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0 MEMORANDUM January 18, 1984 TO: A. L. Rhyne F. C. J. L. R. J. J. D. T. S. Schultz Stone Heck Dunn Marmor FROM: H. J. Minnemeyer SUBJECT: Safety Evaluation and Advisory Committee The SEAC group will meet on Thrusday, January 19, 1984 at 1:15 PM in the Research Center small conference room. Agenda 1. Approve minutes and make new appointments 2. Progress report since last meeting August 30, 1983 (Minnemeyer) 3. Progress report on guidelines to interpret results with recommendations (Stone) 4. Review B10, B44, B45, B99 5. New candidates for review a) B10, B97, B98 b) B104, B108 c) B9, B29, B39, B87, B100, B101, B115 6. Other new business - A 7. Schedule next meeting ?2 ~ H. J. Minnemeyer( HJM: fr

r COMPOUND: Lemon Oil, Naardenized 06069 (B101)* LD50 Ames Assay Mouse Lymphoma Rabbit Eye Cardiovasc./Respir. 5-Day Range-Finder - (1981) Moderately Irritating MTD = 3750 mg/kg (male rats) > MTD = 5000 mg/kg (female rats) MTD = 1500 mg/kg (male mice) MTD = 750 mg/kg (female mice) Enzyme Induction 0 Immunosuppression SOURCE: Naarden *Testing stopped 4/83 COMPOUND: d-Limonene, P&F (B102) 14-Day Subacute Pending Ames Assay - (Confirmed) Mouse Lymphoma - Rabbit Eye Minimally Irritating Cardiovasc./Respir. - 5-Day Range-Finder MTD = 1750 mg/kg (males) MTD = 750 mg/kg (females) Enzyme Induction 0 (females), - (males) Immunosuppression - SOURCE: Naarden (RY26331); Glidden (SCM Terpene Products)

s COMPOUND: Oil, Cardamon L00689 (B115) LD50 Ames Assay - (Confirmed) Mouse Lymphoma - - Rabbit Eye Mildly Irritating Rabbit Eye (low dose) * Cardiovasc./Respir. - 5-Day Range-Finder MTD = 3125 mg/kg (males) MTD = 3750 mg/kg (females) Enzyme Induction + Immunosuppression - *Not retested since usage level x 100 exceeds tested dose SOURCE: Naarden COP".POUND: Caramel - Flavor "T" (B116) LD0 >4320 mg/kg (i.p.) 14-Day Subacute Pending Ames Assay - Mouse Lymphoma Rabbit Eye Minimally Irritating Cardiovasc./Respir. - 5-Day Range-Finder MTD > = 5000 mg/kg Enzyme Induction Immunosuppression SOURCE: Sethness Products

COI3?OUhD: Geranyl Acetate RY25091 (B107) LD50 Ames Assay - (Confirmed) Mouse Lymphoma + (with Activation) Chromosomal Aberration - Rabbit Eye Minimally Irritating Rabbit Eye (low dose) Minimally Irritating Cardiovasc./Respir. 5-Day Range-Finder Enzyme Induction Immunosuppression MTD = 5000 mg/kg (rats) > MTD = 2500 mg/kg (male mice) > MTD = 1875 mg/kg (female mice) + SOURCE: Naarden COMPOUND: 2-A-3MP -(B108) LD50 (Rats, p.o.) LD50 (Mice) Ames Assay Mouse Lymphoma Rabbit Eye - Rabbit Eye (low dose) Cardiovasc./Respir. 5-Day Range-Finder Enzyme Induction 448 mg/kg (females) 529 mg/kg (combined sexes) 450 mg/kg (i.p.) - (Conf irmed) Moderately Irritating Minimally Irritating MTD = 375 mg/kg (males) MTD = 313 mg/kg (females) -* ~_& Immunosuppression 14-Day Toxicity** Significant increase in absolute and relative liver weights in 200 mg/kg females *Significantly increased liver/body wt. ratio **50,100, and 200 mg/kg (both sexes) SOURCE: Pyrazine Specialists

CO~fl?OL'VD: Myristic Acid (B99) LD50 Ames Assay -(Contracted) Mouse Lymphoma - Rabbit Eye Moderately Irritating Rabbit Eye (low dose) * Cardiovasc./Respir. - > 5-Day Range-Finder MTD = 5000 mg/kg I Enzyme Induction - Immurosuppression - *Not retested since usage level x 100 exceeds tested dose SOURCE: Naarden (RY27640); Eastman Organic Chemicals CO~OUND: Peppermint Oil N02923 (B100) 14-Day Subacute 785 mg/kg (males, ip) 711 mg/kg (females, ip) Ames Assay - (Confirmed) Mouse Lymphoma - Rabbit Eye Moderately Irritating Cardiovasc./Respir. - 5-Day Range-Finder MTD = 1750 mg/kg Enzyme Induction + Immunosuppression SOURCE: Naarden

, ~ COMPOUND: Chocolate, Artificial (7M02619) (B87) LD 0 > 1000 mg/kg (i.p.) 14-Day Subacute > 5000 mg/kg (ip) Ames Assay - (Confirmed) Mouse Lymphoma - Rabbit Eye Minimally Irritating Rabbit Eye (low dose) * Cardiovasc./Respir. - > 5-Day Range-Finder MTD = 5000 mg/kg • Enzyme Induction 0 Immunosuppression - *Not retested since usage level x 100 exceeds tested dose SOURCE: Naarden COMPOUND: *Walnut CD79429 (B88) (Formulation Change - New VB113) LD0 > 8640 mg/kg (i.p:) Ames Assay - (1977) Mouse Lymphoma Cardiovasc./Respir. 5-Day Range-Finder MTD > = 5000 mg/kg Enzyme Induction Immunosuppression *Testing stopped 1/26/82 SOURCE: Naarden

, COMPOUND: Oil, Nutmeg, East India Select (B39) LDS0 1593 mg/kg (i.p.) 14-Day Subacute 2743 mg/kg (males, ip) 3001 mg/kg (females, ip) Ames Assay - (Confirmed) Mouse Lymphoma - Chromosomal Aberration - Rabbit Eye Non-irritant Cardiovasc./Respir. - 5-Day Range-Finder MTD = 3125 mg/kg (males) N.TD = 1750 mg/kg (females) Enzyme Induction + l Immunosuppression - SOURCE: J. Manheimer; Flavor Resources COMPOUND: New England Rum Flavor SA 90562 (B40) *(replaced by B109) LD50 Ames Assay Mouse Lymphoma Cardiovasc./Respir. 5-Day Range-Finder Enzyme Induction Immunosuppression SOURCE: Naarden *testing stopped 6/82

, COMPOUND: Heliotropin, Extra (B29) LDSO 940 mg/kg (males) (i.p.) 906 mg/kg (females) (i.p.) 14-Day Subacute 1055 mg/kg (combined sex, ip) Ames Assay - (Confirmed) Mouse Lymphoma - Rabbit Eye - Cardiovasc./Respir. - 5-Day Range-Finder MTD = 1375 mg/kg (males) MTD = 750 mg/kg (females) Enzyme Induction 0 Immunosuppression - SOURCE: Norda COMPOUND: Lovage Oil (B30) LD50 14-Day Subacute Pending Ames Assay - (Pending) Mouse Lymphoma Cardiovasc./Respir. Insoluble Multi-Dose Range-Finder Pending Enzyme Induction Pending Immunosuppression Pending SOURCE: - Polarome

0 r ~ CO;iPOL'ND: Alcohol (C-8) (Octanol-1) (B103) 14-Day Subacute Pending Ames Assay - (Confirmed) Mouse Lymphoma - Rabbit Eye Severely Irritating Cardiovasc./Respir. - 5-Day Range-Finder MTD = 5000 mg/kg- Enzyme Induction 0 (female mice) Immunosuppression - SOURCE: Naarden (RY28000); Givaudan CO.IPOUNND: Aldehyde (C-11) 10-Ulvdecenal (B104)* LD50 Ames Assay - (1981) Mouse Lymphoma - Rabbit Eye Mildly Irritating Cardiovasc./Respir. Insoluble > Multi-Dose Range-Finder MTD = 5000 mg/kg Enzyme Induction - (sleep times)** Immunosuppression 5 Ea- 4. //Ej SOURCE: Aldrich Chemical Co. *Testing stopped 7/83 rr- - rr - _ °_° **Insufficient data to evaluate in vitro studies due to toxicity in the rat ***Higher mean spleen weights in B104 - treated mice -

c:uTOUND : Oi 1, Cardamon (B9 ) LD50 757 mg/kg (i.p.) 14-Day Subacute 1337 mg/kg (males, i.p.) 1105 mg/kg (females; i.p.) Ames Assay - (Contracted) Mouse Lymphoma - Rabbit Eye Non-irritant Cardiovasc./Respir. - (Insoluble according to w2mo of 7/2/83) 5-Day Range-Finder I~.•I'D -'- 5000 mg/kg (males) MrD = 2500 mg/kg (females) Enzyne Induction + Inrunosuppression - SOURCE: Norda CONIPOLJDID: Oil, Cori ander (B10) ID 50 1440 mg/kg (i.p. ) 14-Day Subacute 1254 mg/kg (irales, i.p.) 1001 mg/kg (females, i.p.) Ames Assay - (Confirmed) Mouse Lyrrphoma - Rabbit Eye Severely Irritating Rabbit E<ye (law dose) Minimally Irritating Cardiovasc./Respir. - (Insoluble according to memo of 7/2/82) 5-Day Range-Finder MIV = 2500 irg/kg (males) MID = 1250 mg/kg (females) Enzyme Induction Imrnznosuppression Sf~6~i:f~ 0/( SCUBCE: Crompton-Knowles; Polarome; Aroma Rescurces