a n d S a a d , S. , 1978, Pol . J. P h a r m . P h a r m . , 30, p . 3 5 .

24. Sun , A .Y . , 1976, Anna l s N.Y. Acad . Sci . , 2 7 3 , , p . 2 9 5 .

25 . T a y l o r , J . M . , J e n n e r , P .M. a n d Jones , W . I . , 1964, Tox. Appl . P h a r m . , 6, p . 3 7 8 .

26. T e s h k e , R. , H a s u m u r a , Y. a n d L i e b e r , C . S . , 1974, Biochem. B i o p h y s . Res . Comm. , 60, p . 8 5 1 .

27. T o x i c o l o g i c a l M o n o g r a p h s , Twen ty - f i f th Meeting Join t FAO/WHO Expe r t Committee on Food A d d i t i v e s , 1981, in p r e s s .

28 . Uh lemann , E . R . , R o b b e r e c h t , P . a n d G a r d n e r , J . D . , 1979, G a s t r o e n t . , 76, p . 9 1 7 . —

29. V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s . Van Nos t r and Reinhold Comp.

30. Weisb rod t , N.W., Kienz le , M. a n d Cooke, A . R . , 1973, P r o c . Soc. Exp . Biol . Med . , 142, p . 4 5 0 .

3 1 . Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman a n d Ha l l , London .

32. Wolff, T . , 1978, I n t . Congr . Ser . Exc . Med. , 440, p . 1 9 6 .

3 3 . Y a s h u d a , Y. , C a b r a l , A.M. a n d Antonio , A . , 1976, P h a m a c o l . , 1 4 , p . 4 7 3 .

P r o p a n - 2 - o l ( I s o p r o p a n o l )

1. An tonova , V . I . a n d S a l m i n a , Z . A . , 1978, Gig . S a n i t . , 1, p . 8 .

2 . Akhrem, A . A . , P a p o v a , E.M. a n d M e t e l i t s a , D . I . , 1978, Biokhimiya (Moscow), 43 , p . 1 4 8 5 .

3 . B a r a s h k o v , S.G. a n d E l ik , F . I . , 1978, K h i m . - F a r m . Z h . , _12, p . 1 1 5 .

4 . Beauge , F . , Clement , M., Nordmann , J . a n d Nordmann , R. , 1977, Arch . I n t . P h y s i o l . B i o c h . , 85 , p . 9 3 1 .

5 . Beauge , F . , Clement , M. , Nordmann , J. a n d Nordmann , R. , 1979, Chem. Biol. I n t e r a c t . , 26, p . 1 5 5 -

6. B u r r o u g h s , G.E. a n d Thomas ime , J . , 1976, Report 75-145-327, Formica C o r p . , Ohio.

7. C h a p i n , M.A. , 1949, ] . Maine Med. A s s . , 40, p . 2 8 8 .

8. C i u c h t a , H . P . , S a v e l l , G.M. a n d S p i k e r , R . C . J r . , 1979, Tox. App l . P h a r m . , 49, p . 3 4 7 .

9 . Coleman, R . L . , L u n d , E.D. a n d Shaw, P . E . , 1972, J. A g r i c . Fd . Chem. , 20, p . 100.

10. DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. Ass . J . , 35 , p . 2 1 .

11 . Dubowsk i , K.M. , 1976, Chim. Chem. , 22, p . 8 6 3 .

12. F o l l a n d , D . S . , Schaf fne r , W., Ginn , H . E . , Crofford , O.B. a n d McMurray , D . R . , 1976, JAMA, 236, p . 1 8 5 3 .

13. G u n t e r , B . J . , L igo , R. a n d Ruhe , R. , 1976, PB Report 273711

14. IARC, 1977, Vol. _15, p . 2 2 3 .

15- I v a n e t i c h , K.M. , L u c a s , S. , M a r s h , J .A. a n d Z iman , M.R. , 1978, D r u g .

Me tab . D i s p . , 6, p . 2 1 8 .

16. M a c i n l y t e , N . , 1978, Gip . T r . P r o j . Z a b o l . , 12, p . 8 .

17. McCreery , M.J. a n d Hunt , W.A., 1978, N e u r o p h a r m . , \]_, p . 4 5 1 .

18. M c l n n e s , A . , 1973, B.M.J. , J_, 357.

19. Monick, J . A . , 1968, Alcohols . Chapman & Re inho ld , N.Y. 20. N o v o k o v s k a y a , M . I . , K l y u k v i n a , T . D . , K i r i l l o v a , N.N. a n d S h a p o s h n i k o v ,

Y n . K . , 1978, Prom. S a i n t . Och. Gazov, 5, p . 2 1 .

2 1 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d T o x i c o l o g y . , J. Wiley & Sons, N.Y.

22. P i l o t t i , A. , A n c k e r . K . , A r r h e n i u s , P . a n d Enze l l , C , 1975, T o x . , 5, p . 4 9 -

23 . Poh l , J . , 1922, Bioch. Z . , 127, p .66

24. Powis , G. , 1975, Bioch. ] . , 148, p .269

25. Rot te r , N . , Ro l le r , W. a n d Kund i , M., 1977, Z e n t r a l b l . B a k t . , B, J_b4, p . 4 2 8 .

26. S i e b e r t , 11., S i e b e r t , G. and Bohn, G. , 1972, Dtsch . Apoth .Z . 112, p .1040 .

27. T e x i c o l o g i c a l M o n o g r a p h s , F o u r t e e n t h Report of Joint FAO/WHO Exper t Committee on Food A d d i t i v e s , WHO/Food Add/70-39 , 1970, p . 1 1 4 .

28. T r a i l e r , G.J. a n d P l a a , G . L . , 1972, J. P h a r m . Exp . T h e r . , 183, p . 4 8 1 .

29. T r a i l e r , G.J . and P l a a , G . L . , 1973 Can . J. P h y s . P h a r m . , 5j_, p . 2 9 1 .

30. V e r s c h u c r e n , K., 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s , Van Nos t rand Reinhold Comp.

3 1 . Wewalka , G. , Kol ler , M., Rol le r , W. and S t a n e k , G. , 1977, Z e n t r a l b l . B a k t . , B, 1_65, p . 242.

32. Whr igh t , U., 1973, Dev. Tox ico l . Env . S e t . , 4, p . 9 3 .

33 . Wolff, T . , 1978, I n t . Congr . Ser . Exp . Med. , 440, p . 1 9 6 .

34. Y a s h u d a , Y. , C a b r a l , A.M. and Anton io , A. 1976, P h a r m a c o l . , 14, p . 4 7 3 .

35 . Z a k h a r i , S. et a l . , 1977, I s o p r o p a n o l and Retones in the E n v i r o n m e n t , CRC P r e s s , Oxford.

Buta n - l - o l

1. Ai t io , A. , 1977, Res. Comm. Chem. P a t h o l . P h a r m a c o l . , 2 - P-773-

2 . Ashford , M.L.J , and Wann, R . T . , 1979, J. P h y s i o l . , 295, p . 8 6 P .

3 . Auty , R.M. a n d B r a n c h , R .A. , 1976, J. P h a r m . Exp . T h e r . , 197, p . 6 6 9 .

4. Ba ikov , B .R . , Gusev , M . I . , Novikov, Y.V. a n d Y u d i n a , T.V. 1973, Gig . S a n i t . , 2, p . 1 3 .

5. Ba ikov , B.R. a n d R h a c h a t u r y a n , M.Rh . , 1973, Gig . S a n i t . , 38, p . 7 .

6. B i k f a l v i , 1. a n d P a s z t o r , L . , 1977, S z e s z i p a r , 25, p . 9 6 .

7. B i r k e t t , P . J . , 1974, C l in . Exp . P h a r m . P h y s i o l . , J_. p . 4 1 5 .

8. Bonte, W., 1978, B l u t a l k o h o l , 1_5, p . 3 9 2 .

9 . Bonte, W., 1979, B l u t a l k o h o l , 1_6, p . 1 0 8 .

B r a y , W.J. a n d Humphr i e s , C. , 1978, J. Sci . Food. A g r i c , _29, p . 8 3 9 . 10

11 . B rowning , E . , 1965. Tox ic i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s , E l s e v i e r , Amste rdam.

12. B u r d e n k o , V . P . a n d Bagmetov, N . P . , 1975, T r . Volgogr . Gen. Med. I n s t . , 26, p . 7 4 . —

13- C a t e r , B .R . , Cook, M.W., G a n g o l l i , S.D. a n d G r a s s o , P . , 1977, Tox ico l . Appl . P h a r m a c o l . , 4 1 , p . 6 0 9 .

14. C e d e r b a u m , A . I . , D icke r , E. and Cohen, G. , 1978, Biochem. , 17, p . 3 0 5 8 .

15. C e d e r b a u m , A . I . , D icke r , E . , Rub in , E. a n d Cohen, G. , 1979, Biochem. , 18, p . 1 1 8 7 . —

16. C h a n g , S . S . , P e t e r s o n , R.J . a n d Ho, C , 1978, J. Am. Oil Chem. S o c , 55, p . 7 1 8 . —

17. C a m p e r e , A.L. a n d Gr i f f i t h , W.L . , 1978, Dev. I n d . M i c r o b i o l . , 20, p . 5 0 9 .

18. De F e l i c e , A . , Wilson, W. a n d Ambre, J . , 1976, Tox ico l . Appl . P h a r m a c o l . , 36, p . 5 1 5 .

19. Di Vincenzo , G.D. a n d Hami l ton , M . L . , 1979, Tox ico l . Appl . P h a r m a c o l . , 48, p . 3 1 7 .

20. Dmi t r i ev , M.T. a n d M i s h c h i k h i n , V .A . , 1979, Gig . S a n i t . , 6, p . 4 5 .

2 1 . D u b i n i n a , O.N. a n d Raks imov , G .G . , 1976, Gig . T r . O k h r . , _9, p . 1 0 0 .

22. Dumont, J . P . a n d Adda , J . , 1978, J. A g r i c . Food. Chem. , 26, p . 3 6 4 .

23- F i s h e r , G . S . , L e g e n d r e , M.G. , L o v g r e n , N .V . , S c h u l l e r , W.H. a n d Wells, J . A . , 1979, J. A g r i c . Food Chem. , _27,' p . 7 .

24. F l a t h , R.A. a n d T a k a h a s h i , J . M . , 1978, J. A g r i c . Food Chem. , 26, p . 8 3 5 -

25 . F l a t h , R . A . , F o r r e y , R .R . , John , J . O . a n d C h a n , B . G . , 1978, J. A g r i c . Food Chem. , 26, p . 1 2 9 0 .

26. G e p p e r t , von E . , S t u r z , J . , H a a s e , W. a n d I s s e l h a r d , W., 1976, Arzneim. F o r s c h . , _26, p .1333-

27. G u k a s y a n , Z h . G . , B a r y s h e v a , K . F . , S a a k y a n , O.A. a n d A r u s t a m y a n , R .A . , 1979, Met. A r m n i . , _21_, p . 18.

28 . H a s t i n g s , J . J . H . , 1978, Econ. M i c r o b i o l . , 2, p . ' 3 1 .

29. Heske th , T . R . , K e i g h t l e y , C .A . , Metca l fe , J . C . a n d R i c h a r d s , C D . , 1978, J. P h y s i o l . , 278, p . 5 P .

30. J a d d o u , H .A. , P a v e y , J .A . a n d M a n n i n g , D . J . , 1978, J. D a i r y R e s . , 45 , p . 3 9 1 .

3 1 . J e n n e r et a l . , 1964, F d . Cosmet. T o x i c o l . , 2 , p . 3 2 7 .

32. J u l i a n o , R .L . a n d G a g a l a n g , E . , 1979, J. Ce l l . P h y s i o l . , 98, p . 4 8 3 .

3 3 . K a l e k i n , R.M. a n d B r i c h e n k o , V . S . , 1972, Nauch . T r . , I r k u t s k . Med. I n s t . , No. 115, p . 2 2 .

34. K h a c h a t u r y a n , M. , 1973, Vopr . Gig . Goroda , p . 7 1 .

35- K u d r e w i c z - H u b i c k a , Z . , Ko laczkowska ,M. , Borzemska , M. a n d Wesolowska, A . , 1978, Pol . T y g . L e k . , 33 , p . 3 9 5 -

36. MacGregor , D . C . , Schonbaum, E. a n d Bigelow, W.G. , 1964, C a n . J. P h y s i o l . P h a r m a c o l . , 42, p .689 -

37 . M a i c k e l , R . P . a n d M c F a d d e n , D . P . , 1979, Res . Comm. Chem. P a t . P h a r m . , _26, p . 7 5 .

38 . McCreery , M.J . a n d Hunt , W.A., 1978, N e u r o p h a r m a c o l o g y , 17, p . 4 5 1 .

39 . M c L a u g h i n , J . J r . , M a r l i a c , J . P . , V e r r e t , M . J . , M u t c h l e r , M.K. a n d F i t z h u g h , O .G. , 1964, Amer. I n d . Hyg. Ass . J . , 25 , p . 2 8 2 .

40. M e s l a r , H.W. a n d White, H . B . , I I I . , 1978, A n a l . Biochem. , 9J_, p . 7 5 .

4 1 . Mikheev , M . I . , F r o l o v a , A.D. a n d L y u b l i n a , E . I . , 1978, E k s p e r i m . Prom. T o k s i k o l . , p . 1 1 .

42. Monick, J . A . , 1968, Alcoho ls : T h e i r C h e m i s t r y , P r o p e r t i e s a n d M a n u f a c t u r e . C h a p m a n a n d Re inho ld , N.Y.

4 3 . M o s h l a k o v a , L . A . , S o l d a t c h e n k o v a , T . P . a n d D r u z h i n i n a , V.A. , 1976, Gig . Aspecty O k h r . , p . 6 5 -

44. N i z a r , T . I . , K h a l i l , M., Abd E l - G a l i l , Abou-Ze id , A. , E l - D i w a n y , A . I . a n d Mohamad, Y . , 1979, I n d i a n , Chem. Manuf. , 17, p . 5 .

45. N o v o k o v s k a y a , M . I . , K l y u k v i n a , T . D . , K i r i l l o v a , N.N. a n d S h a p o s h i n i k o v , Y u . K . , 1978, Prom. S a n i t . O c h i s t k a G a z o v . , _5, p . 2 1 .

46. Obe, G., Ris tow.M.J . a n d Herma, J . , 1977, Adv . E x p . Med. B i o l . , 85, A, p . 4 7 .

47. Obe, G. a n d Ristow, M . J . , 1977, Muta t ion R e s . , 55, p . 2 1 1 .

48 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d T o x i c o l o g y . Vol. I I , I n t e r s c i e n c e P u b l i s h e r s , N.Y.

49. P e t r o v a , N . I . a n d V i s h n e v s k i i , A . A . , 1972, N a u c h . T r . , I r k u t s h . Med. I n s t . , 115, p . 1 0 2 .

50. P i k c i u n a s , I . a n d S a n a t i n a , K . G . , 1976, A k t u a l . Vopr . O k h r . , p . 1 4 6 .

5 1 . P o s t e l , W. a n d Adam, L . , 1978, B r a n t w e i n W i r t . , 118, p .404-

52. P u r c h a s e , I . F . H . , 1969, S.A. Medica l J . , 53 , p . 7 9 5 .

53 . P u s k i n , J .A . a n d M a r t i n , T . , 1978, Mol. P h a r m . , _1_4, p . 4 5 4 .

54. R u m y a n t s e v , A . P . , Ost roumova , N . A . , K u s t o v a , S.A. , L o b a n o v a , I . U a . , T i u n o v a , L . V . , C h e r n i k o v a , V.V. a n d Kolesn ikov , P . A . , 1976, Gig . S a n i t . , 1 1 , p . 1 2 .

55. R u m y a n t s e v , A . P . , Geer , V . G . , Ost roumova , N.A. , S p i r i n , B.A. a n d S h a k h i d z h a n y a n , L . G . , 1975, Gig. S a n i t . , 10, p . 1 1 2 .

56. R u m y a n t s e v , A . P . , L o b a n o v a , I . Y a . , T i u n o v a , L.V. a n d C h e r n i k o v a , V . V . , 1979, T o k s i k o l . S a n i t . Khim. P l a s t m a s s , _2, p . 2 4 -

57. S a a d , S . F . , 1976, IRCS Med. Sci . L i b r . Compend. , 4, p .499-

58 . S a k a g a m i , Y. , Yokoyama, H. , K i t a n a k a , E. a n d I o k u , M., 1977, O s a k a -

f u r i t s u Koshu, 11 , p . 1 5 .

59. S a n a t i n a , K.G. , 1973, Vopr . Epidemio l . Gig . L i t o v . SSR, p . 1 8 3 .

60. S a v e l ' e v , A . I . , B a b a n o v , A.G. , Skobe i , . N.A. a n d T r o i t s k a y a , I . A . , 1975, F i z i o l . P a t o l . p . 5 9 .

6 1 . S c h r e i e r , P . , D r a w e r t , F . a n d Winkle r , F . , 1979, ]■ A g r i c . Food Chem. , 27, p . 3 6 5 .

62. S h a l a b y , E . S . , D a n a s o r y , M.E1. a n d M a s s o u d , A . A . E . , 1973, J. E g y p t . Med. A s s . , 54, p . 3 4 0 .

63 . S h e h a t a , M. a n d S a a d , S . , 1978, Pol . J. P h a r m a c o l . P h a r m . , 30, p . 3 5 -

64- S i t a n o v , V . S . , B a n d i k , K.A. , E n a k a e v a , V.G. a n d B a r a n o v a , R.K. , 1979, O t k r y t i y a , I z o b r e t . , 38, p . 9 0 .

65- Stock, K. a n d Schmid t , M., 1978, N a u n y n - S c h m i e d e b e r g ' s Arch . P h a r m a c o l . , 302, p . 3 7 .

66. Swords , G., Bobbio , P .A . a n d H u n t e r , G . L . K . , 1978, J. Food S c i . , 43 , p . 6 3 9 .

67. T a v l i n o v a , T . I . a n d D o v y b o r o v a , L . N . , 1979, I z v . V y s s h . Uchebn . Z a v e d . , 22, p . 9 7 2 .

68 . T e s c h k e , R. , H a s u m u r a , Y. a n d L i e b e r , C . S . , 1974, Biochem. B iophys . Res . Commun. , 60, p . 851 .

69 . T r e s s l , H. , F r i e s e , L . , F e n d e s a c k , F . a n d Koepp le r , H . , 1978, J. A g r i c . Food Chem. , _26, p . 1 4 2 6 .

70. Van Den Berg , A . P . , Noordhoek, J. a n d Kcopmann-Kool , E . , 1979a, Biochem. P h a r m a c o l . , _28, p . 3 1 •

7 1 . Van Den Berg , A . P . , Noordhoek, J. a n d Koopmann-Kool , E . , 1979b, Biochem. P h a r m a c o l . , _28, p . 3 7 .

72. V a n d e r k o o i , G. , C h a z o t t e , B. a n d Bie thman , R. , 1978, FEB5 L e t t e r s , 90, p . 2 1 .

73 . V e l a s q u e z , 1964, Med. T r a b a j o , 1_, p . 4 3 -

74- V e r s c h u e r e n , K. , 1977, Handbook of e n v i r o n m e n t a l d a t a on o r g a n i c c h e m i c a l s .

Van Nos t r and Reinhold Company .

75. W a l l g r e n , H. , I960, Acta P h a r m . T o x . , _16, p . 2 1 7 .

76. Walton, M.T. a n d M a r t i n , J . L . , 1979, Mic rob . Techno l . , 1_, p .187 -77. Wi l l i ams , R . T . , 1959, De tox ica t ion m e c h a n i s m s . 2nd E d . , Chapman a n d Ha l l ,

London .

78 . Winne, D . , 1978, N a u n y n - S c h m i e d e b e r g ' s Arch . P h a r m a c o l . , 301 , p . 1 7 5 .

79. Woidich, H. , P f a n n h a u s e r , W. a n d E b e r h a r d t , R. , 1978, Mit t . B u n d e s l e h r - V e r . W e i n - O b s t b a u , K l o s t e r n e u b u r g , 28, p . 5 6 .

80. Wolff, T . , 1978, E x c e r p t a Med. , 440, p . 1 9 6 .

8 1 . Z a i k i n a , E . I . , T e r e k h o v a , A . I . , Chudov , L . N . , S h a t e n s h t e i n , A . I . , P e t r o v , E . S . , S h c h e r b a k , V . P . , Z a k o m y r d i n , A .A. , S i m e t s k i i , M.A. and S o k h a d z e , L . A . , 1978, O t k r y t i y a , I z o b r e t . , 55 , p . 1 8 .

82. Z a i k o v , Kh. a n d Bobev, G. , 1978, Kh ig . Z d r a v e o p a z . , 2 1 , p . 1 4 1 .

8 3 . Yabumoto, K. , Y a m a g u c h i , M. a n d J e n n i n g s , W.G., 1978, Food Chem. , 3 , p . 7 .

84. Yaj ima, I . , Y a n a i , T . , N a k a m u r a , M. , S a k a k i b a r a , H. a n d Habu , T . , 1978, A g r i c . Biol. Chem. , 42, p . 1 2 2 9 .

85- Y a s h u d a , Y. , C a b r a l , A.M. a n d Antonio , A . , 1976, P h a r m a c o l o g y , 14, p . 4 7 3 .

B u t a n - 2 - o l

1. A b b o n d a n d o l o , A. , B o n a t t i , S. , Co r s i , C , C o r t i , G. , F i o r i o , R. , L e p o r i n i , L . , M a z z a c c a r o , A. a n d Nie r i , R. , 1981. The use of o r g a n i c s o l v e n t s in m u t a g e n i c i t y t e s t i n g , Mut. Res . , ( in p r e s s ) .

2 . B a r t h a , T . , Gonczi , L. a n d Mollo, A . , 1973, Egesz . , 22, p . 2 2 0 .

3 . Beaud , P . a n d Ramuz, A . , 1978, Mitt . Geb. L e b e n s . H y g . , 69, p . 4 2 3 .

4 . B i k f a l v i , I . a n d P a s z t o ŕ , L . , 1977, S z e s z i p a r , 25, p . 9 6 .

5. Bonte, W., 1978, B l u t a l k o h o l , _15, p . 3 3 2 .

6. Bonte, W., Decker , J. a n d Busse , J . , 1978, B l u t a l k o h o l , _16, p . 1 0 8 .

7. B r i n g - M a n n , G. and Kuehn, R., 1977, Z.Wasse r Abw. F o r s c h . , _10, p . l 6 l .

8. Dumont, J . P . a n d A d d a , J . , 1978, J. A g r i c . Food Chem. , 26, p . 3 6 4 .

9- F i s h e r , G . S . , L e g e n d r e , M.G. , L o v g r e n , N . V . , S c h u l l e r , W.H. a n d Wells, J . A . , 1978, J. A g r i c . Food Chem. , 27, p . 7-

10. F r e g e r t , S. , Gro th , 0 . , G r u y b e r g e r , B . , M a g n u s s o n , B . , Mobacken , H. a n d Rorsman , H. , 1971, Acta Derm. Vener . S t o c k h . , 5 1 , p . 2 7 1 .

1 1 . F r e g e r t , S. , Gro th , 0 . , Hjor th , N . , M a g n u s s o n , B . , Rorsman , H. a n d Ovrum, P . , 1969, Acta Derm. Vener . S t o c k h . , 49, p . 4 9 3 -

12. Ha tch , L . F . a n d M a t a r , S . , 1978, H y d r o . P r o . , 57, p . 1 5 3 .

13 . J u h n k e . I . a n d L u e d e m a n n , 0 . , 1978, Z .Wasse r Abw. F o r s c h . , 11 , p . l 6 l .

14. L a l a s i d i s , G. a n d S j o b e r g , L. B. , 1978, J. A g r i c . Food Chem. , 26, p . 7 4 2 .

15. Ma iccke l , R . P . a n d M c F a d d e n , D . P . , 1979, Chem. P a t h o l . P h a r m a c o l , 26, p . 7 5 .

16. McCreeny, M.J. a n d Hunt , W.A., 1978, N e u r o p h a r m . , 17, p . 4 5 1 -

17- Monick, J . A . , 1968, "Alcoho l s : t h e i r C h e m i s t r y , P r o p e r t i e s a n d M a n u f a c t u r e " , Re inho ld Book, N.Y.

18. Munch, J . C . a n d S c h w a r t z e , E .W. , 1925, J. L a b . C l i n . Med. , _10. P-985-

19. O l i a s J imenez , J . M . , D o b a r g a n e s G a r c i a , M . C . , G u t i e r r e z R o s a l e s , F . a n d G u t i e r r e z G o n z a l e z - Q u i j a n o , R. , 1978, G r a s a s Acei tes ( S e v i l l e ) , 29, p . 2 1 1 .

20. P a t t y , F . A . , 1963, Vol. I I , I n t e r s c i e n c e P u b l i s h e r s New York, p .1445-

2 1 . Poh l , J . , 1908, Arch . E x p . P a t h o l . P h a r m a k o l . , ( S u p p l . ) , p . 427 -

22. S c h r e i e r , P . , D r a w e r t , F . a n d Winkle r , F . , 1979, J. A g r i c . Food Chem. , 27, p . 3 6 5 . —

23. V e r s c h u e r e n , K. , 1977, Handbook of e n v i r o n m e n t a l d a t a on o r g a n i c c h e m i c a l s . Van Nos t r and Re inho ld Company , N.Y.

24. W a l l g r e n , H. , I960, Acta P h a r m a c o l . T o x i c o l . , _16, p . 2 1 7 .

25- Wi l l i ams , R . T . , 1959, De tox ica t ion m e c h a n i s m s , Chapman a n d Ha l l , London .

26. Woidich, H. , P f a n n h a u s e r , W. a n d E b e r h a r d t , R. , 1978, Mit t . B u n d e s l e h r -V e r s u c h s a n s t . W e i n - O b s t b a u , K l o s t e r n e u b u r g , 28, p . 3 6 .

27- Y a s h u d a , Y. , C a b r a l , A.M. a n d Antonio , A . , 1976, P h a r m a c o l o g y , 14, p . 4 7 3 .

T e r t i a r y Bu tano l

1. A b b a s o v , A . Z . , P a n o v , V.N. a n d Al iev , A .M. , 1971, Gig_. S a n i t . , 36, p . 6 1 .

2 . Afzal , S.M.J, a n d K e s a v a n , P . C . , 1979, I n t . J . R a d i a t . B i o l . , _35, p . 2 8 7 .

3 . Akhrem, A . A . , P o p o v a , E.M. a n d M e t e l i t s a , 0 . 1 . , 1978, Biokhimya (USSR), 43 , p . 1 4 8 5 .

4 . Be l l i n , S . I . a n d Edmonds , H . L . , J r . , 1976, P r o c . West. P h a r m . S o c , 19, p . 3 5 1 . —

5. B r i n g m a n n , G. a n d Kuehn , R. , 1978, Mit t . I n t . Ver . T h e o r . Angew. Limnol . , _21, p . 2 7 5 .

6. D e r a c h e , R. , 1970, I n t e r n a t i o n a l E n c y c l o p e d i a of P h a r m a c o l o g y on T h e r a ­p e u t i c s , s e c . 20, Ed. J. T r e m a l i e r e s . Vol. 2, Pe rgamon P r e s s .

7. Drey fus , M. , V a n d e n b u n d e r , B. a n d Buch, H . , 1978, FEBS L e t t e r s , 95 , p . 185.

8. G i l l e t t e , L . A . , Mi l l e r , D.L. a n d Redmann , H . E . , 1952, I n d . Was tes , 24, p . 1 3 9 7 . —

9. M a i c k e l , R . P . a n d McFadden , D . P . , 1973, Chem. P a t h . P h a r m a c o l . , 26, p . 7 5 .

10. McComb, J .A. a n d G o l d s t e i n , D . B . , 1979, J. P h a r m a c o l . E x p . T h e r . , 210, p . 8 7 .

1 1 . McCreery , N.J . a n d Hunt , W.A., 1978, N e u r o p h a r m . , J 7 , p . 4 5 1 .

12. Monick, J. A. , 1968, Alcoho ls : t h e i r c h e m i s t r y , p r o p e r t i e s a n d m a n u f a c t u r e , Re inhold Book C o r p o r a t i o n , New York.

13. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. I I , I n t e r s c i e n c e P u b l i s h e r s , N . Y . , p . 1 4 4 9 .

14. Ross , D . H . , 1976, A n n a l s N.Y. Acad . S c i . , 275, p . 2 8 0 .

15. S g a r a g l i , G . P . , Rizzot t i Con t i , M. , Benc in i , R . , Del ia Cor t e , L. a n d Gio t t i , A . , 1975, Boll . Soc. I t a l . Biol . S p e r . , 5 1 , p . 1 7 0 2 .

16. S u g i y a m a , T . , M i u r a , R. a n d Yamano, T . , 1976, Adv. E x p . Med. B i o l . , 74, p . 2 9 0 . —

17. V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s . Van Nos t r and Reinhold Company .

18. W a l l g r e n , H . , N i k a n d e r , P . , B o g u s l a w s k y , P . a n d L i n k o l a , J . , 1974, Acta P h y s i o l . S c a n d . , j U , p . 8 3 -

19. Wei sb rod t , N.W., Kienz le , M. a n d Cooke, A . R . , 1973, P r o c . Soc. E x p . Biol . Med . , 142, p . 4 5 0 .

20. Wi l l i ams , R . T . , 1959, De tox ica t ion m e c h a n i s m s . E d s . C h a p m a n a n d H a l l .

2 1 . Wood, J .M. a n d L a v e r t y , R. , 1979, P h a r m a c . Biochem. B e h a v . , _10, p . 1 1 3 -

22. Wood, J .M. a n d L a v e r t y , R. , 1976, P r o c . Univ . Otago Med. S c h . , 54, p . 8 6 .

23 . Z a m a r a k h i n a , L . E . , 1973, Gig . S a n i t . , _38, p . 7 2 .

24. Y a s h u d a , Y . , C a b r a l , A.M. a n d Anton io , A . , 1976, P h a r m a c o l o g y , 14, p . 4 7 3 .

Benzyl Alcohol

1. Ashford , M.L . J , a n d Wann, K . T . , 1976, P h y s i o l . R e v . , 56, p . 1 7 7 .

2 . B a k e r , N. a n d Huebo t t e r , R . J . , 1971, Life Sci . , _10, p . 1 1 9 3 .

3 . B a l t e s , W. a n d S o e c h t i g , I . , 1975, Z. Lebensm. U n t e r s . F o r s c h . , 169, p . 9 .

4 . Ba r , F .K. a n d G r i e p e n t r o g , F . , 1967, Mediz in . E r n a h r . , 8, p . 2 4 4 .

5 . B r a y , H .G. , T h o r p e , W.V. a n d White, K. , 1951, Biochem. J . , 48 , p . 8 8 .

6 . C o u l i b a l y , Y . , Seek, S. a n d Crouze t , J . , 1979, Ann. Techno l . A g r i c , 28 , P . 1 7 . —

7. Dawson, G.W., J e n n i n g , A . L . , Drozdowsk i , D. a n d K ide r , E . , 1977, J . H a z a r d . M a t e r . , 14, p . 3 0 3 .

8 . De L a n d , F . H . , 1973, Tox ico l . App l . P h a r m a c o l . , 25 , p . 1 5 3 .

9. D i a c k , S .L. a n d Lewis , H . B . , 1928, J. Biol . Chem. , 77, p . 8 5 .

10.

34.

E i c h b a u m , F.W. a n d Y a s a k a , W.J . , 1976, Bas ic Res . C a r d . , 7 1 , p . 3 5 5 .

11 . F r e u n d , G. , 1973, Life S c i . , _13, p . 3 4 5 -

12. G i l d m e i s t e r , E. a n d Hoffman, F . , Die A t h e r i s c h e n O l e . , Vol. I I l b , Akademie V e r l a g , B e r l i n .

13 . G r a h a m , B.E. a n d K u i z e n g a , M.H. , 1945, J. P h a r m a c o l . , _84, p . 3 5 8 .

14. Holmberg , B. a n d Malmfors , T . , 1974, E n v i r o n m . R e s . , ]_, p . 183.

15. Holmberg , B . , J a k o b s o n 1. a n d Malmfors , T . , 1974, E n v i r o n . R e s . , ]_, p . 1 9 3 .

16. Hjo r th , N . , 1961, Eczematous a l l e r g y to b a l s a m s , A a r h u u s St i f t . K u n k s g a a r d , C o p e n h a g e n , p . 9 6 .

17. J e n n e r et a l . , 1964, F d . Cosmet. T o x i c o l . , 2, p . 327 -

18. Kimura , E . T . , D a r b y , T . D . , K r a u s s , R.A. a n d B r o n d y k , H .D . , 1971, Tox ico l . App. P h a r m . , 18, p . 6 0 .

19. Motoyosh, K. , Toyosh ima , Y. , Sa to , M. a n d Y o s h i m u r a , M., 1979, Cos. T o i l . , 94, p . 4 1 .

20. L a g e r h o l m , B . , 1958, Acta A l l e r g . _1_2, p . 2 9 5 .

2 1 . Ma ie r , G.A. a n d Rob inson , J . D . , 1977, Bioderm. P h a r m . , 26, p . 7 9 1 .

22. McCreery , M.J. a n d Hunt , W.A., 1978, N e u r o p h a r m a c o l o g y , 17. , p . 4 5 1 .

23 . Menczel , E. a n d M a i b a c h , H . I . , 1972, Acta Derm. V e n . , 52, p . 3 8 .

24. Monick, J. A . , 1968, "Alcoho l s : t h e i r C h e m i s t r y , P r o p e r t i e s a n d M a n u f a c t u r e " , Chapman - Re inho ld , N.Y.

25 . Novak, E . , S t u b b s , S . S . , S a n b o r n , E .C . a n d E u s t i c e , R .M. , 1972, Tox ico l . App l . P h a r m a c o l . , 23 , p . 5 4 .

26. Nunomura , N . , S a s k i , M., Asao , Y. a n d Yoko t suka , T . , 1976, A g r i c . Biol . Chem. , 40, p . 4 8 5 .

27. O p d y k e , D . L . , 1973, Fd . Cosm. T o x i c o l . , JJ. , p . 1 0 1 1 .

28 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. I I , I n t e r s c i e n c e , N . Y . , p . 1 4 7 3 .

29. P i l o t t i , A . , Ancke r , K., A r r h e n i u s , E. a n d E n z e l l , C. , 1975, T o x i c o l o e v . 5 p . 4 9 . ^ -

30. P u s k i n , J .A. a n d M a r t i n , T . , 1978, Mol. P h a r m a c o l . , U, p . 4 5 4 .

3 1 . Scha fe r , E .W. , 1972, Tox ico l . Appl . P h a r m a c o l . , _2]_, p . 3 1 5 .

32 . S c h m i e d e b e r g , 0 . , 1881, Arch . E x p t l . P a t h o l . P h a r m a k o l . , _14, p . 2 8 8 .

3 3 . S e i z i n g e r , E. a n d D i m i t r i a d e s , D. , 1972, J a p c a , 22, ( 7 ) .

S e n a n a y a k e , U.M. , Lee , T .H. a n d Wil ls , R . B . H . , 1978, J. A g r i c . Food Chem. , 26, p . 8 2 2 . J s

35 . S h a r p , D.W., 1978, Tox ico logy , 9, p . 2 6 1 .

36 . S n a p p e r , I . , G r u n b a u m , A. a n d Neube rg , J . , 1923, Ned. T i i d s c h r . G e n e e s k . , 1, p . 4 2 6 . i

37 . V a n d e r k o o i , G. , C h a z o t t e , B. a n d B ie thman , R. , 1978, Febs L e t t e r s , 90, p . 2 1 .

3 8 . V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s . Van Nos t r and Reinhold Company .

39- Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman a n d H a l l .

40 . Y a s a k a , W.J . , E i c h b a u m , G.W. a n d Og ia , S. , 1979, C a r d i o v a s c u l a r R e s . , 13 , p . 7 1 1 .

Glycero l

1. B o r c h g r e v i n k , C . F . a n d Have l , R .J . 1963, P r o c . Soc. E x p . Biol . Med. , 113, p . 9 4 6 .

2 . Bovet , D . , C a n t o r e , G.A. a n d G u i d e t t i , B . , 1961, Gazz . I n t . Med. C h i r . , 66, p . 3 0 2 1 .

3 . Bowesman, C . , 1938, Br . J. S u r g . , _26, p . 8 6 .

4 . Bucke l l , H. a n d Walsh, . L . , 1964, L a n c e t , 2, p . 1 1 5 1 .

5 . Cameron , G.R. a n d F i n c k h . , E . S . , 1956, J. P a t h o l . , 71_> P-165-

6. C a n t o r e , G . P . , G u i d e t t i , B. a n d V i rno , M. , 1966, P o l i c l i n i c o , 73, p . 5 5 3 .

7. C a n t o r e , G . P . , G u i d e t t i , B. a n d V i rno , M. , 1965, J. N e u r o s u r g . , 21_, p . 2 7 8 .

8. C a n t o r e , G . P . G u i d e t t i , B. a n d V i rno , M., 1963, E x c e r p t a Med. I n t . C o n g r . S e r . , 60, p . 1 2 8 .

9- C h a h l , J . S . a n d O t t a w a y , J . H . , 1971, Biochem. ] . , 125, p . 7 3 .

10. C h u r c h i l l , P . , B idon i , A . , F l e i s c h m a n n , L. a n d Becker -McKenna , B . , 1977, Am. J. P h y s i o l . , 233, p . 2 4 7 .

1 1 . De i chmann , W., 1940, I n d . Med . , 9, p . 6 0 .

12. Dominguez-Gi l , A. a n d C a d o r n i g a , R. , 1971, F a r m a c o . P r a t . , 26, p . 5 3 5 .

13 . F i n c h k , E . S . , 1957, J. P a t h . B a c t . , 73 , p . 6 9 .

14. Have l , R . J . , 1965, Ann. N.Y. Acad . S c i . , 131, p . 9 1 .

15. H a r t w e l l , US P u b l i c Heal th Se rv ice P u b l i c a t i o n No. 149, 1951 a n d Supp lemen t , 1957.

16. J o h n s o n , J . D . , Hurwi t z , R. a n d Kre tchmer , J. N u t r . , 1971, 101, p .299 -

17. K iyosh i , K. a n d R y u t a , I . , 1972, Toho I g a k k a i Z a s s h i , _19, p . 4 1 5 .

18. K r a r u p , N . , L a r s e n , J .A . a n d Olsen , C. , 1975, Acta P h a r m a c o l . T o x i c o l . , 37, p . l .

19. Kruhoffer , P . a n d Ni s sen , O . I . , 1963, Acta P h y s i o l . S c a n d . , 59, p . 2 8 3 .

20. Ma ignon , F . a n d G r a n d e l a u d e , C . , 1930, C.R. Acad . S c i . , 190, p . 8 9 0 .

2 1 . M a n d e l l , S . , T a y l o r , J .M. a n d K o t s i l i m b a s , D . G . , 1966, J. N e u r o s u r g . , 24, p . 9 8 4 .

22. McCurdy, D .K . , S c h n e i d e r , B. a n d S c h r e i e , H . G . , 1966, Am.J. O p h t h a l m o l . , 6 1 , p . 1 2 4 4 .

23 . Monick, J . A . , 1968, Alcohols , Chapman a n d Reinho ld , N.Y.

24. P a p a n i c o l a o u , N . , C a l l a r d , P . , B a r i e t y , J. a n d Mil l i ez , P . , 1975, C l i n . Sci . Mol. Med. , 49, p . 5 0 7 .

25. Pfei f fer , C. a n d A r n o v a , I . , 1937, P r o c . Soc. E x p . Biol. Med. , 37, p . 4 6 7 .

26. P i t t e r , P . , 1976, Water R e s . , _10, p . 2 3 1 .

27. P r i d y b a i l o , N.D. a n d Sokolov, V . D . , 1975, T r . Vses . N a u c h n o - I s s l e d . T e k h n o l . I n s t . P t i t s e v o d , 39, p . 1 9 5 .

28. R a p a t z , G. a n d L u y e t , B . , 1968, G i o d y n a m i c a , _10, p . 1 9 3 -

29. R e s t i v e - M a n f r i d i , M.L. a n d P e c o r i - G i r a l d i , J . , 1967, Ann. O p h t h a l m . C l i n . O c u l . , 93 , p . 1 1 9 5 .

30. S a u e r , F . D . , E r g l e , J .D . a n d F i s h e r , L . J . , C a n . ] . Anim. S c i . , 1973, 53 , p . 2 6 5 . —

3 1 . S c h u b e l , K., 1937, S i t z u n g s b . P h y s . Med. Soz. zu E r l a n g e n , p . 2 6 3 -

32. S c h w a r z , K. et a l . , 1962, Klin . Woch. S c h r . , 40, p . 1 1 8 3 .

33 . Sen io r , B. a n d L o r i d a n , L . , 1968, N. E n g l . ]■ Med. , 279, p . 9 5 8 .

34. Simon, I . , 1915- Arch . P a r m a c o l . S p e r . , 20, p . 120.

35. S l o v i t t e r , H.A. , 1956, Am. ] . Med. S c i . , 231, p . 4 3 7 .

36. Smith, A . U . , 1950, L a n c e t , 2, p . 9 1 0 .

37. Smyth, H . F . , Sea ton , J. a n d F i s h e r , L. 1941, J. I n d . Hyg. T o x . , 23 , p . 2 5 9 .

38 . Solez, K., Kramer , E . C . , Fox, J .A. a n d H e p t i n s t a l l , R . H . , 1974, Kidney I n t . , 6, p . 2 4 .

39. Solez, K., Altman , J . , Rienhoff, H.Y. , Rie l a , A.R . , F i n e r , P.M. a n d H e p t i n s t a l l , R . H . , 1976, Kidney I n t . , 10, p . 1 5 3 -

40. S t a p l e s , R., Misher , A. a n d W a r d e l l , J . j r . , 1967, J. P h a r m . S c i . , 56, p . 3 9 8 .

4 1 . Sugimoto , K., 1935, Arb . D r i t t e n Abt. Ana t . I n s t . K a i s e r l i c k U n i v . , Kyoto Ser . D, 5, p . 1 5 4 . ~~~

42. T o r r e s , V . E . , Stong , C . G . , Romero, J . C . a n d Wilson, M . D . , 1975, Kidney I n t . , 7, p . 1 7 0 .

43 . T o x i c o l o g i c a l M o n o g r a p h s , Twen t i e th Report Join t FAO/WHO E x p e r t Committee on Food A d d i t i v e s , WHO/Fd. Add. S e r / 1 0 , 1976, p . 13.

44. T o u r t e l l o t t e , W.W., R e i n g l a s s , J . L . a n d Newki rk , T . A . , 1972, C l i n . P h a r m a c o l . T h e r . , _13, p . 159.

45 . V a l e r i , R. a n d H e n d e r s o n , M . E . , 1964, J . A . M . A . , 188, p . 1 1 2 5 .

46. Virno , M., Delia Rocca, L . , P e c o r i - G i r a l d i , J. a n d C a n t o r e , G . P . , 1966, Gazz . I n t . Med. C h i r . , 71, p . 1 1 6 0 .

47- Virno , M., Bucci , M.G. a n d P e c o r i - G i r a l d i , J . , 1966, Am. J. O p h t a l m o l . , 62, p . 824.

48 . Virno , M., Bucci , M.G. , P e c o r i - G i r a l d i , J. a n d C a n t o r e , G . P . , 1 9 6 5 , Boll, o c u l . , 55 , p . 2 2 5 .

49- Z i l v e r s m i t , D .B. a n d McCand les s , E . L . , 1957, P r o c . Soc. E x p . Biol. Med . , 95 , p . 7 5 5 .

50. Z i l v e r s m i t , D . B . , S o l k l y , N .K. , T r u m b u l l , M.L. a n d McCand le s s , E . L . , 1956, J. L a b . C l i n . Med. , 48, p . 3 8 6 .

5 1 . Werb, R . , C l a r k , W . F . , L i n d s a y , R .M. , Jones , E . O . P . , T u r n b u l l , D . l . a n d L i n t o n , A . L . , 1978, C l i n . Sci . Mol. Med. , 55 , p . 5 0 5 .

52 . Wes t fa l l , F . D . , 1977, A g r i c u l t u r e , F o r e s t r y a n d Wild l i fe , 513 B.

5 3 . Wilson, J . , C l a p p , M . J . L . a n d C o n n i n g , D .M. , 1978, B r . J . C a n c e r , 38, p . 2 5 0 .

54. Wink le r , B . , S tee l , R. a n d A l t s z u l e r , N . , 1969, Am. J. P h y s i o l . , 216, p . 1 9 1 .

55- Wolf, H . , H e l i c h a r , V. a n d M i c h a e l i s , R. , 1968, Biol . Neona te , _12, p . 1 6 2 .

P r o p a n e - l , 2 - d i o l

1. Amma, M . R . P . , D a n i , H.M. , A h l u w a l i a , P . , D h i n g r a , A . , K a u r , J . , Kau r , C. , S h a r m a , S . , J a i n . K . , S i n g h , S. a n d S a r e e n , K. , 1978, L i p i d s , J_3, p . 4 5 5 .

2 . A r u l a n a t h a m , K. a n d Myron, G. , 1978, J. P a e d . , 93 , p . 5 1 5 .

3 . B a r t s c h , W. , Sponer , G. , D ie tmann , K. a n d F u c h s , G. , 1976, A r z n e i m . - F . , 26, p . 1 5 8 1 .

4 . B a y l e y , H . S . , S l i n g e r , S.J . a n d Summers , J . D . , 1967, P o u l t r y S c i . , 46, p . 1 9 .

5 . Bost, J . a n d R u c k e b u s c h , Y. , 1962, T h e r a p i e , J 7 , p . 8 3 .

6. B u d d e n , R. , Kuehl , U.G. a n d B a h l s e n , J . , 1979, P h a r m . T h e r . , 5, p . 4 6 7 .

7. Curme, G .O . J r . a n d J o h n s t o n , F . , E d s . , 1952, G l y c o l s . , Am. Chem. Soc. M o n o g r a p h , Se r i e s 114.

8. D a v i e s , R . E . , H a r p e r , K.H. a n d Kynoch, S .R. , 1972, J. Soc. Cosm. Chem. , 23 , p . 3 7 1 .

9 . D a v i s , D . J . a n d J e n n e r , P . M . , 1959, Toxico l , a p p l . P h a r m a c o l . , _1, p . 5 7 6 .

10. D e a n , M.E. a n d Beres fo rd , H . S . , 1974, Tox. App l . P h a r m a c o l . , 28 , p . 4 4 .

1 1 . Dominguez-Gi l , A. a n d C a d o r n i g a , R. , 1971, F a r m . Ed. P r a t . , 26, p . 5 3 5 .

12. F a r s u n d , T . , 1978, V i r c h . A r c h . , B, 27, 1-6.

13 . G e b h a r d t , D . O . E . , 1968, T e r a t o l o g y , 1, p . 1 5 3 .

14. G o r b a n , N.S . a n d N e c h a e v a , A .V . , 1972, Vod. K a n . G i r . Soo . , _15, p . 7 2 .

15- H i l lman , M.G. a n d S c h n e i d e r , W.C. , 1975, J. Comp. P h y s . P s y . , 88 , p . 7 7 3 .

16. Kens ton , H . D . , M u l l i n s , M.D. a n d P o m e r a n t z , L . , 1939, Arch . P a t h o l . , 27 p . 4 4 7 . —

17. K o n r a d o v a , V . , V a v r o v a , V. a n d J a n o t a , J . , 1978, Fol . M o r p h . , ( P r a g u e ) , 26, p . 2 8 .

18. L e h m a n n , K.B. a n d F l u r y , F . , 1943, Toxico logy a n d Hygiene of I n d u s t r i a l S o l v e n t s , Wil l iams a n d Wi lk ins , Ba l t imore , p . 2 5 8 .

19. L i p k a n , G.N. a n d P e t r e n k o , V . S . , 1972, F i z . Akt . V e s h . , 4 , p . 1 2 5 .

20. L o p a t i n , P . V . , Safonov , V . P . , L i t v i n o v a , T . P . a n d Yak imenko , L . M . , 1972, Khim. F a r m . Z h . , 6, p . 3 6 .

2 1 . Majewsk i , H . S . , K l a v e r k a m p , J . F . a n d Scot t , D . P . , 1978, Water R e s . , 12, p . 2 1 7 . —

22. M a r t i n , G. a n d F r i b e r g , L . J . , 1970, P e d i a t . , 77, p . 8 7 7 .

23.

25.

28

29

38.

39 .

40.

4 1 .

McCreery , M.J. a n d Hunt , W.A., 1978, N e u r o p h . , J_7, p . 4 5 1 .

24. Mi l l e r , O.N. a n d B a z z a n o , G. , 1965, Ann. N.Y. Acad . S c i . , 119, p . 9 5 7 .

Mogre, K.M. , Amlad i , S .R . , Soman, P .D . a n d She th , U .K. , 1977, J. P o s t e r . Med. ( B o m b a y ) , 23 , p . 7 3 .

26. Monick, J. A . , 1968, Alcoho l s . Chapman a n d R e i n h o l d .

27. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , J. Wiley, N.Y.

P e v n y , I . a n d U l r i c h , M. , 1975, H a u t a r z t , 26, p . 2 5 2 .

R a z v i , F . , S h a r m a , G. a n d P o l a s a , M., 1979, A r o g y a , 5, p . 6 0 .

30. R u d d i c k , J . A . , 1972, Tox ico l , a p p l . P h a r m a c o l . , 21_, p . 1 0 2 .

3 1 . S a k a m i , W., 1950, Fed . P r o c , FASEB, 9, p . 2 2 .

32 . S a k a m i , W., 1950, J. Biol . Chem. , 187, p . 3 6 9 .

3 3 . S a k a m i , W. a n d Welch, A . D . , 1950, J. Biol . Chem. , 187, p . 3 7 9 .

34. Shmid t , A . A . , C h e r n y s h e v a , D .A . , B a s k a e v a , A . E . , A r e n d a r u k , A . A . , R a d c h e n k o , L . M . , T e p l o v a , R.V. a n d A n t o k o l s k a y a , M . Y a . , 1973, Khle . Kond. Prom. , _1, p . 2 2 .

35 . Sho re , R.N. a n d S h e l l e y , W.B . , 1974, A r c h s . Derm. , 109, p . 3 9 7 .

36. S t e n b a c k , F . a n d S h u b i k , P . , 1974, T o x i c . App l . P h a r m . , 30, p . 7 .

37. Thomas , J . F . , Kese l , R. a n d Hodge, H . C . , 1949, J. I n d . Hyg. T o x i c o l . , 3 1 , p . 256.

T o s h i y u k i , M. a n d K a g e a k i , A . , 1977, Sho. E i s . Z a s . , _18, p . 4 6 6 .

T o x i c o l o g i c a l M o n o g r a p h s , Seven t een th Report of Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s . WHO/Food Add. S e r . / 5 , 1974, p . 4 9 1 .

V e r s c h u e r e n , K., 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s , Van Nos t r and Reinhold Comp.

Waldo, D.R. a n d S c h u l t z , L.H. J. D a i r y . S c i . , I960, 43 , p . 4 9 6 .

42. Wieham, C . A . , McGuire , T . A . , M e h l t r e t t e r , C .L . a n d P a l m e r , H .H . , 1973 P r o d . D e v e l . , ]_, p . 5 9 .

43 . Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman & Ha l l .

44. Y a s a k a , W.J . , E i c h b a u m , F.W. a n d Oga , S. , 1979, C a r d i o v . R e s . , _13, p . 7 1 1 .

45 . Z a r o l i n s k i , J . F . , Browne, R.K. a n d P o s l ey , L . H . , 1971, Toxico l , a p p l . P h a r m a c o l . , 19, p . 5 7 3 . ^ ~

C y c l o h e x a n e

1. B r o w n i n g , E . , 1965, T o x i c i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s , E l s e v i e r , Ams te rdam, p . 130.

2 . E l l i o t t , T . H . , P a r k e , D.V. a n d Wi l l i ams , R . T . , 1959, Biochem. J . , 72, p . 1 9 3 .

3 . F a b r e , R . , T r u h a u t , R. a n d P e r o n , M. , 1952, Arch . M a l a d . P r o f e s s . , J_3, p . 4 3 7 .

4 . K imura , E . T . , E b e r t , D.M. a n d Dodge, P . W . , 1971, Tox ico l . a p p l . P h a r m a c o l . , 19, p . 6 9 9 .

5 . L a u n o y , L. a n d L e v y - B r u h l , M. , 1920, Compt. Rend . Soc. B i o l . , 83 , p . 2 1 5 .

6. L a z a r e w , N.W., 1929, Arch . E x p t l . P a t h o l . P h a r m a k o l . , 143, p . 2 2 3 .

7 . McCann, J . e t a l . , 1975, P r o c . Nat . Acad . S c i . , 72, ( 12 ) , p . 5 1 5 3 -

8. Mohn, G. a n d P h i l i p p , E . M . , 1974, H o p p e - S e y l e r ' s Z. P h y s i o l . Chem. , 355, p . 5 6 4 .

9 . P a c a u l t , A. a n d C a r p e n t e r , S . , 1949, Compt. R e n d . , 22, p . 3 4 4 .

10. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , V o l . 1 1 , p . 1208.

1 1 . She l l Chem. C y . , 1959, I n d u s t r i a l Hygiene B u l l e t i n , Safe ty Da ta Sheets 57-82 .

12. T r e o n , J . F . , C r u t c h f i e l d , W.E. a n d K i t zmi l l e r , K . V . , 1943, J. I n d . H y g . , 25 , p . 199 a n d 323 .

13 . V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Da ta on O r g a n i c C h e m i c a l s , Van Nos t r and Re inho ld Comp. , London, p . 2 0 4 .

14. Vio la , P . L . , I960, Bol l . Soc. I t a l . Biol . S p e r . , 36, p . I 9 6 0 .

15. Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman & Ha l l , London , p . 1 1 4 .

L igh t Pe t ro leum

1. WHO, 1981, Report of t h e 25th Jo in t FAO/WHO E x p e r t Committee, T e c h n . Rep . Se r . ( in p r e s s ) .

2 . Bohlen , P . , S c h u n e g g e r , U . P . a n d L a u p p i , E . , 1973, Tox ico l . a p p l . P h a r m a c o l . , _25, p . 2 4 2 .

3 . Nomiyama, K. a n d Nomiyama, H. , 1974, I n t . Arch . A r b e i t s m e d . , 32, p . 7 5 .

4 . DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. i n d . Hyg. Ass . J . , 35 , p . 2 1 .

5 . Kramer , A . , S t a u d i n g e r , H. a n d U l l r i c h , V . , 1974, Chemico-Biol . I n t e r a c t i o n s , 8, p . 1 1 .

6. Not ten , W.R.F . a n d H e n d e r s o n , P . T h . , 1975, Biochem. P h a r m a c , 24, p . 1 2 7 .

7. K imura , E . T . , E b e r t , D7M. a n d Dodge, P . W . , 1971, Tox ico l , a p p . P h a r m a c o l . , 19, p.699.

8. Her skowi tz , A . , I s h i i , N. a n d S c h a u m b u r g , H. , 1971, New E n g l a n d J. of Med . , 285, p . 8 2 .

9 . Yamamura , Y . , 1969, F o l i a . P s y c h i a t r . Neuro l . J a p . , _23, p . 4 5

10. S h i r a k e , T . , T s u d a , T . , T e r a o , A. a n d A r a k i , S. , 1974. J. Neurol . S c i . , 2 1 , p . 1 0 1 .

1 1 . Spence r , P . S . , S c h a u m b u r g , H .H . , R a l e i g h , R .L . a n d T e r h a a r , C . J . , 1975, A r c h s . N e u r o l . , 32, p .219-

12. Wi l l i ams , R .T . 1959, De tox ica t ion M e c h a n i s m s , Chapman & H a l l , London .

2 - N i t r o p r o p a n e

1. B ingham, E. a n d R o b b i n s , A . , 1980, NIOSH P u b l . No. 80-192.

2 . Browning E . , 1965, Tox ic i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s . E l s e v i e r , Amste rdam, p . 2 8 4 .

3 . Busey , N .M. , U l r i c h , C .E . a n d Lewis , T . R . , 1978, Tox. a p p l . P h a r m . , 45, A b s t r . 154.

4 . DHEW, 1977, C u r r e n t I n t e l l i g e n c e Bu l l e t i n 17-

5 . F i s h b e i n , L . , 1977, P o t e n t i a l I n d u s t r i a l C a r c i n o g e n s a n d M u t a g e n s , EPA 560 /5 -77-005 , p . 3 1 1 .

6. G a u l t i e r , M. et a l . , 1964, Arch . Mai . P rof . , 25 , p . 4 2 5 .

7. Gleason M.N. , Gosse l i n , R .E . a n d Hodge, H.C. 1963, C l i n i c a l Toxicology of commerc ia l p r o d u c t s , 2nd e d n . , Wil l iams & W i l k i n s , Ba l t imore , p . 8 6 .

8. H a r r i s , S . J . , Bond, G . P . a n d Niemeier , R.W., 1979, Tox. App l . P h a r m . , 48, (1) p a r t 2, A b s t r . No. 69-

9. Hawley , G.G. , 1971, The c o n d e n s e d Chemica l D i c t i o n a r y . 8th E d n . , Van Nos t r and Reinhold Comp. , N . Y . , p . 6 2 5 -

10. S a x , N . I . , 1975, D a n g e r o u s P r o p e r t i e s of I n d u s t r i a l M a t e r i a l s , 4th E d n . , Van Nos t r and Re inho ld Comp. N.Y. p . 9 7 2 .

11 . T o x i c o l o g i c a l M o n o g r a p h s , Twen ty - f i f t h Report of the Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s , WHO Food Add. , 1981, in p r e s s .

12. V e r s c h u e r e n , K. , 1977, Handbook of e n v i r o n m e n t a l d a t a on o r g a n i c c h e m i c a l s . Van Nos t r and Reinhold Comp. , N . Y . , p . 4 9 4 .

13- Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman & Ha l l , London .

Toluene

1. Banfe r , W., 1961, Z e n t r . A r b e i t s m e d . A r b e i t s s c h u t z . , 11 , p . 3 5 .

2 . B a t c h e l o r , J . J . , 1927, Am. J. H y g . , 7 , p . 2 7 6 .

3 . B r o w n i n g , E . , 1965, T o x i c i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s , E l s e v i e r , Ams te rdam, p . 6 6 - 7 6 .

4 . C a r p e n t e r , C . P . , Sha f fe r , C . B . , Weil, C .S . a n d Smyth, H . F . , j r . , 1944, J^ I n d . H y g . , _26, p . 6 9 .

5 . Collom, W.D. a n d Winek, C . L . , 1970, C l i n . T o x i c o l . , 3, p . 1 2 5 .

6. DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. Ass . J . , 35 , p . 2 1 .

7. Du tk i ewicz , T. a n d T y r a s , H . , 1968, Arch . G e w e r b e p a t h . G e w e r b e h y g . , 24, p . 2 5 3 . —

8. F a b r e , R. , T r u h a u t , R. , B e r n i c h a n , J . a n d L o i s i l l i e r , F . , 1955, Arch . Mlad . P r o f e s s . , _16, p . 2 8 5 .

9 . Gontzea , I . , B i s t r i c e a n u , E. , D r a g h i c e s c o , M. a n d Manea , M. , 1968, Arch . Sc i . P h y s i o l . , 22, p .397 -

10. M c L a u g h l i n , J . J r . , M a r l i a c , J . - P . , V e r r e t t , M . J . , M u t c h l e r , M.K. a n d F i t z h u g h , G .O . , 1964, I n d . Hyg. J . , 25 , p . 2 8 2 .

1 1 . Nomiyama, K. a n d Nomiyama, H. , 1974, I n t . Arch . A r b e i t s m e d . , 32, p . 7 5 .

12. P a g n o t t o , L . D . a n d L i e b e r m a n , L . M . , 1967, Am. I n d . Hyg. A s s . J . , 28, p . 1 2 9 .

13. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. 2, I n t e r s c i e n c e , N . Y . , p . 1 2 2 6 .

14. P r e s s , E. a n d Done, A .K. , 1967, P e d i a t r i c s , S p r i n g f i e l d , 39, p . 6 1 1 .

15. R e i s i n , E. , T e i c h e r , A-., J a f fe , R. a n d E l i a h o u , H . E . , 1975, B r . J . I n d . Med. , 32, p . 1 6 3 .

16. Sa to , A . , F u j i w a r a , Y . , H i r o s a w a , K. , 1972, J a p . J. I n d u s t r . H l t h . , 14, p . 3 .

17. Speck , B. a n d Moesch l in , S . , 1968, S c h v e i z . med. W s c h r . , 98 , p . 1 6 8 4 .

18. T o x i c o l o g i c a l M o n o g r a p h s , Twen ty - f i f th Report of t h e Jo in t FAO/WHO Expe r t Committee on Food A d d i t i v e s , 1981, in p r e s s .

19. Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman & Ha l l , p . 1 9 4 .

D ie thy l e t h e r

1. Bunke r , J . P . , 1962, A n a e s t h . , 23 , p .107 -

2 . DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. Ass . ] . , 35 , p . 2 1 .

3 . H a g g a r d , H.W., 1924, J. Biol . Chem. , 59, p .737 -

4 . K imura , E . T . , E b e r t , D.M. a n d Dodge, P .W. , 1971, Tox . a p p l . P h a r m . , 19, p . 6 9 9 . —

5 . Mol i tor , H . , 1936, J. P h a r m . E x p . T h e r . , 53 , p . 2 7 4 .

6. Morch, E . T . , A y c r i g g , J . B . a n d B e r g e r , M . S . , 1956, J. P h a r m . E x p . T h e r . , 117, p . 1 8 4 .

7. R o b b i n s , B . J . , 1935, J. P h a r m . E x p . T h e r . , 53 , p . 2 5 1 .

8 . T o x i c o l o g i c a l M o n o g r a p h s , T w e n t y - t h i r d Report of t h e Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s , 1979, i n p r e s s .

9 . Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , Chapman a n d H a l l , London .

D i b u t y l e t h e r

1. B r o w n i n g , E . , 1965, T o x i c i t y a n d Metabol ism of I n d u s t r i a l S o l . e n t s , E l s e v i e r , Amste rdam, p . 5 0 6 .

2. D r e w . R . T . , P a t e l , J .M. a n d L in , F a n - N a n , 1978, Tox. a p p l . P h a r m . , 45 , p . 2 1 9 .

3 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. I I , Wiley, N . Y . , p . 1 6 6 4 .

4 . S i l v e r m a n , L . , S c h u l t e , H . F . a n d F i r s t , W.W., 1946, J. I n d . Hyg. T o x . , 28, p . 2 6 2 .

5 . Smyth, H . F . j r . a n d C a r p e n t e r , C . P . , 1948, J. I n d . Hyg. T o x . , 30, p . l .

6 . Smyth, H . F . j r . , C a r p e n t e r , C . P . , Weil, C .S . a n d P o z z a n i , U . C . , 1954, Arch . I n d . H y g . , K), p . 6 1 .

7. V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s , Van N o s t r a n d Reinhold Comp. p . 150.

F u r f u r a l

1. B r o w n i n g , E . , 1965, T o x i c i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s , E l s e v i e r , p . 4 8 1 .

2 . J e n n e r et a l . , 1964, F d . Cosm. T o x . , 2, p . 327 -

3 . O p d y k e , D . L . J . , 1978, F d . Cosm. T o x . , Hi, ( S u p p l . ) , p . 7 5 9 .

4 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. I I , Wiley, N.Y.

5 . Wi l l i ams , R . T . , 1959, De tox ica t ion M e c h a n i s m s , Chapman a n d H a l l , p . 5 4 8 .

Acetone

1. A b b o n d a n d o l o , A . , Bonot t i , S . , C o r s i , C . , C o r t i , G. , F i o r i o , R. , L a p o r i n i , L . , M a z z a c c a r o , A. , N ie r i , R. , B a r a l e , R. a n d L o p r i e n o , N . , 1981, The use of o r g a n i c s o l v e n t s in m u t a g e n i c i t y t e s t i n g , Mut. R e s . , ( in p r e s s ) .

2 . A b s h a g e n , U. a n d R i e t b r o c k , N . N . , 1969, Arch . P h a r m a k . , 264, p . 1 1 0 .

3 . Ai t io , A . , 1977, Chem. P a t h . P h a r m a c , _18, p . 7 7 3 .

4 . A l l r e d , P.M. a n d S t r a n g e , J . R . , 1977, Arch . E n v i r o n . Contam. T o x i c o l . , 6, p . 4 8 3 . ~

5 . A n d e r s , M.W., 1971, Rev. P h a r m a c , JJ_, p . 3 7 .

6. A n d e r s , M.W., 1973, F o r t s c h r . Arzneim. , _17, p . 1 1 .

7. A n d e r s , M.W., 1969, A r c h s . Biochem. B i o p h y s . , 126, p .269 -

8. A n d r e j e w s k i , S. a n d P a r a d o w s k i , M. , 1975, Po l . J. P h a r m a c o l . , 27, p . 5 3 .

9 . B a d r e , R. , Gu i l l e rm , R. , A b r a n , N . , B o u r d i n , M. a n d Dumas , C. , 1978, Ann. P h a r m . F r a . , 36, p . 4 4 3 .

10. B a r t o l u c c i , G . B . , De Rosa , E . , Cocheo, V . , Manno , M. , De Z a n c h e , L . , N e g r i n , P . a n d F a r d i n , P . , 1979, Cuoio , P e l l i , M a t e r . C o n c i a n t i , 55, p . 3 6 3 .

11 . B e a u g e , F . , Clement , M. , Nordmann , J. a n d Nordmann , R. , 1977, Arch . I n t . P h y s . B i o c h . , 85 , p . 9 3 1 .

12. B l u z a t , R. , Jono t , 0 . , L e s p i n a s s e , G. a n d Senge , J . , 1979, Tox ico logy , 14, p . 1 7 9 . —

13- Bondol i , A . , M a g o l i n i , S . , M a r c h e t t i , B . , M e h r a b a n , M. , 1975, Acta Med. Rom., _13,, p . 2 2 7 .

14. B r a y , W.J . , H u m p h r i e s , C. a n d I n e r i t e r , M . S . , 1978, J. Sci . Food A g r . , 29, (2) p . 1 6 5 . —

15- B r i n g m a n n , G. a n d Kühne , R. , 1976, Z. W a s s e r / A b w a s s e r , , 117, H.9-

16. B r u g n o n e , F . , P e r b e l l i n i , L . , G r i g o l i n i , L. a n d Apos to l i , P . , 1978, I n t . Arch . Occup . E n v i r o n . H e a l t h , 42, p . 5 1 .

17. C a c c u r r i , S . , 1937, Biochim. e T e r a p . S p e r . , 24, p . 1 6 8 .

18 . C a m p b e l l , D. a n d Moore, R . H . , 1979, Am. I n d . Hyg. A s s o c . J . , 40, p . 9 0 4 .

19. C h e r r y , C . P . a n d G l u c k s m a n n , A . , 1965, B r . J . C a n c e r , 19, p . 2 8 7 .

20. Conk le , J . P . , Camp, B.J . a n d Welch, B . E . , 1975, E n v i r o n . H e a l t h , 30, p . 2 9 0 .

2 1 . D a r a c h u n i e n e , J. a n d V a i t e k u n i e n e , D . , 1973, Vopr . Ep idemio l . Gig . L i t o v . , p . 1 5 6 .

22. DiVincenzo, G . D . , Yanno , F . J . V . a n d A s t i l l , B . D . , 1973, Am. I n d . Hyg. Ass . J , 34 , p . 3 2 9 .

2 3 . Dowden, B . F . a n d B e n n e t t , H . J . , 1965, JWPCF, 37 , (9) p . 1 3 1 0 .

24. D u e n g e s , W. a n d Kiese l , K. , 1979, Adv. C h r o m a t o g r . , 14, p . 6 9 7 .

25 . E a g l e , J . L . , J r . , 1973, Am. I n d . Hyg. Ass . J . , 34, p . 5 3 3 .

26. E l k i n s , B . , 1959, The c h e m i s t r y of i n d u s t r i a l t o x i c o l o g y , New York, J . Wiley, 2nd e d i t i o n , p . 3 4 9 .

27 . F o l l a n d , D . S . , Scha f fne r , W., Ginn , H . E . , Crofford , O.B. a n d McMurray , D . R . , 1976, JAMA, 236, p . 1 8 5 3 .

28 . F r e d e r i c k , J . , McPherson , J . W . , B r idges a n d D e n n i s , V . P . , 1976, Biochem. J . , 154, p . 7 7 3 .

29. F r e e m a n , A . E . , W e i s b u r g e r , E . K . , W e i s b u r g e r , J . H . , Wolford, R . G . , M a r y a k , J .M. a n d H u e b n e r , R . J . , 1973, J. Nat . C a n e . I n s t . , 5 1 , p . 7 9 9 .

30. Ge l l e r , I . , G a n s e , E . , K a p l a n , H. a n d H a r t m a n n , R . J . , 1979, P h a r m a c o l . Biochem. B e h a v . , 11 , p . 4 0 1 .

3 1 . Goeke, G. , 1977, B l u t a l k o h o l , U, p . 4 0 1 .

32 . H a r r i s , L . C . a n d J a c k s o n , R . H . , 1952, Br i t . Med. J . , 2, p . 1 0 2 4 .

33- H a s t i n g s , J . H . , 1978, Econ. M i c r o b i o l . , 2, p . 3 1 .

34. Hung , G .W.C. , 1977, Microchem. J . , 22, p . 1 5 7 .

35 . I k e d a , M. a n d H i r a y a m a , T . , 1978, S c a n d . J . Work E n v i r o n . H e a l t h , _4, p . 1 1 .

36 . Kami, T . , 1977, J. Agr ._Food Chem. , 25 , p . 1 2 9 5 .

37 . K imura , E . T . , E b e r t , D.M. a n d Dodge, P . W . , 1971, Tox ico l . Appl . P h a r m a c o l . , 19, p . 6 9 9 .

38 . Koehler , A . E . , Windsor , E. a n d Hi l l , E . , 1941, J. Biol . Chem. , 140, p . 8 1 1 .

39 . L a h a m , S . , P o t v i n , M. a n d S c h r a d e r , K. , 1979, Chemosphe re , 8, p . 7 9 .

40. Majewsk i , H . S . , K l a v e r k a m p , J . F . a n d Scot t , D . P . , 1978, Water R e s . , 1 2 , p . 2 1 7 .

4 1 . Mazzu l lo , K. , 1975, O e s t e r r . Z. Onkol . , 2, p . 4 9 .

42. McDonald, I . A . , H a c k e t t , L . P . a n d Dusc i , L . J . , 1975, C l i n . Chim. Acta , 63 , p . 2 3 5 .

43 . M c L a u g h l i n , J . , 1964, Am. l n d . Hyg. Ass . ] . , 25 , p . 2 8 2 .

44. Moshonas , M.G. a n d Shaw, P . E . , 1979, J. Agr . Food Chem. , 27, p . 1 3 3 7 .

45- N iza r , T . I . , K h a l i l , A . E . M . , Abou-Ze id , A . , E l - D i w a n y , A . I . a n d Mohamad,

M.Y. , 1979, I n d i a n Chem. Manuf. , 1_7, (2) p . 5 -

46. Nomiyama, K. a n d Nomiyama, H. , 1974, I n t . Arch . A r b e i t s m e d . , 32, p . 8 5 -

47- P a p e c , I . , H e n d e r s o n , M. , Van Herrewege J . , D a v i d , J. a n d S o g a r , W., 1979, Biochem. G e n e t i c s , 17, p . 5 5 3 -

48. P a t t y , F . A . , 1963, I n d u s t r i a l Hyg. T o x i c o l . , Vol. I I , p . 1 7 2 6 .

49. P l i s h k e r , M . F . , T h o r p e , J .M. a n d Goldsmi th , L . A . , 1978, Arch . Biochem. B i o p h . , 191, p . 4 9 .

50. Powis , G. a n d Boobis , A .R . , 1975, Bioch. P h a r m . , 24, p . 4 2 4 .

5 1 . Powis , G. , 1975, Biochem. J . , 148, p .269 -

52. P r i c e , K . S . , et a l . , 1974, JWPCF, 46, p . 1 a n d p . 6 3 .

53 . Rhim, J . S . , P a r k , D .K . , W e i s b u r g e r , E.K. a n d W e i s b u r g e r , J . K . , J. Nat . C a n e . I n s t . , 52, p . 1 1 6 7 .

54. Rothkopf, H . , 1936, Z. g e s . e x p . Med . , 99, P .464 .

55- Sack , G. , 1940, Arch . G e w e r b e p a t h . G e w e r b e h y g . , 10, p . 8 0 .

56. S a k a m i , W. a n d L a f a y e , J . M . , 1951, Biol . Chem. , 193, p . 1 9 9 -

57. S c h w a r t z , L . , 1898, Arch . E x p t l . P a t h o l . P h a r m a k o l . , 40, p . 168.

58 . Scot t , J . E . , 1977, A n a l y s t , 102, p .614-

59- S e i z i n g e r , E. a n d D i m i t r i a t e d , D . , 1972, JAPCA, 22, No. 1.

60. S e p p a l a i n ^ n , A.M. , Husman, K. a n d Mor tenson , C. , 1978, S c a n d . J. Work E n v i r o n . H e a l t h , _4, p . 3 0 4 .

6 1 . She l l Chemica l s C o . , 1969, l n d . Hyg. Bu l l . I . C . , 69, p . 10.

62 . Smyth, M . F . J r . , 1962, l n d . Hyg. J . , 23 , p . 9 5 .

6 3 . Smith , C . J . , 1975, L a b . P r a c t . , 24, p . 9 -

64. Spec to r , W.S . , 1956, Handbook of Tox ico logy , Vol. I .

65- S p e n c e r , P . S . , Bischoff, M.C. a n d S c h a u m b u r g , H .H . , 1978, Tox. App l . P h a r m . , 44, p . 1 7 .

66 . S t e v e n s , J . T . , M c P h i l l i p s , J . J . a n d S t i t z e l , R . E . , 1972, Tox . Appl . P h a r m . , 23 , p . 2 0 8 .

67 . S w e n b e r g , J . A . , P e t z o l d , G.L. a n d H a r b a c h , P . R . , 1976, Biochem. Bioph. Res . Comm. , 72, p . 7 3 2 .

68 . T r a i g e r , G.J . a n d P l a a , G . L . , 1972, J. P h a r m . E x p . T h e r a p . , 183, p . 4 8 1 .

69 . T r a i g e r , G.J . a n d P l a a , G . L . , 1973, C a n . J. P h y s i o l . P h a r m a c o l . , 51_, p . 2 9 1 .

70. T r a i g e r , G.J . a n d P l a a , G . L . , 1974, Arch . E n v i r o n . H e a l t h , 28, p . 2 7 6 .

7 1 . V a i n i o , H. a n d H a r m i n e n , 0 . , 1972, Xenob io t i ca , 2, p . 2 5 9 .

72. V a i n i o , H. a n d Z i t t i n g , A . , 1978, S c a n d . J. Work E n v i r o n . H e a l t h , _4, p . 4 7 .

73 . V a l d i g u i e , P . , 1935, Compt. Rend. Soc. B i o l . , 118, p . 8 5 8 .

74- V a l t e k u n i e n e , D . , 1973, Vopr . Ep idemio l . G i g . , p . 1 4 1 .

75 . Van D u u r e n , B . L . , O r r i s , L. a n d Nelson, N . , 1965, J. Nat . C a n e . I n s t . , 35 , p . 7 0 7 . —

76. V e r s c h u e r e n , K. , 1977, Handbook of e n v i r o n m e n t a l d a t a on o r g a n i c c h e m i c a l s , Van Nos t r and Reinhold Company .

77. V i g l i a n i , E .C . a n d Z u r l o , N . , 1955, Arch . G e w e r b e p a t h . G e w e r b e h y g . , 13, p . 5 2 8 . —

78. Z e l l e r , H . , 1964, Naunyn Schmiedebe rgs Arch . E x p . P a t h . P h a r m a c , 247, p . 3 5 9 . —

79. Z u r l o , N. a n d Met r ico , L. , I960, Med, l a v . , p . 2 9 8 .

80. Walke r , N . E . , 1967, Tox. Appl . P h a r m . , 10, p . 2 9 0 .

8 1 . Walke r , N.J . 1973, J. D a i r y S c i . , 40, p . 2 9 .

82 . Wiberg , G . S . , 1971, C l i n . T o x i c o l . , 4, p . 9 9 .

83- Wil l iams R . T . , 1959, De tox ica t ion Mechan i sms , Chapman a n d H a l l , London .

84. Wolff, T h . , 1978, E x c e r p t a Med. , 440, p . 1 9 6 .

85 . Y o s h i k a w a , K. , A d a k i , K., H a l p r i n , K.M. a n d L e v i n e , V . , 1976, Br. J. Derma to l . , 94, p . 6 1 1 .

Methyl e t h y l ke tone

1. B r o w n i n g , E . , 1965, T o x i c i t y a n d Metabol ism of I n d u s t r i a l S o l v e n t s , E l s e v i e r , Ams te rdam, p . 4 2 1 .

2 . C o u r i , D. et a l . , 1977, Tox. Appl . P h a r m . , 4 1 , p . 2 8 5 .

3 . Die tz , F . K . , T r a i g e r , G.J . a n d S t e l l a , V . , 1979, Tox. Appl . P h a r m . , 48, (1) A155. —

4 . DiVincenzo, G .D . , K a p l a n , C . J . a n d D e d i n a s , J . , 1976, Tox. a p p l . P h a r m . , 36, p . 5 1 1 .

5 . Dyro , F . M . , 1978, C l i n . T o x . , 13 ( 3 ) , p . 3 7 1 .

6 . H a y d e n , J . W . , Comstock, E.G. a n d Comstock, E . S . , 1976, C l i n . T o x . , 9 ( 2 ) , p . 1 6 9 . ' _

7. H e t l a n d , L . B . , C o u r i , D. a n d -Abde l -Rahman , M . S . , 1976, Tox. a p p l . P h a r m . , 37, p . 1 1 .

8 . K imura , E . T . , E b e r t , D.M. a n d Dodge, P . H . , 1971, Tox ico l . a p p l . P h a r m a c o l . , _19, p . 6 9 9 . —

9. Kohl i , R . P . , et a l . , 1967, I n d . J. Med. R e s . , 55 (11 ) , p . 1 2 2 1 .

10. L e o n a r d o s , G. , K e n d a l l , D. a n d B a r n a r d , N . , 1969, J. Air Po l l . C o n t r . A s s . , _19 ( 2 ) , p . 9 1 .

1 1 . N a k a h a r i a n d Mori , 1939, P r o c . I m p . Acad . J a p a n , 15, p . 2 7 8 .

12. N a k a h a r i a n d Mori , 1940, P r o c . I m p . Acad . J a p a n , 34, p . 1 4 3 .

13. O p d y k e , D . L . J . , 1977, Food C o s m . T o x . , _15, (6) p . 6 2 7 .

14. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. 2, I n t e r s c i e n c e , N . Y . , p . 1 7 3 1 .

15. P r i c e , K . S . , Waggy , G.T. a n d Conway , R .A . , 1974, J. Water P o l l . Con. F e d . , 46, ( 1 ) , p . 6 3 .

16. S a i d a , K. , Mende l l , J .R . a n d Weiss, H . 5 . , 1975, J. N e u r o n a t h . E x p . N e u r o l . , 35 , p . 2 0 7 .

17- Schwetz , B .A . , Leong , B .K.J . a n d G e h r i n g , P . J . , 1974, Tox ico l . a p p l . P h a r m a c o l . , 28 , p . 4 5 2 .

18. S p e n c e r , P . S . a n d S c h a u m b u r g , H .H . , 1976, Tox ico l , a p p l . P h a r m a c o l . , 37, p . 3 0 1 .

19. T r a i g e r , G . J . , B r u c k n e r , J .V. a n d Cooke, P . M . , 1975, Tox. a p p l . P h a r m . , 33 , p . 1 3 2 .

20. Un i l eve r L t d . , 1971, U n p u b l i s h e d S t u d i e s .

2 1 . V e r s c h u e r e n , K. , 1977, Handbook of E n v i r o n m e n t a l Data on O r g a n i c C h e m i c a l s , Van Nos t r and Reinhold Comp. , N . Y . , p . 4 5 3 -

22. Wes ley-Hor ton , A. et a l . , 1965, Cance r R e s . , 25 , p . 1759-

23 . Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , C h a p m a n & H a l l , London , p . 9 5 .

24. Wurs t e r , D .E . a n d Munies , R. , 1965, J. P h a r m . Sci . , 54 ( 4 ) , p . 5 5 4 .

D i i s o p r o p y l ke tone

Chloroform

1. De S a l v a , S. , Volpe, A . , L e i g n , G. a n d R e g a n , T . , 1975, Fd . Cosm. Tox. , 1 3 , p . 5 2 9 .

2 . DiVicenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. Ass . J . , 35 , p . 2 1 .

3 . H e l l e k a n t , 1964, Acta P h a r m . T o x . , _21_, p . 2 4 0 .

4 . IARC, 1979, Monographs on the E v a l u a t i o n of t h e C a r c i n o g e n i c Risk of Chemica l s to Humans , 20, p . 4 0 .

5 . Kutob , S.D. a n d P l a a , G . L . , 1962, J. P h a r m a c , 135, p . 245 -

6. P l a a , G.L. a n d L a r s o n , R . E . , 1965, Tox. a p p l . P h a r m . , 7_, p . 3 7 .

7. Re i t z , R . H . , Q u a s t , J . F . , S to t t , W.T . , W a t a n a b e , P .G . a n d G e h r i n g , P . J . , 1980, Water c h l o r i n a t i o n , Ann Arbor P r e s s , p . ( in p r e s s ) .

8 . R e y n o l d s , E . S . , 1972, Biochem. P h a r m a c , 21, p . 2 5 5 5 -

9. Ta rd i f f , R . G . , 1976, 96th Ann. Conf. Amer. Water Works A s s . , New O r l e a n s .

10. T r a i g e r , G .T . a n d P l a a , G . L . , 1974, A r c h s . e n v i r . Hl th . , ' 28 , p . 2 7 6 .

D i c h l o r o m e t h a n e

1. A s t r a n d , I . , Ovrum, P . a n d C a r l s s o n , A . , 1975, S c a n d . J. Work. E n v i r o n . H l t h . , 1, p . 7 8 .

2 . B a l l a n t y n e , B . , G a z z a r d , M . F . a n d S w a n s t o n , D.W., 1976, P rev iew of "Tox i co logy" in BIBRA In fo rma t ion B u l l e t i n , 1 5 , p . 2 7 7 -

3 . B o r n s c h e i n , R . L . , H a s t i n g s , L. a n d Manson , J . M . , 1980, Tox ic . App l . P h a r m . , 52, p . 2 9 -

4 . Committee of t h e American Conference of G o v e r n m e n t a l I n d u s t r i a l H y g i e n i s t s , 1973, M i c h i g a n ' s O c c u p a t i o n a l H e a l t h , 2 2 ( D , p . 3 .

5 . DiVincenzo , G . D . , Yanno , F . J . a n d A s t i l l , B . D . , 1972, Am. i n d . Hyg. Assoc. J . 33 , p . 1 2 5 .

6. DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Amer. i n d . Hyg. A s s o c . J . , 35 , p . 2 1 .

7. DiVincenzo, G.D. a n d Hami l ton , M . L . , 1975, Tox ico l , a p p l . P h a r m a c o l . , 32, p . 3 8 5 .

8 . G a m b e r a l e , F . , A n n w a l l , G. a n d H u l t e n g r e n , M. , 1975, S c a n d . J. Work. E n v i r o n . H l t h . , J_» P - 9 5 .

9 . H a r d i n , B.D. a n d Manson , J .M. 1980, Tox ic , a p p l . P h a r m . , 52, p . 2 2 .

10. IARC, 1979, Vol. 20, 460.

11 . K imura , E . T . E b e r t , D.M. a n d Dodge, 1971, P . W . , Tox ico l , a p p l . P h a r m a c o l . , 19, p.699.

12. Loyke , H . F . , 1973, A r c h s . P a t h . , 95 , p . 1 3 0 .

13 . Norpo th , K., Wi t t i ng , U . , S p r i n g o r u m , M. a n d Wi t t i ng , C h . , 1974, I n t . Arch . A r b e i t s m e d . , 33 , p . 3 1 5 .

14. R a t n e y , R . S . , Wegman, D.H. a n d E l k i n s , H . B . , 1974, Arch , e n v i r . Hl th . , 28, p . 2 2 3 .

15- R e y n o l d s , E . S . , 1972, Biochem. P h a r m a c , 22, p .2555-

16. Roth, R . P . , Drew, R .T . a n d F o u t s , J . R . , 1975, Tox ico l , a p p l . P h a r m a c o l . 33 , p . 4 2 7 .

17. Schwetz , B .A . , L e o n g , ^ B.K.J . a n d G e h r i n g , P . J . , 1975, Tox ico l . a p p l . P h a r m a c o l . , 32, p . 8 4 .

18. S t e w a r t , R . D . , F i s h e r , T . N . , Hosko, M . J . , P e t e r s o n , J . E . , B a r e t t a , E.D. a n d Dodd, H . C . , 1972, A r c h s . e n v i r . H l t h . , 25 , p . 3 4 2 .

19. T o x i c o l o g i c a l M o n o g r a p h s , F o u r t e e n t h Report of t h e Jo in t FAO/WHO Expe r t Committee on Food A d d i t i v e s ; FAQ Nu t r i t i on Meet ings Report Ser ies No. 48A; WHO/Food A d d . / 7 0 . 3 9 , 1970, p . 9 4 .

20. Winneke , G. a n d F o n d o r , G.G. , 1976, Occ. Hl th . Safe t . , 45 , p . 3 4 .

T r i c h lor e t h y l e n e

1. B a r t s c h , H. , M a l a v e i l l e , C , B a r b i n , A. a n d P l a n c h e , G. , 1979, Arch . Tox ico l . , 4 1 , p . 2 4 9 .

2 . Van D u u r e n , B . L . , Go ldschmid t , M . B . , L o e w e n g a r t , G. , Smith , A . C . , Melchlorme, S . , Se ldman , I . a n d Roth, D . , 1979, JNCI, 63 , p . 1 4 3 3 .

3 . F a h r i g , R. , 1977, Arch . T o x i c o l . , 38 , p . 8 7 .

4 . H e n s c h l e r , D . , Romen, W., E l a s s a r , H.M. , R e i c h e r t , D . , Ede r , E a n d R a d w a n , Z . , 1980, Arch . T o x i c o l . , 43 , p . 2 3 7 .

5 . 1ARC, 1979, Vol. 20, p . 5 4 5 .

6. I s m a i l o v , A.S . a n d R y s k a l , G.V. , 1976, Uch. Z a p . Min. v y s s h . , _1. P - 6 .

7. Konie tzko , H . , H a b e r l a n d t , W., H e i l b r o n n e r , H . , Re i l l , G. a n d W e i c h a r d t , H. , 1978, Arch . T o x i c o l . , 40, p . 2 0 1 .

8 . M a l t o n i , C . , 1979, Med, d . L a v . , in p r e s s .

9 . Wa te r s , E . M . , G e r s t n e r , H.B. a n d Huff, E . J . , 1977, J. Tox. Env . H y g . , 2 , p . 6 7 1 . ** -

1 , 2 - D i c h l o r o e t h a n e

1. Alumot, E . , Nachtomi , E . , M a n d e l , E . , Ho l s t e in , P . , Bondi , A. a n d H e r z b e r g , M., 1976, Fd . Cosmet. Toxico l . , _U, p . 105.

2 . Alumot, E . , Me id l e r , M., Ho l s t e in , P . a n d H e r z b e r g , M., 1976, F d . Cosmet. T o x i c o l . , 14, p . l l l .

3 . B a h l m a n , L . J . et a l . , 1978, Am. I n d . Hyg. Assoc. J. , 39, A-35-43 .

4 . DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Am. I n d . Hyg. Ass . J . , 35 , p . 2 1 .

5 . G r u e n g e r i c h , F . P . , C rawfo rd , W.M.J r . , Domoradzk i , J . Y . , MacDonald , T . L . a n d W a t a n a b e , P . G . , 1980, Tox. a p p l . P h a r m a c , 55 , p . 3 0 3 .

6. IARC, 1979, Vol. 20, p . 4 2 9 .

7. Kemper, F . H . , 1973, U n p u b l i s h e d Repor t .

8. M a l t o n i , C , 1978, U n p u b l i s h e d Report to EEC Working Group on C l a s s i f i c a t i o n of D a n g e r o u s S u b s t a n c e s .

9 . N a t i o n a l C a n c e r I n s t i t u t e , 1978, PHEW P u b l i c a t i o n No. (NIH) 78-1305.

10. Von O e t t i n g e n , W.R. , 1955, P u b l . Hl th . S e r v . P u b l . , No. 414.

1 1 . R a n n u g , U. , S u n d v a l l , A. a n d Ramel , C , 1978, Chem. Biol . I n t e r a c t . . 20 p . l . —

12.

14.

R a n n u g , U. a n d Bei je , B . , 1979, Chem. Biol . I n t e r a c t . , 24, p . 2 6 5 .

13 . R a n n u g , U. , 1980, Muta t ion R e s . , 76, p . 2 6 9 .

T o x i c o l o g i c a l M o n o g r a p h s , F o u r t e e n t h Report of t h e Jo in t FAO/WHO Expe r t Committee on Food A d d i t i v e s ; FAQ Nut r i t i on Meet ings Report Ser ies No 48A-WHO/Food a d d . / 7 0 . 3 9 , 1970, p .91~ — "

Carbon t e t r a c h l o r i d e

1. Alumot, E . , Nachtomi , E . , M a n d e l , E . , Ho l s t e in , P . , Bondi .A . a n d H e r z b e r g , M. , 1976, F d . Cosm. T o x . , _14, p . 1 0 5 .

2 . Cohen, 1957, N e u r o p a t h . , ]_, p . 2 3 8 .

3 . D a m b r a u s Kas a n d C o r n i s h , 1970, Tox. Appl . P h a r m . , 17, p . 8 3 .

L,. DiVicenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Amer. I n d . Hyg. Ass . J . , _35, p . 2 1 .

5 . G e r h a r d et a l . , 1972, Virchows Arch . Abt . B. Z e l l p a t h . , _10> P-184-

6. G lende , E . A . , 1972, Biochem. P h a r m a c , 2 1 , p . 1 6 9 7 .

7. H e r z b e r g , M. , 1976, Fd . Cosm. T o x . , U, p . 1 0 5 .

8 . 1ARC, 1979, Vol. 20, p . 3 7 3 .

9 . J o h n s t o n , G.W. a n d Wi l l i ams , A . O . , 1966, I r . J. med. S c i . , 6, p . 2 3 .

10. K l a a s s e n , C D . a n d P l a a , G.L. 1967, P r o c . Soc. e x p . B i o l . M e d . , _124, p . 1 1 6 3 .

1 1 . Max imchuk , A.J . a n d R u b i n s t e i n , D . , 1961, Ann. Occup . H y g . , _4, p . 4 9 .

12. P l a a , G.L. a n d L a r s o n , R . E . , 1965, Tox. a p p l . P h a r m . , ]_, p . 3 7 .

13 . P r e n d e r g a s t , J . A . , Jones , R .A . , J e n k i n s , L . J . a n d S i e g e l , J . , 1967, Tox. a p p l . P h a r m . , _1£, p . 2 7 0 .

14. Re ube r , M.D. , 1970, JNCI, 45 , p .1237-

15. R e u b e r , M.D. , Glover , E . L . a n d Dove, L . F . , 1969, G e r o n t o l o g i a , _15, p . 7 .

16. T a y l o r , H.W., L i j i n s k y , W., Net teshe im, P . a n d S n y d e r , C M . , 1974, C a n c e r R e s . , 34, p . 3 3 9 1 .

17. Wong, L .C .K . a n d DiStefano, V . , 1966, Tox. a p p l . P h a r m . , 9, p . 4 8 5 .

C i s - 1 , 2 - d i c h l o r o e t h y l e n e ( a c e t y l e n e d i c h l o r i d e )

T r a n s - 1 , 2 - d i c h l o r o e t h y l e n e ( a c e t y l e n e d i c h l o r i d e )

1. F r e u n d t , K . H . , L i e b a l d t , G . P . a n d L i e r b e r w i t h , E . , 1976, P e r s . Coram.

D i c h l o r o d i f l u o r o m e t h a n e

1. Aza r , A . , R e i n h a r d t , C . F . , Maxf i e ld , M . E . , Smith , P . E . a n d Mul l in , L . S . , 1972, Am. I n d . Hyg. Ass . J . , 33 , p . 2 0 7 .

2 . Aza r , A . , T r o d i i m o w i t z ^ H . J . , T e r r i l l , J . B . a n d Mul l i n , L . S . , 1973, Am. I n d . Hyg. Ass . J . , 34, p . 1 0 2 .

3 . C l a y t o n , J . W . , 1966, Tox. Anes th . P r o c . Res . S y m p . , 77.

4 . G r a f o r d , L . , 1969, Food T e c h . , _18 (4) 152.

5 . Hoffmann, B . , 1968, Aeroso l . R e p . , 7 (3) 108.

6. M a r i e r , G. , M a c F a r l a n d , H . , Wiberg , C . S . , B u c h w a l d , H. a n d D u s s a u l t , P . , 1974, C a n . Med. Ass . J . , I l l , p . 3 9 -

7. Q u i g l e y , A.D. a n d S h e r m a n , H . , 1966, U n p u b l i s h e d r e p o r t No. 12-66 from Hacke l l L a b o r a t o r y .

8 . Smith , J .K. a n d C a s e , M . T . , 1973, Toxico l , a p p l . P h a r m a c o l . , 26, p . 4 3 8 .

9 . T o x i c o l o g i c a l M o n o g r a p h s , N ine teen th Report of t h e Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s : FAQ N u t r i t i o n Meet ings Report Ser ies No. 55A; WHO A d d i t i v e s Se r i e s No. 8, 1975- p . 5 8 .

D ic h lo ro f l uo rome thane

1. A v i a d o , D .M. , 1974, P r o g r . R e s . , Jj3, 365.

2. A v i a d o , D.M. a n d Be le j , M.A. , 1974, Tox ico logy , 2, p . 3 1 .

3 . Be le j , M.A. , Smith , D.G. a n d Av iado , D .M. , 1974, Tox ico logy , 2, p . 3 8 1 .

4 . F r i e d m a n et a l . , 1973, Tox ico logy , _1, p . 3 4 5 -

1 , 2 - D i c h l o r o t e t r a f l u o r o e t h a n e

1. P a t t y , F .A. 1963, I n d u s t r i a l Hygiene & Tox ico logy , Vol. II I n t e r s c i e n c e .

2. A v i a d o , D .M. , 1974, P r o g r . R e s . , _18, p . 3 6 5 -

1 , 1 , 2 - T r i c h l o r o t r i f l u o r e t h a n e

1. A v i a d o , D.M. a n d Be le j , M.A. , 1974, Tox ico logy , 2, p . 3 1 .

2 . A v i a d o , D.M. a n d Be le j , M.A. , 1975, Tox ico logy , _3, p . 7 9 .

3 . Be le j , M.A. , Smith , D.G. a n d A v i a d o , D .M. , 1974, Tox ico logy , 2,, p . 3 8 1 .

4 . C l a y t o n , J . W . , 1968, T o x i c i t y of A n a e s t h e t i s , (Ed) R .B . F i n k . , Wil l iams a n d W i l k i n s , Ba l t imore , p . 7 7 -

5 . DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Amer. I n d . Hyg. A s s o c . J . , 35 , p . 2 1 .

6. E p s t e i n , S .S. et a l . , 1967, N a t u r e , 214, p . 5 2 6 .

7. I m b u s , H.R. a n d A d k i n s , C. , 1972, Arch , e n v i r n . H l t h . , 24, p .257-

8. Kub le r , K. , 1963, J. Soc. Cosmet. Chem. , U, p . 2 6 3 .

9- Michae l son a n d H u n t s m a n , 1964, J. Med. Chem. , _7, p . 3 7 8 .

10. Smith , J .K. a n d C a s e , M . T . , 1973, Tox ico l , a p p l . P h a r m a c o l . , _26, p . 4 3 8 .

l i . S t o p p s , G.J . a n d M c L a u g h l i n , M. , 1967, Amer. I n d . Hyg. A s s o c . ] . , 28, p . 4 3 .

12. T r o c h i n o w t z , H . J . , Azar , A . , T e r r i l l , J . B . a n d Mul l i n , L . S . , 1974, A m . I n d . Hyg. Assoc. J . , _35, p . 6 3 2 .

Methyl a c e t a t e

1. Opoyke , D . L . J . , 1979, Fd . Cosmet. T o x i c o l . , _17 (Supp l ) p . 8 5 9 .

E t h y l a c e t a t e

1. Althoff, E . , 1931, Z. Med. B e a m t e . , _15, p . 4 2 0 .

2 . Amer. Conf. Govern . I n d . H y g . , 1971, Documenta t ion of T h r e s h o l d Limit V a l u e s , 3 rd e d n .

3 . C e n t r a l I n s t i t u t e for Nu t r i t i on a n d Food Resea rch 1974, Report R4319-

4 . C e n t r a l I n s t i t u t e for Nu t r i t i on a n d Food Resea rch 1974, Report No. 4414.

5 . Dixon , M. a n d Webb, E .C . ( E d s . ) , 1964, Enzymes , Acad . P r e s s , N .Y. , p . 2 1 8 .

6. G a l l a h e r , E . J . a n d Loomis, T . A . , 1975, Tox. a p p l . P h a r m . , 34, 309.

7. G r e e n z a i d , P . a n d J e n c k s , W . P . , 1971, B i o c h . , K), 1212.

8. J o r d a n , W . P . j r . a n d D a h l , M.V. , 1971, Arch . De rm. , 104, p . 5 2 4 .

9 . L e h m a n n , K.N. a n d F l u r y , F . , 1943, Toxico logy a n d Hygiene of I n d u s t r i a l S o l v e n t s , Wil l iams a n d Wi lk ins , B a l t i m o r e .

10. Nomiyama, K. a n d Nomiyama, H . , 1974, I n t . Arch . A r b e i t s m e d . , 32, 8 5 .

11 . Von O e t t i n g e n , W . F . , I960, Arch . I n d . H l t h . , I960, _21, p . 2 8 .

12. Se th , P .K. a n d S r i v a s t a v a , S . P . , 1974, Bu l l . E n v . Cont . T o x i c , _12, 612.

13 . S i e g e r s , C . - P . , S t r u b e l t , 0 . a n d B r e i n i n g , H . , 1974, P h a r m a c o l o g y , ^ 2 , p . 2 9 6 .

14. Smyth, H . F . a n d Smyth, H . P . j r . , 1928, J. I n c . Hyg. T o x i c o l . , K). p . 2 6 1 .

15. T o x i c o l o g i c a l M o n o g r a p h s , E l even th Report of t h e Jo in t FAO/WHO Expe r t Committee on Food A d d i t i v e s ; FAQ Nu t r i t i on Meet ings Report Ser ies No.44A WHO/Food A d d . 7 6 8 . 3 3 , 1968, p . 2 3 .

E thy l l a c t a t e

1. L a t v e n , A.R. a n d Mol i tor , H . , 1939, J. P h a r m a c o l . Exp t . T h e r a p . , 65 , p . 8 9 .

2 . L e e g w a t e r a n d v a n S t r a t e n , 1979, U n p u b l i s h e d Report b y C .B . Chemie Combina t i e Amste rdam.

3 . Lewin , L . , Gifte und V e r g i f t u n g e n , 1929, F o u r t h E d . , S p r i n g e r , B e r l i n .

4- T o x i c o l o g i c a l M o n o g r a p h s , T w e n t y - t h i r d Report of t h e Jo in t FAO/WHO Expe r t Committee on Food A d d i t i v e s , WHO/Food A d d . , 1979, No. 14, p . 4 1 .

5 . Yosh i t a , M. a n d Morimoto, A . , 1970, A g r i c . Biol . Chem. , 34, ( 5 ) , p . 6 8 4 .

Butyl a c e t a t e

1. Ambros io , L. a n d D ' A r r i g o , 1962, Fo l ia Med. , 45 , p . 5 2 5 .

2 . B u l ' b i n , L . A . , 1968, Gig7 S a n i t , 33 , ( 4 ) , p . 2 2 .

3 . DiVincenzo, G.D. a n d K r a s a v a g e , W.J . , 1974, Amer. I n d . Hyg. Assoc. J . , 35 , p . 2 1 .

4- G e n e r a l Foods C e n t r a l R e s e a r c h , 1976-77. U n p u b l i s h e d r e p o r t .

5 . I n t e r n a t i o n a l Resea rch a n d Development C o r p o r a t i o n , 1977. U n p u b l i s h e d r e p o r t .

6. M c L a u g h l i n , J. J r . , M a r l i a c , J . - P . , V e r r e t t , M . J . , M u t c h l e r , M.K. a n d F i t z h u g h , O .G. , 1964, I n d . Hyg. J . , 25 , p . 2 8 2 .

7. Nelson, K.W., Ege , J . F . , Ross, M. Woodman, L . E . a n d S i l v e r m a n , L . , 1943, J. I n d u s t r . H y g . , 25 , p . 2 8 2 .

8. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , I I , New York, I n t e r s c i e n c e .

9 . P e t r o v s k a y a , O.G. a n d B u l ' b i n , L . A . , 1969, Gig . N a s . Mest. , 8, p . 1 2 0 .

10. S a y e r s , R . T . , S c h r e n k , H.H. a n d P a t t y , F . A . , 1936, P u b l . Hl th . Rep. W a s h . , 5 1 , p . 1 2 2 9 .

1 1 . Scheu f l e r , H. , 1970, Biol . R u n d s c h . , U, ( 4 ) , p .227 -

12. S p o r n , A. , Schoebesch , 0 . , Maren , V. a n d R u n c a n u , L . , 1963, I g i e n a , 12, ( 5 ) , p . 4 3 7 .

Benzyl b e n z o a t e

1. D o u g h e r t y , A . , 1945, J. Am. Med. A s s . , 127, p . 8 8 .

2. G r a h a m , J . R . , 1943, Br. Med. J . , _1, p . 4 1 3 .

3 . G r u b e r , C M . , 1953, J. L a b . C l i n . Med. , 9, p . 1 5 a n d 92.

4 . Hjor th , N . , 1961, Eczematous A l l e rgy to B a l s a m s , A a r h u u s S t i f t s b o g t r y k k e r i e , H u n k s g a a r d C o p e n h a g e n , p . 4 4 .

5 . M e l l a n b y , K. , 1963, S c a b i e s , Oxford War M a n u a l , Oxford U n i v e r s i t y P r e s s .

6. O p d y k e , D . L . J . , 1973, F d . Cosmet. T o x i c o l . , U_, p .1015-

7. P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , I n t e r s c i e n c e , New York, p . 1 8 9 7 .

8. S c h w a r t z , L . , T u l i p a n , L. a n d B i r m i n g h a m , D . J . , 1957, O c c u p a t i o n a l D i s e a s e s of the S k i n , 3 rd E d . , Lea a n d F e b i g e r , P h i l a d e l p h i a , p .949 -

9. Wi l l i ams , R . T . , 1959, De tox ica t ion Mechan i sms , 2nd E d . , Chapman a n d H a l l , London , p . 3 2 0 .

T r i e t h y l c i t r a t e

1. B r u n s , F .H. a n d Werne r s , H . P . , 1962, Kl in . W o c h s c h r . , _22, p . 1 1 6 9 .

2 . O p d y k e , D . J . J . , 1979, F d . Cosmet. T o x i c o l . , _17, p . 3 8 9 -

3 . P a t t y , F . A . , 1963, I n d u s t r i a l Hygiene a n d Tox ico logy , Vol. 2, p . 1882.

4 . T o x i c o l o g i c a l M o n o g r a p h s , T w e n t y - t h i r d Report of t h e Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s , WHO/Food A d d . , 1979, No. 14, p . 9 3 -

Die thy l t a r t r a t e

Isopropyl myristate

1. F i tzgera ld , J . E . , Kurtz, S.M., Schardein, J .L. and Kaump, D.M., 1968, Toxicol, app l . Pharmacol. , 13, p.448.

2. Giles, A.J . j r . and Byron, W.R., 1969, Fd. Cosmet. Toxicol. , ]_, p .541.

3 . Horton, A.W., Van Dreal, P.A. and Bingham, E.L. , 1966, Advances in Biology of Skin. Vol. VII Carcinogenesis . Pergamon Press , Oxford, p . 165.

4. Kligman, A.M., 1966, J. Invest . Derm., 47, p .393.

5. Opdyke, D.L.J . , 1976, Fd. Cosmet. Toxicol., J_4, p.323-

6. Parker , F.L. and James, G.W., 1978, J. Pharm. Pharmacol . , 30, p.236.

7. Pat ty , F.A., 1963, Indus t r i a l Hygiene and Toxicology, Vol. I I , Interscience, N.Y., p.1874.

8. Schwartz, L. , 1950, Ann. Allergy, 8, p .63 .

9. Stenback, F. and Shubik., P . , 1974, Tox. app l . Pharmacol . , 30, p . 7 .

10. The Givaudanian , 1953, p . 3 .

11. Weitzel, G. , 1951, Hoppe-Seyler's Z. Physiol. Chem. , 287, p.254.

12. Yanagi, M. and Onishi, G. , 1971, J. Soc. Cosmet. Chem. , 22, p.851-

Glycerol mono-, d i - and t r iace ta te

1. Chenowoth, M.B., Kandel, A., Johnson, L.B. and Bennett, D.R., 1951, J. Pharmacol. Exp. Ther., 102, p.31.

2. Pat ty , F .A. , 1963, Indus t r i a l Hygiene and Toxicology, Vol. I I , 2nd ed . , Interscience, New York, p.1868.

3. Toxicological Monographs, Nineteenth Report of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additive Series No. 8, 1975, p .80.

4. Toxicological Monographs, Twentieth Report of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additive Series No. 19, 1976, p .56.

Glycerol t r ipropionate

1. Pat ty , F .A. , 1963, Indus t r i a l Hygiene and Toxicology, Vol. I I . Interscience, New York, p.1871.

Glycerol Tr ibutyra te

1. Pat ty , F .A. , 1963, Indus t r i a l Hygiene and Toxicology, Volume I I , In te r ­science, New York, p.1871.

2. Sax, N . I . , 1975, Dangerous Properties of Indus t r i a l Materials , 4th Edition, Van Nostrand Reinhold.

D i e t h y l e n e g lyco l monoethyl e t h e r

1. B r e n n a a s , 0 . , I960, Nord. Med . , 64, p . 1 2 9 1 .

2 . B rowning , E . P . et a l . , 1939, J. I n d . Hyg. T o x i c o l . , _2]_, p . 1 7 3 .

3 . B u t t e r w o r t h , K . R . , G a u n t , I . F . a n d G r a s s o , P . , 1976, I n fo rma t ion B u l l e t i n , BIBRA., _15, p . 1 1 2 .

4 . C a r p e n t e r , C . P . , 1947, J. Am. Med. A s s o c , 135, 880.

5 . C r a n c h , A . G . , Smyth, H . F . j r . a n d C a r p e n t e r , C . P . , 1942, Arch . De rma to l . S y p h . , 45 , p . 5 5 3 .

6. Von O e t t i n g e n , W.R. a n d J i r o u c h , E . A . , 1931, J. P h a r m . E x p t . T h e r . , 42, p . 3 5 5 .

7. O p d y k e , D . L . J . , 1974, F d . Cosmet. T o x i c o l . , _12, p . 5 1 7 .

8. Smyth, H . F . , Sea ton , J. a n d F i s c h e r , L . , 1941, J. I n d . Hyg. T o x i c o l . , 23 , p . 2 5 9 .

9 . Smyth, H . F . j r . a n d C a r p e n t e r , C . P . , 1948, J. I n d . H y g . T o x i c o l . , 30, p . 6 3 -

10. S t e n g e r , E . G . , A e p p l i , L . , Mul l e r , D . , Pehe im, E . Z . a n d T h o m a n n , P . , 1941, A r z n e i m i t t e l - F o r s c h . , 2 1 , p . 8 8 0 .

1 1 . T o x i c o l o g i c a l E v a l u a t i o n s , Twen t i e th Repor t , Jo in t FAO/WHO E x p e r t Committee on Food A d d i t i v e s , WHO Tech . Rep. Ser . No. 599, FAQ Food a n d Nut r . Ser . No. 1, 1976, p . 1 2 a n d 30.

REPORT OF THE SCIENTIFIC COMMITTEE FOR FOOD ON SULPHITING AGENTS

(Opinion expressed 15 January 198l)

TERMS OF REFERENCE

To give an opinion on "the effects on health due to the ingestion of sulphur dioxide and other sulphiting agents from foodstuffs.

BACKGROUND The Commission is currently reviewing the technology associated with the use of sulphites in the production of wine and an appreciation of the safety of this practice forms an essential part of the review. The ingestion of sulphites from wine cannot be taken in isolation from its ingestion from other foods and so the Scientific Committee for Food was asked to advise on the safety in use of sulphur dioxide and other sulphites in foodstuffs in view of the extensive use of these substances.

CURRENT REVIEW

The Committee was provided with a number of extensive reports on the problem of the use of sulphiting agents in food and beverages. These included a report by Prof. Jaulmes on the safety of these substances, a publication of the Federation of American Societies for , Experimental Biology (FASEB) , reports by F.W. Beech, C. Cantarelli, D. Jakob and P. Sudraud on the technological possibilities for reducing sulphur dioxide in wine, and a report by F. Custot^ setting out the legally permitted and actually detected levels of SO- in food within the EEC.

The Committee noted that sulphites were preservative agents for food with antiseptic and antifungal properties, known since antiquity, which have, however, a disagreeable taste and odour limiting their use and which irritate the mucosal surfaces of the body. Even small concentrations in the atmosphere are toxic on inhalation but this aspect, and the contribution to the total body burden of SO2 from atmospheric intake has not been considered to be relevant in the context of the present evaluation.

Ingestion of sulphiting agents is generally at low levels but derives from their legally controlled uses in specified foods, non-alcoholic beverages, wines, beers and ciders. Sulphites also occur naturally as a by-product of fermentation. Recent estimates made available to the Committee quote daily intakes, as averages for the whole of Europe of 15 mg SO2 = 0.25 mmol/person from food and non-alcoholic beverages, 40 mg SOp = 0.63 mmol/ person if an additional 300 ml of wine is consumed, and 90 nig SOp = 1.41 mmol/person if 700 ml of wine is drunk daily. Sulphites are present in food and beverages usually in chemical combination with certain constituents. In some beverages they may also be present in the uncombined state. It is of interest that the estimates of intake from food and non-alcoholic beverages are closely similar to estimates made for the U.S. and Belgium.

Sulphites are chemically reactive and their biological importance relates particularly to their destructive effect on the vitamins, especially thiamin. Sulphites in food are partly oxidised during ingestion and digestion to sulphates. Sulphites also react during ingestion and after absorption with cellular and tissue fluid macromolecules in a reversible manner. Extremely rapid conversion to sulphates occurs in the tissues predominantly through the action of the enzyme sulphite oxidase. The latter is present predominantly in the liver, heart, kidneys, spleen, brain and lungs. The Bulphates are finally eliminated rapidly in the urine. Sulphites are also formed endogenously from the metabolism of S—containing aminoacids. The average endogenous formation of sulphite in man is estimated to be about 1680 mg SO2 «= 26.25 mmol/day, all of which is eliminated as urinary sulphate.

The toxicity profile of sulphites has been examined in numerous investigations in laboratory animals and also in man ' •-'» »'• . Large doses are acutely toxic but low doBes, administered over prolonged periods or for the lifespan of experimental animals, have shown no specific adverse effects. No deleterious effects have been noted on reproduction nor is there any evidence for a teratogenic or carcinogenic potential. Shapiro" haB shown that large doses

47

produce weak mutagenic effects in some in vitro test systems but not- under in vivo conditions. These findings are therefore unlikely to be relevant as a mutagenic risk for man from the ingestion of sulphites in food and beverages.

Sulphites perform several useful functions in food technologically including the suppression of unwanted fermentation, as antibacterial agents against microbiological contamination of food, as bleaching agents and antioxidants. These aspects, particularly the antimicrobial activities, need to be considered when a risk assessment for man is being made.

The more recent information presented to the Committee on the low level of intake of sulphites from all food and beverage sources, on the pathway and kinetics of the metabolism of sulphites in animals and man, on the high efficiency of the enzymatic detoxification systems, and on the considerable endogenous production of sulphites being some 20 to 40 fold the dietary intake, is of fundamental importance for the evaluation of the health hazard from ingested sulphites.

OPINION

The Committee noted that a numerical value for the ADI of ingested sulphite had been established by JECPA (1974)5. The Committee also considered the results of the study in pigs by Til°, in which the no—adverse-effect level was reported to be 0.23% SO2 in the diet equivalent to 92 mg/kg b.w. (92 mg SO2 = 1.44 mmol). The pig study is of particular relevance because this species is closer to man than the traditional rodent laboratory animals by virtue of the pysiology of its gastro—intestinal tract. Taking the above information together with the knowledge of the efficient metabolism of the sulphite oxidase system in the mamalian tissues and the smallness of the dietary intake of sulphite compared to the daily endogenous production in man, would permit a more flexible approach in the consideration of the safety—in-use of sulphite as preserving agent in food and beverages.

The Committee concluded that for the great majority of the population no hazard to health would arise from the ingestion of sulphites at levels currently found in food and beverages. Nevertheless, the Committee wishes to reemphasize its previously stated opinion, applicable to all food additives, that their use should be restricted to the minimum level necessary technologically, particularly in foods which are an important source of thiamin.

The Committee is aware that congenital deficiency of hepatic sulphite oxidase has been described as a rare metabolic disorder in man. There are only few data on the normal develop­ment of this enzyme with age in various species, and on the factors controlling sulphite oxidase activity. Information on these aspects would be helpful in assessing any special risk factors which may apply to select subpopulations or to vulnerable sections of the population, in whom malnutrition has lead to marginal body reserves of thiamin.

REFERENCES 1. Jaulmes, P., (1979) Rapport presente a. la CEE.

2. PASEB (1976) Evaluation of the Health Aspects of Sulphiting Agents as Food Igredients, SCOGS-15, Report to FDA of USA, Bethesda, USA.

3. Beech, F.W., Cantarelli, C , Jacob, D., and Sudraud, P., Techniques for reducing the sulphur dioxide content of wines; technological considerations and recommendations, EEC Study P.202.

4. Custot, F., (1979) Collecte de donnees analytiques concernant la teneur en anhydriude sulphureux des vins et de certaines denrees alimentaires, Juillet 1979*

5. JECFA (1974)t Wld.Hlth.Org.tech., Rep.Ser., 1974t no. 539*

6. T i l , H.P. , (l970) Toxcologisch Onderzoek Naar de Werking von Sulf iet b i j r a t t e n , Varkens en Kwantels, Ph.D. Thesis submitted to Utrecht Universi ty.

7 . Wucherpfenning, K., (1979) A propos de l a t o x i c i t e de l ' a c ide sulfureux, 4ch session of the Expert Group O.I.V. Technologie du v in , Ball de O.I.V., 52%, 12-25

8. Shapiro, R., (1977) Genetic effects of b isu lphi te (sulphur dioxide) Mutation Res. , 39i 149-175.

48

Acknowledgements

The Committee is grateful for the assistance given "by:

Prof. P. Jaulmes, Professeur Honoraire à la Faculté de Pharmacie, 4 rue Donnat, 34000 MONTPELLIER, Prance

and

Prof . L. G a t t i , V ia C o l l a l t o Sabino 77 , 1-00199 ROMA, I t a l y

49

European Communities — Commission

EUR 7421 — Reports of the Scientific Committee for Food (Eleventh series)

Luxembourg: Office for Official Publications of the European Communities

1981 — 49 pp. — 21 x 29.7 cm

Series: Food - Science and Techniques

DA, DE, EN, FR, IT, NL

ISBN 92-825-2557-0

Catalogue number: CD-NR-81-001-EN-C

Price (excluding VAT) in Luxembourg

ECU 3.63 BFR 150 IRL 2.50 UKL 2 USD 3.80

The Scientific Committee for Food was established by Commission Decision 74/234/EEC of 16 April 1974 (OJ L 136 of 20.5.1974, p. 1) to advise it on any problem relating to the protection of the health and safety of persons arising from the consumption of food, and in particular the composition of food, processes which are liable to modify food, the use of food additives and other processing aids as well as the presence of contaminants.

The members are independent persons, highly qualified in the fields associated with medicine, nutrition, toxicology, biology, chemistry, or other similar disciplines.

The present series relates to opinions on the effects on health due to the ingestion of sulphur dioxide and other sulphiting agents from foodstuffs, and extraction solvents.

NOTICE TO THE READER All scientif ic and technical reports published by the Commission of the European Communit ies are announced in the monthly periodical "euro-abstracts". For subscript ion (1 year: BFR 2 000) please write to the address below.

Price (excluding VAT) in Luxembourg ECU 3.63 BFR 150 IRL2.50 U K L 2 USD3.80

L-2985 Luxembourg Catalogue number: CD-NR-81-001-EN-C

OFFICE FOR OFFICIAL PUBLICATIONS ISBN 92-825-2557-0 OF THE EUROPEAN COMMUNITIES