# Toxicity Testing: Strategies to Determine Needs and Priorities(1984)

## Chapter: 5. RESULTS

« Previous: 4. DATA EVALUATION
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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Suggested Citation:"5. RESULTS." National Research Council. 1984. Toxicity Testing: Strategies to Determine Needs and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/317.
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- RESULTS A select universe of 65,725 listings of chemical substances was compiled from lists of pesticides and registered inert ingredients of pesticide formulations, cosmetic ingredients, drugs and excipients in drug formulations, food additives, and other chemicals in commerce as listed in the Inventory of the Toxic Substances Control Act. A sample of 675 substances chosen by a stratified random process was selected from the 65,725 entries. A random subsample of 100 substances with at least prescribed minimal toxicity information (see Chapter 2) was then selected from the random sample. The sample and subsample contained representatives of seven categories of substances: (1) pesticides and inert ingredients of pesticide formulations, (2) cosmetic ingredients, (3) drugs and excipients in drug formulations, (4) food additives, and chemicals in commerce, which were divided into substances with (5) 1977 production of at least 1 million pounds, (6) 1977 production of less than 1 million pounds, and (7) 1977 production unknown or inaccessible owing to manufacturers' claims of confidentiality. The findings presented in this chapter are based on analyses of the sample of 675 substances randomly selected from the select universe, including data on the subsample of 100 (selected from the random sample of 675) by application of criteria regarding the presence of minimal toxicity information. Some specific analyses were based solely on the sample or the subsample. Others were baser on combined information on both the sample and the subsample. In each instance, the origin of the information is stated to aid the reader in understanding the nature and implications of the data. The Committee on Sampling Strategies and the Committee on Toxicity Data Elements recognize that their estimates of testing need may be less than the reference protocol guidelines call for, even though some tests may have been done not at all or not in compliance with the guidelines. Although additional testing is desirable, some circumstances make it unnecessary to perform some or all tests because other available information--including that from prior testing of a substance, its history of intended use, and other anticipated exposures to it (such as occupational and environmental)--may permit some judgment of health hazard in the absence of full data. The reference protocol guidelines can be expected to change with time, as public and scientific perceptions of hazards change, as the technologic ability to detect hazard improves, and as willingness to accept particular hazards changes. Substances on the list of one category were often on lists of other categories. The overlap among the seven categories was determined for 81

substances in the sample. This information provided the basis for estimating that the select universe contained about 53,500 distinct substances, the lower and upper 90% confidence limits being 49,800 ana 57,900, respectively. However, all reported findings are for specific categories of the select universe, rather than for the select universe as a whole. When categories or parts of them were combined, appropriate weighting factors were assigned to account for duplication among lists. Inert ingredients of pesticide formulations and excipients of drug formulations were included in the select universe, because the Committee on Toxicity Data Elements desired to include to the fullest extent in the select universe the substances that were of possible interest to NTP because of their potential for human exposure. Of the 50 pesticides and inert ingredients of pesticide formulations in the sample, 37 were on the list of active pesticides, 11 were on the list of inert ingredients, and 2 were on both lists; of the 15 in the subsample, 12 were on the list of active pesticides, 2 were on the list of inert ingredients, and 1 was on both. Of the 50 drugs and excipients in drug formulations, 22 were on the list of active drugs, 18 were on the list of excipients, and 10 were on both; of the 32 active drugs, 23 were listed as prescription drugs, 3 as nonprescription drugs, and 3 as both; of the 28 excipients, 13 were found in prescription formulations, 1 was found in nonprescription formulations, and 7 were found in both. Of the 15 in the subsample, 7 were listed as active drugs, 4 as excipients, and 4 as both; of the 11 active drugs, 8 were listed as prescription drugs, 1 as a nonprescription drug, and 1 as both; of the 8 excipients, 2 were found in prescription formulations, none was found only in nonprescription formulations, and 3 were found in both. These numbers are presented to give the ensuing descriptive analyses a sense of proportion regarding active pesticides, drugs, and nonactive components of their formulations. The committees did not conduct separate analyses to distinguish the findings for active ana nonactive substances, although the data may permit others to consider such separate analyses for their own purposes. QUANTITY AND NATURE OF TEST ING It was recognized from the beginning that the quantity and nature of testing needs were such that they could never be fulfilled adequately only by the use of specific testing regimens. Although tests of substances will always be needed, a better understanding of the "how" and "why" of toxic injury itself at the subcellular, cellular, organ, and whole-animal levels will be necessary to fulfill future needs in the most efficient and economical manner. The Committee on Toxicity Data Elements used a battery of toxicity tests as the basic "measuring stick" for quantitation of testing needs. At the same time, it rejected the concept that every substance in the select universe requirea the adequate 82

performance of a complete battery of toxicity tests to make possible a human health-hazard assessment, even if that were practical. Thus, other criteria, including data from human exposures, were also used for judgments about testing adequacy. The Committee on Toxicity Data Elements recognizes that meeting the testing needs will require the establishment of priorities for the tests and the substances needing them. SAMPLE OF 675 SUBSTANCES Minimal toxicity information was defined as specific combinations of five basic types of tests prescribed by the Committee on Toxicity Data Elements: acute, subchronic, chronic, repro~uctive/developmental, and mutagenicity. The tests most frequently encountered for each category of substances in the sample of 675 during the search for prescribed minimal toxicity information are presented in Table 7. The data in these tables include the best estimates of the Committee on Sampling Strategies and the Committee on Toxicity Data Elements with upper and lower 90% confidence limits. In some cases, confidence limits are wide because of the unavoidable restrictions on sample sizes in specific segments of the select universe. As indicated in Table 7, 25-82% of the select universe was estimated to have no toxicity information, on the basis of what the committees were able to discover from the published and unpublished literature available to them. In each of the seven categories of the sample of 675 substances, testing for acute, subahronic, and mutagenic effects was present more frequently than testing for chronic or reproductive/developmental effects. For the select universe of drugs and excipients in drug formulations, about 75% were estimated to have information on acute toxicity and about 62% were estimated to have information on subchronic testing. For pesticides and inert ingredients of pesticide formulations, these values were about 59% and 51%, respectively. Testing was absent most frequently for chemicals in commerce, particularly for chronic and reproductive/developmental effects. All frequencies, even though some were higher than others, are based on a limited number of substances that had minimal toxicity information. The degree of testing, as determined by the search for prescribed minimal toxicity information and as presented in Table 7, was based on a search strategy that was designed to qualify substances for the subsample of 100 by rapidly identifying information where it was most likely to be found. The rationale for this approach and the search strategy used are presented in Chapter 3. The search was conducted for each of the 675 substances in the sample and may be assumed to be efficient in identifying all or most of the existing information. However, unlike the search strategy for the subsample of 100, it was not exhaustive. As a result, the estimates presented in Table 7 may be slight understatements of the amount of minimal testing that has been conducted. 83

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G, c ~ 4 ,C ~C ~ ~ ~ u ~· - ~o ~ In ~ ~ · - U] ~,,C #4 · - ~ U) ~ ~ ~ · - 4 C C 8 ~1 dJ ~n C U] C ~X O C ~ ~ O ~ C · - 0 4 - u' u: ~O n5 ~ ·- ~ C · - {Q C ~ C ~C · - 8 CO ~ ~C O ~ O U) t ~·^ 41 60 tJI ~ _1 ~ O 4 ~· - O ~ ~ ~ Od ~ · C ~ C X · - C · - (,0 O ~ ~ u, · - a, c ~ ~ ~n U] · - ~O ~ 4J ~·- ~ ~ ·- t8 ~ ~· - ~ JJ ~ ~ ~· - C · - 0 ~· - ~n W ~ 00 ~ ~ O ~ C W ~d · - P4 ~Es4 u, ·r4 ~· - .C £ ~ O SUBSAME'LE OF 10 0 SUBSTANCES - Table 8 lists the test types used in the detailed analysis of the subsample according to the degree to which they were performed on the substances in each intended-use category that had the prescribed minimal toxicity information. Acute oral rodent studies and acute parenteral studies had been done most frequently. Except for drugs and excipients in drug formulations, the next most commonly conducted test was for genetic toxicity. Toxicokinetic, dermal, and eye irritation studies were done on some chemicals in commerce. Except for the three categories of chemicals in commerce, the test types encountered next most frequently included investigations of effects of subchronic oral administration for 14, 28, or 90 d in rodents and of chronic oral administration. These were followed in frequency by tests of teratology, acute skin and eye irritation, carcinogenicity in rodents, acute dermal effects, and acute inhalation effects. Acute oral administration in nonrodents and subahronic oral administration for 90 d in nonrodents were also performed occasionally. For the three categories of chemicals in commerce, studies investigating carcinogenicity and subchronic toxicity in rodents were also performed. The locations of the 33 test types in Table 8 are based on small random samples, and the percentages of testing for specific types might change if new random samples were examined. It is evident from the results presented in Tables 7 and 8 that the amount of testing information available on any category of substances is related to the regulatory history of that category. In general, proportionately more testing has been undertaken on drugs and excipients in drug formulations and on pesticides and inert ingredients of pesticide formulations than on other substances. Among all categories, drugs and excipients in drug formulations have the longest history of regulatory interest. Of the substances examined in this category, about 39% were found to meet the requirements adopted by the Committee on Toxicity Data Elements for minimal toxicity information. In contrast, only about 20% of the compounds in the three categories of chemicals in commerce were found to meet the requirements for minimal toxicity information, although these requirements were much less strict than those adopted for drugs and excipients in drug formulations. The committees recognize that some toxicity tests may not have been known to them. Although toxicity-test information on the subsample of 100 substances was sought from industries and other interested parties via a Federal Register notice and by direct contact with manufacturers and importers of sampled chemicals in commerce, some industrial information probably remained unavailable. Similarly, the committees were not able to examine toxicity, physical, and chemical information on cosmetic ingredients, drugs, excipients in drug formulations, and food additives contained in the files of FDA, except for food additives listed as generally regarded as safe (GRAS). 85 ~a ~n E~ a, 3 o s U ~ .,. 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X Q ~ 4 ~ {: Q O ~ : S U ~ ~ ~ E ~E~ cn ro ~C ~u, ~1 1 .= ~C ~· - C O 1 ~U ~ tJ I X ·-l I ~ ~ :^ O X a, 0 ~ ~c 4 ~O ~ ~U ~O -1 JJ 1 · - C) ~ 1 X ~>t ~4 ~ O ~O ~ ~ X Ll -1~ ~ -1 ~ N 0 a' U~ 1 -1 :^ ~O ~ U ~ ~ ~, .Ll 1 1 1 1 C X ~ ' - ns 05 ~ X · - 1 1 1 1 ~a, 0 u ~ ~ ~ 0 ~ -4 ·e a) ~ 4 ~ ~ s: ~ ~ ~C O ~ ~U O ~ O ~ ~ O U ·~ · - O ~U O U ~ ~ O O :3 4 ~C Q ¢¢ ~ ~ ~ ~ ~ l :^ :,,, 4,, >q :^ ,4 . ~, ~4 ~ U ~U I ·- ~O 1 ·,4 ~ ~ I ~I U I X ~ . - X C ~r/ I - - 1 O ~ X 0 0 x :>, x a:) tl V 0 4) ~O ~O .~. ~ ~4.' ~ - - ~1 >, X C ~I ~4 - ~ ~O ~O ~ o ~ o 4 ~ X 4 rl ~ ~S ~ ~ ~i ~ ~ ~X to ,1 0 o I I ~ ~ 1 ~ ~ ~ ~ ~ O ~ 1 ^ ~1 4J 1 1 ~\ ·~1 ~1 0 0 . - 45 ~ 4~ 0 ·- ~ ~O d. ~4~ 1 1 C X ~ ~ ~ ~ ~ X ~ ~ ~ I a, 0 ~ ~ ~ ~ ~ c ¢0 4 ~ ~ ·e C S ~ ~ ~ ~ 4 ~ ~ -1 ·e ~ ·- ~ ~ ~ ~ ~c ~ {Q c ~ ~ c ~ a' u, O O c: o. ~ 0 e ~ ~ 0 0 0 u 0 0 0 c ~0 ~ ~ ~ o ~ ~ ~- Ll ~ ~L'on ~ ~ ~ s ~ ~ ~ ~ s C C ~ : s 4~ 0 ~4 ~ C ~ ~ ~ X ~ :3 U ~ C ~ {: ~ 54 :3 ~ ~ ~ 3 ~Y X 3 so ~ 3 ~ ~ C ~ ~ o L. tQ 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 E~ 86 ·e ~1 1 ~1 U1 :~ ~C 1 |~ c~ ~ c · - ~:^ o u c ~r ~ ~ ~u ~4~ ~ ~ "l !a' ~11 ~ 1 ~ ~ U ~ t) ~ 1 ~ X 1 ~ U C a,1 ~ ~ O ~ O ~X ~ C U ~ ~ O ~ 0 1 ~O ~1 1 ~ ~ ~X Ll C O ~ ~ ~ U ~ 4J ~ ~ ~ X · - ~ 1 X P4 0 1 0 C ~ ~X ·- O · - ~ ~ O O ~ ~ C ~ O ~J ~ 1 ~ O C ~O O X ~ ~ ~ JJ ~ ~ O ~O ~ O ~ ~ ~ ~ ~ O ~ ~ O ~ ~ ~ ~ u I r ~ ~ c c) ~ u ~ ~c ~ ~ 1 ~ ~ · - ~ ~ O ~ 1 ~ 1 ~ c ~ ~ ~ 1 ~ ~0 ~ 1 C O ~ 4 ~ X ~ ~ ~ S ~X ~ ~ ~ O ~ C U 1 N ~ ~· - C ~O N ~ ~ ~ · - O O · - ·- ~ a~ dJ ·~ O ·e ·^ ~·- ~ ~ O ~ ~ ~ C C dJ ~·e C ~ O · ·e X J~ ~ ~ · ~ =-~4 ·e ·- ~ 1 S ~ ·^ ·- ~ ~ O ~ O ·e C) t) C U C U ~I C ~ 04 C) ~ ~ ~ 1 U ~ ~ ~ ~ .- ~ ~ U 4 ~3 ~- ~ -4 40·~ 40·~ ~ 40 u] ~ ~ tU ~ e 0 c c ·- ~ ~ ~ ~·- ~·- ~ ~4 ~ c ~ c ~ c ~ ~a c ~ c ~ s ~ 0 ~ c ~ ~c ~ ~ c c ~ c u ~ 4) 0 0 o 0 0 0 u 0 0 ~ ~ 0 u ~ ~ ~ ~ ~ ~ ~n 0 ~ c '-~- C ~ ~ ~ ~ ~ k4 ·- k4 Ut C ~ ~ Q ~ ~ C V ~Ll ~ C dJ C Od )~ k o Oc ~ ~ S o~ S oC S O ~ oC C ~ S 0 0~ '= ~ '- ~ C C S O ~ ~ ~ C S oC S C 11 C ~ ~ C ·- ~ ~ ~ ~ ~ ~ ~ ~ ·- ~ ~ ~ .- C Q S ~U Y :3 ~ ~Q Y ~ u: ~n #¢ ~n u ~z ~u~ ; ~u ~u ~ u: u ~u aJ ~1 U C 1 C ~ ^0 c ~r ~ ~f, ~ · - 1 C 1 C~ U O1 U O ~ ~ 1 · - ~ · - ~ w ~ ~ ~ ~ x x - - ~ c ~ ~ o o o o ~ ~ ' - O ' - ~ JJ :- ~ CL ~ W C., 1 ~ ~ ~ ~ · - ~r ~ 1 · - ~ ~ Q4 ~ ~ ~ ~ o ~ · - w · - ·e ~ ·e o ·e o x ~ ~ ~ .^ o ·e :3 ~ ~ · - ~ · - . ~ ~ o ~ c o o ~ · - C ~ C ~ ~ ~ ~ ~ Q S C S C O ~ E ~ ~ O ~ O ~ O C ~ ~ ~P4= C Q ~ ~ V co u ~u ~u ~z C o C ~ · - 1 1 C U ~ 1 0 ~V ·- O C ~ X ~ O Q' O 0 1 C , - ~ ~ 1 0 L4 ~ 1 ~- - C 1 U ~ ~C ~ ~ rl . - ~ · - · - O ~ J~ C U N :^ ~ ~- - O · - O ~ · - _I JJ ~ ~ ~ ~ U ~ C n' · - ·~- - to 1 · - S ~ . - 1 C ~ ~ ~ · - o. - ~ C ~ O C ~) U) ~ U) C O ~ ~ C ~ O ~ O IV ~ O ~V . - U) ,., i., ~ dJ C C ~ ~ ~ ~ ~ · - U ' - · - ~ C 4~ 0 4) 0 ~ ~ U Q ~ ~ :, U ~ U ~ ~ ~ ~ U E ~ U ~ ~ ~ ~ a, · - 2~ U .C ~o o ·~1· - · - 0 1 · - O O ~ S O ~ O ~ O X C~1 ~ ~ U C · - ~ ~ ~ ~ ~ O O ~ 1 ~ ~ I O ~ 1 ~ 1 C J~J · - S ~ S 0 1 ·~1 ~ _' 4 0 J ~C -I C ~ t~1 J~ N _~ ~.,- ·- C C ~·- ·e ·e ·- O Ll JJ ·~ ·e ~ ~ ~ V ~ V ^= ·^ ~ V ~ U ~ V ~ Ll ~ JJ ·- J-1 ' - 4~ C ~ dV U] ·- ~ ·- J~ ~ -I ~ C. - C · - C. - · - ~ C C C · - C . - C 'O ~4 U O U O O GS J~ ~ O U O V 0 .~1 4 ·r' 4 - - ~ C Q. U] 4 · - ~ . - 4 a, ~ X ~ x s X ~ms x s x 0 U O U O C _~ C C ·^ U'O U O U ~ U U :, ~ ~ Y Y ~ U 1 1 ~1 1 ~ ~ :^ 1 1 U 1 :^ 4 ~C ·- ~ ~ C ~ O ~ C ~ ~ U · - 1 ~C ~ ~· - ~) ~ :^ ~) · - U 1 a, ~1tl, ~ ~1 V ~ U 1~ ~ ~ V X · - 1 1 1 ~ V V O ~U C ~a:, · - O ~C a, cV ~ ~ C 0 o C ~CI ·- O ~ O ·X -t ~O I O4 3 4 3.- u ~ ~ ~ ~O . - ~C ~ ~ ~ ~ ~ ~ ~ ~ O ~S ~ O ~JJ O ~ O C t ~U r. 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U :>, ~ ~ C 1 JJ c ~ c u ~ ~ ~ ~ ° ~ C ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ U 1 C ~ ~ ~ U ~ X U 1 ~ U a,. - ~ 1 C O ~ 4 a)~ - O O ~ C a) ~ C 1 C~ U U ~J X ~ 1 0 ~ ~ ~ O ~ X 4 ~ C O ~ ~ ~ 1 - - ~ -~ O U 1 · - Q' O ~ w 0 1 0 0 ·- ~ ~ >' ~ X C X J~ ·- C ~ ~ ~ ~ 4 ~ V 1 4 ~ ~ ~ C 4 J~ O O O O O X O ~ 4 JJ 1 _4 ~ _4 O ~ ~ S ~ 0~- 0 ~ '- ~ JJ -~ O 1 ·- Q~ Q5 V ~ dV U -I 4 ~ V 1 JJ ~ J~ C 8 1 C ~ ~ ~ E 1 · - . - C 1 ~ 1 ~ 4 . - ~ ~ ~ ~ 1 ~ O t0 S O O ~ ~ 4 ~ 4 _t C U 1 S e, ~ ~J X _. ~ N ~ ~ ~ ~ . - N ~ =~ - O · - ~ ~ (IJ ~ O ~ ~ ~ C -~ ~ 0 4 . - 4 ~ ~ J~ t~- - JJ Ll U - -~1 ~ 4 C (V C ~ ·. ~ ·e O J~ O ·. ~ ~ C ~ ~ · - ·e ~ 1 . - ~ ·. ,= ~ ^~4 ·. ~ _. ~ . - ~ 4J O ~J ·- ~4 V ~ 4 1 C ·~ U V >~ U ~ ~ J~ U ~ ~ ~ V ~ :> U] U C V V rl ~ U] ·rl J~ 0,) C tV ~ 3 ·- ~ O _4 C ·- J~ ~ 4~ -1 O ~0 C -1 ~ ~ ~- J~ (U C ~ C · - C O ~ '~ C ·r4 .~ C ~- C ·~1 ~ C ~ S 11) C ~ C C ~ C O U ~ ~ O ~ O O U (IJ ~ O ~ O U J~ C O O ~ u~ O O O O ~ ~J rn C 4 · - V, ~ C C ~ 4 rl C U ~ 4 · - C ~ ~ ~ D 4 4 ~ ~ ~ C O4 ~ S X ~ U ~ O Q S X ~ 4 ~ S X 4U tJ~ S C O C S C C 1 S dJ C :' t) O~ ~ U ~ ~ U O Q ~ ~ C V O ~ O V 0 4 ~ V O U o U ~ C ·- =~ = - ~ 4 ~ 4 ~ ~ ~ U ~ -^ Q ~ =~ Q C ~ ~ Q C ~ ~ Q =-- Y cn :~: t5 u cn c~ ~s ;n ;n cn n ~ ~ u~ 3 u~ ~ cYn ~q c~ ~ ~ ~ ~ 1 1 1 0 U, C o o ~ ~ ~ 0 87 - :' ·~ - c 8 - as ED N ·,4 in E Q :3 ;0 C o A. ~0 In _ O ~ - o Be U 88 C C o .-, 0 ~ ~ :' ·- o ~ P4 ~ a: be: ~ o _ a. 0 In ~ In c - ~ o · - .,' In A I: o _ o C - ~ o .,. JJ Ll eq E~ 88 1 :^ 1 V C · - O ~ 1 1 ·~1 · - 1 1 ~X C o o ~ ·- ., .,l JJ ·,' i., ~ ~ JJ X ·~4 · - ~ · - o 4 ~· - V ~ ~ ~ · - X ~ · - . - 1 1 1 1 ~ ~ ~V ~ ~ · - 1 1 1 1 1 1 Ll ~ ~ U]~ :~t U) 1 o ~ ~ o~ ~ ~ o · - 4~ Q] a o ~ o~ ~ V o :' U 1.0 1 ~4~ ~· - 4 .,'. - . - ~X ·,4 ,6 ~o ~ X ~· - ~ · - o ~ 4 ~ ~ ~ · - 1 1 1 1 1 C ~ ·~1 /t X I I I I I ~ :^~ ~ e 0 · - ~ ~ ~ ~ e O C ~ ~ O · - ~· - = ~ X O ~ 0 4~ 0 JJ ~ L. :' ~:' ~ :' C : ~1 ~1 ·,4 C ~O · - 1 · - X 1 O .,~ ·- · - ~ X · - U] 1 1 ~1 1 1 o 1 1 JJ 1 1 1 ~ ~·~ ~ ~ · - ~e ~ L4 ~ · - ~ L. V a, ~n · - 0 C ~ O ~ ~ ~0 a, ~ ~ ~ ~ L, ~ O ~ O · - : ~:~ ~ ~ ~X o, a, ~o,o, ~a ~r ~iD U~ 0 1 1 1 1 11 1 0 0 0 0 0 00 0 CD ~ ~ 1 1 1~ ~ ~>' ~ ~ c .,, ~4,, ~ ~1 · - C 1 1 1 - V ~C) 41) ~ ~ ~O · - 1 ~ ~ X · - 1 1 · - ~ O ~4 C 1 ~;>' O O X a, 1: X O ~o4 0 ~ ~ X ~ ~ O ~C O O ~ ~ ~ ~ O O ~rl ·~ J O I ~1 _~ O ~ O C L4 ~ S · - 4 ~_I x e ~·- :> ~I ~ ~ ~c ) ~ I ~ o. : O O ~ O ~ ~ ~ 1 ~ 1 ~c ~ 1 · - ~ ~O J~ a~ ~00 ~·- N~ ~ 4~ ~ -~ ~C ~ O O ~ I X -1 ~1 (IJ~' ~ ~ I ~ N ~ ~ I · - ~ ~ C ~ ~· - _ ~ o ~ -4 ·- m~- ~O O O ~ · - 1 ~ ~ ~ ·e O ~ ~ ·- tl~ _I ~ J~ JJ ·- X ~cn ~ . ·e 1 nS 1 ~1 ~ O · - ~ O ~ ~ ~ ~ ~ ~ ~ 1 ~ C U ~ ·. ~ ·- oC ~ C u] JJ ~ ~ ~ ~ . - ~ ~ ~ C . - ~ . - ~ H ~ ~ C C ~ ·- C n' ~ ~ ~ C ·- C -- O ~ C O ·- ~ ~ C ~ ~ C ·- 0 c Y a) ~ ~ ~0 ~ 0 0 ~ 0 v P~ ~ ~ ~ ~O ° O ° ~ O ~ ~J O eq C · - ~ O C ~ · - ~ ~ O Q ~ ~ ad 4 ~ ~ ~ C ~ C au 0 =: "o c~ ·-l C C S ~ ·- S X S X ~ D ·- ~ C S ~ ~ ~ O ·~ ~ ~ O ~ O ~ ~ O ~ O ~ ~ ~ ~ ~ O ~ I ~ ~,- C ~ :, D ~ X · - ~ ~ ~Q ~ ~ Q ~ Q ~ ~ ~, - ~ · - 9 C Q ~ ~ ~ =- - C) c~ ~0 Y s ~ns : ~: ~a) ~:3 u ~ cn ~ :n u ~ u ~x: ~u ~cn ;n ~ u~ I I ,0 ~1 1 JJ >, .,4 0 1 · - · - 1 1 ·- C ~ t) · - I U C I t) ra~ ~ ~ ~ ~ . - X ~: ·~4 0 1 1 ~ I~ O C~ ,4 , ~ ~ C O O X ·~H ~I X ~·- X ' O ~ ~ O · - O ~C O ~ ~ ~ O ~C ~ ~ O ~·- O ~M~ O ~ O ~ C I ·- O S ·- C ~ ~·-~ ~ ~ ~1 O ~-4 ~ 1 ·- ~O ~ 1 ~ 1 ~ ~^ = ~ ~ 1 ~ ~ ~ ~ S O X ~ ~ S ~ ~ O ~ ~ · - ~ ~ I N 4~ ~:^ ~l I C ~O N ~l I ~ '~ C ~ ~ ~U · - U ~ ~- - Ll ~ O O ·,4 ~· - ~ O ~ ~ · - O I . - U · - ·e ~ ~ :r' · ~ ~ F-. , - ·e ·e - - I ~ · - X ~ ' - P~ · - ·~ ~ ~ U ~. - ~ · - ~ U U ~ ~ ~ ~ ~ ~ O ~ ~ ~ ~1 S ~ · - ·,~ ·e ~ ~ ~ ~ · - ·e · - ~ · - ~ ~ ~ ~ ~ ~ ~ ~ C I : ~ ~ ~ ~ ~ ~4 ~ ~ c ~ e ~ ~ ~ c ·,~ s 0 ~ ~ ~ ~ ~ ~ ·- ~ 0 0 C 0 U 0 0 ~ ~ 0 ~ 0 ~ 0 U ~ ~ r~ ~ 0 U au ~ ·r4 ~ ~ ~ ~ ~ ~ · - ~ · - Q O D O ~ ~4 C ~ ~ l a~ Ll S ~ ~C X a) ~: ·- s ~ ~ x s X 0 ~ ~ ~ ·- c ~ ~c O U O U O ~ O ~ ~ U O O ~ O ~ ~ ~-- U O ~ Q C) D ~ Q ~J ~ · - ~ Q ~ ~ ~ ~ Q ~ ~ ~ ~ X ~ ~ ~ ~ · - 3 3 ~.~= ~ 3 3 I ~ P u 1 a) C a, ~ · - 1 ~ O ~ ~ C ~ 0 1 ~O O U · - C 0 -1 0 n' 0 1 S X ~·^ ~1 U 0 4J 4 ~JJ ~1 ~1 ~ 1 4J · - · - ~1 ~ S ~ ~ 1 :>. U N ~ ~ C ~ · - ~ I · - U C ·,4 · - X ~ ·~, ~.. ... - .,4 O ·- ~ U ~ U ~ C ~ Ll 41J ·,. .IJ U) · - 4) ·~1 ~ ~ C a' ~ {Q c ~ c · - c ~ m. - O U ~ ~ O U O U O i,' ·., ~ C ~ ·~ ~ · - ~ ~ ~ ~' - S X S X ·~,< 4J ~ O ~C ~ U O ~ O U C ~ ~ U C U U ~Y ~ 2 <: ~ u, ~ cn 1 1 1 0 ~-1' 89 - c ~l o - a, m ~: N . - U) U) Q :' U) ~C 3 ~g {: C ~ o .~ o P4 ~n .. - ' , ~ ~ . - :~ JJ C a, >' ~ ~ .- . - ~ ~ ~ ~ ~ x 1 ~C ~ ~ O ~ ~ C O -. 1 ~O ~ X ~ ~ JJ ~ JJ x ~x o 1 ~ ~ ~ o tn ~0 JJ O ~ 1 X C - ~ ~ o ~ o 1 ~ ~ ~ ~ V - . - ~ O ~ 1 ~ 1 o x ~ ~ ~ o~ 0 ~ c C ~o ~ Q. ~ C o~ ~ o · - ~Pu _ ~o ·- ~ ~ o ~ C ~ 4, ,. ... - s : ~ C ~ ~ ~ ~ U ~ ~ ~ ~ ~ ~ ~ ~ ~ o ~ ~ ~ ~ O Ll ~ C ~ C - - ~ -- S ~ ~ C ~ Q) o o o o o C) o ~ ~ ~ ~ o ~ C . - ~ . - c s ~ s x s x 0 ~ ~ s ~ a' ~ o c) o u 0 u 0 ~ ~ ~ u ~ 0 JJ C D ~ D ~ ~ ~ u ~ ~ ~ ~ U ~:3 : ~ o :3 ~U <: u: u ~u ~z c ~cn u ~ 1 1 1 eJ >1 1 1 :^ ~U -- O ~ C r0 C U r ~ ~ ~ :~ c ~ ~ L. m- - ~ I I U ~ ~ ~ E X 1 ~ U U ~O ~ O ~ ~ O 1 ~ ~ X ~ U :~ O ~\ :>' ~ X X a, 0 1 ~ V ~ O O O O O ~ ~ 1 X - U) ~ JJ ~ 4~ ~ ~ ~ :>, O ~1 ~ :, ~U 1 1 ~ ~C ~ ~ ~ ~ ~ ~ C C ~ ~r ~1 0 ~1 1 ~ 1 C ~ ~ ~ ~ C ~ :' X ~1 ~ ~ ~ ~ ~ O O ~ C U 0 S 9 O ~ ~ ~ o~ ~ O O P. _ 4~ ·e O ·e O ·e ~ JJ ~ 4 C ~ ~ ~ ~ O JJ ~ 4J ·e GS 1 S Ql V >, u, c ~u c u e u c U ~ L4 I U ~ ~ u ~ 00 0 - ~ ~ ~ QJ ~ ~ ~ JJ ~ C O ~ ~ :3 ~ '' .,, c ~ c ~ c ~ e ~ c 0 ~s c ~ ~ ~ 0 0 0 0 0 ~ ~ ~ ~ ~ Ld ~ ' - ~ ~ C U ~ C .- s C s ~ s C s X ~ U ~ ~ s x: / U 0 U 0 U 0 ~ 0 ~ ~ ~ ~ V 52 C ~ C ~ C 51 ~ ~ ~ ~ U ~ ~ ~ ~ :, ~U CQ ~U) V] ~U] U} co c ~ ~ - ~ ~ o ~ c - ~ o u ~ ~ tn Pd E~ o -,4 4~ ~4 u ~ c ~ y . ~ ~n 1 1 1 1 1 eJ ~ >' :^ ~ ~ 0 ~ c ro c ~ u J~ 1 JJ JJ ~ ~' - ~ ~ C ~ ~ ~ ~ . - ~ . - ~ ~1 U ~ ~ ~ ~ ~ U X 1 ~ U~ 1 ~ U ~U ~C U O ~ O ~ ~ ~ C O 1 X ~ 1 1 ~ ~0 -1 Ll X Ld ~ ~ O ~ ~ ~ :>' O X ~ ~ k4 X X X "l X ' o4 0 1 rl ~ ~ ~ ~ O C ~JJ o ~ 4~ 0 0 0 0 0 ~0 ~ 1 X ~ ~ C ~ ~O .- ~- - ~ ~ ~ ~ ~ c ~ ~ o ~ ~ . - o ~. - U C ~ U 1 1 ~ ~ ~1 ~ C :~ ~ ~ ~ ~ ~ ~ ~ ~ C - - O ~ 0 ~ ~r ~ 0 ~ 1 ~ 1 ~ 1 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ C ~ O X . - ~X ~ ~ ~ 0\ ~ ~ ~ O S O ~ O O ~ ~r' C U ~ ~ ~ ~ ~N . - O ~ )~4 1 0 ~ 1 ~ ~ ~ ~ C ~ ~1 Ll ~ O U O ~ >1 {U ~ ~ ~' - JJ t~ O ~r JJ ·e O O O ·e O ·e ~ -~1 0 1 J~ ~ ~ C ~ ~4 - - ·e ~ C J ~ ~ .13 ·e ·e ~^ 1 ~ 1 X S ~ ~ ~ ~ ~ O ~1 C ~ U ~ C ~ ~ ~ U C V ~ U ~ ~ ~ 1 0 U ~ U ·. a' s ~ .. ~ ~ ~ ~ o' r4 ~ ~ ~ . - ~ ~ ~ c ~ 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ 4 ~ ~ ~ ~ C ~ C ~ C ~ C ~ C-- C ~ S O ~ C O ~ C C ~ ~ ~ ~ ~ C O O ~ O C O O O C O O O O O U O V ~ ~ ~ Ql "l U ~ ~ O JJ O ~ C ~ ~ ~ ~ O ~ ~ 4 t) ~ 4 ~ ~ ~ ~ ~ ~ Q O Q V~ ~ ~ C U Ll C Ll C JJ t: ~, ~ C ~ S ~ S C S ~ S C S ~ S X S X O ~ D ~ U C ~ ~ S ~ ~ ~ ~ ~ ~ C JJ O ~ u O ? O U O O O U O u 0 U O 54 ~ ~ ~ ~ O ~ t' U E ~ E O ~ ~1 ~ C :, C :: ~ ~ ~ ~ ~ ~ Q C ~ C Q ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ U Q ~ ~ ~ ~ ~ ~ ~ ~ U U : ~: ~:3 : ~3 ~ d ~: ~ ~ ~r~ E ~ Y u ~;O u: cn cq u ~cn z ~ ~u~ u ~u ~n 0 u, C Z ~ O ~ ~5 90 QUALITY OF TESTING The Committee on Toxicity Data Elements often found that studies not conforming to present testing protocol guidelines nevertheless yielded acceptable results. The committee established six classifications to describe the quality of test protocols: O G. the highest rating, for a test protocol performed according to current reference protocol Guidelines adopted by the committee. · A, an adequate rating for a protocol that did not strictly follow current reference protocol guidelines, but was nevertheless deemed adequate for conducting a health-hazard assessment. · IN, an inadequate rating for a protocol that was neither conducted according to guidelines nor adequate for conducting a health-hazard assessment, but was judged not to need repetition. This was used largely because other adequately conducted tests provided the necessary or closely related information or because available information was deemed to be sufficient for conducting a health-hazard assessment. · IR, an inadequate rating for a protocol that was neither adequate nor conducted according to guidelines and that was judged to need repetition. · C, a rating denoting indeterminable quality of a test that could not be judged. This rating was most frequently given to abstracts, review articles, and other reports that did not describe protocols fully. · X, a notation for a test that, according to available information, was not done. Table 9 shows the quality ratings of the 33 test types as found to have been done on the 100 substances in the subsample. The proportion of substances on which a given test type was not run (X) ranged from 37% (acute oral testing in rodents) to 100% (subchronic eye toxicity testing). Overall, without regard for either test type or intended-use category, the Committee on Toxicity Data Elements tabulated the quality ratings from evaluations of a total of 664 tests. A tally of these quality ratings for each subsample category and for the subsample as a whole is presented in Table 10. Only about 8% of the tests met the standards of the reference protocol guidelines, and about another 19% were judged to be adequate. When more than one study of the same test type had been done, these percentages are based on the quality rating of the best study. 91 v u] En u] v] c CQ us c v as ED lo o o ~1 v ~n E~ q~ o v ~l o o z - ~ ~ x u] c ~ o E~ ~ 0 ~ ~ ~ ~ uO un C ~0 ~u ~0 a) 0 CO ~ ~ ~ kD \0 ~ ~CO r. co ~a a ~a ~m _ ~ ~ ~ ~ ~ ~ ~ ~ ~O ~ ~ ~ c) ~ - U) 0 - · - V H ~ ~ ~ ~ ~ ~ ~ ~ ~O (~ ·,~ _ _I _ · ~ Z V O ~n ~ · - _ O ~ · - Z ~ ~ a' ~ ~ ~ o' ~ ~u~ Z _ V V C ~ O m z v' a' 4-~ C V ·^ ~ O ~ - O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~O 4 ~ O el - O ~ V ~ 4~1 ~ O · - O ~ m<~ ~ ~n ~ 0 ~ C) ~ ^ C' ~ C ~U' ~ ~ 0 0 0 0 ~0 0 0 ~0 · - - P: E~ V] E~ .,' > ~ ·. ·e . - V ~V ~ .,~ ~·e C O ~ ~ ~V ~k4~-'- ~C ~ O ~ U] 24 0 ~V O V ~O 0 4 O U ~ ~ 1 0 1 ~ ~1 k4 ~ 1 Ld 1 .= ~V ~ 1 0 O O ' - ' - ~ U ~ V O ~ s4 ~U ~ 0 1 --^ ~ ~ ^-- 1 1:>, ~ · - ·~1 1 IJ, U ~ 1 ~ U 1 1 ~ X X J~ C 1 · - ~ 1 ~ · - ~ ~.r4 0 0 ~ 0 1 X ~ ~ v X JJ V U ~ V JJ-~4 ~ O ~ ~ ~ O · - a~ . - ' - ~ O ~ ' - U U X -~ C ~ ~ - ~ U ~ · - .- O ~ 0 k4 J~ V _~ 1 · - 1 _1 >1 X X V L. ·~1 · - ~1 43 16 ~ X a, to O O (V V ~ N 4 ~ O ~J L4 V 4 ~ _~ ~4- - 0 ~ O V ~- - ~ ~ ~eQ ' - U O V O U 0- - ~ · - L. ~ ~ n' ~ ~ ~ C C 1 ~ 1 ~ 1 O O ~ ~ ~ ~ ~ ~ O ~r 0 ~ 0 0 ~n ~ ~ ~ ~ L4 au 0 ou 0 ~ ~ 0 ~S ~ V ~ ~ V V V C U U U :~ ~ ~ ~ :~ :I'- ~53 Q U ~ ~ ~ U U ~ ~ ~; ~ ~; ~ ~ ~ U) U} U) U] . o _ C~ ~ ~ U' kD ~ CO 92 ·e v 9 o 4 C o 1 ·. 4J C o C o r 1V ~VU .,. . - >, u u~ x . - ~ ~ 0 X X V V 0 0 t v - = 0 ~ ~ :>, 4 4 ~ 4 ~ (0 0 4~ 0 - ~q 1 U U O U~ ''I ~ .-1 V .~1 C 1 C C O O 0 1 0 4 4 C~ 4 ~D 4 0 ~C S U U ~ ~ n ~ U] U] U] 0 ·e a' ~ v .~' u x JJ C 0 ~ v cq ~ 1 s .,. 4 O ~ 1 O ~r q ~ - S D :: cn ·e JJ ._, ·,. X o 4 U >, · - ~ O V 4 UD Su U] 4~ CO O a' . - ·,1 X .. O V ~ ·_1 C U O · - .,1 X V O V O ~ ~ 4 S ~ ~ · - ~ C a, U U . - ~ - - t: 1 ': 00 0 4 ~ 4 S ~ U U Q ~2 U] U ~r ~ ~ ~ ~ 0 ~n a, ~o ~ ~ ~ 0 oo ~l- cr ~ ~ ~ CD 0 r~ ~ ~ ~D ~O O ~ ~ O ~ O u' ~ a, ~ 0 ~ O a~ c ~u~ ~ ~ ~ ~o ~ ~ ~ ~ ~ o ~o ~ o u~ ~ , 1 ~u ~ ~c JJ ·~. JJ O D tn ~Q ~o4 ~ c ~ 0 c ~:^ ~n · - 1 0 C >, ~· - c) ~ 0 C ~ ~o · - ~ ~· - C U 1 ~X O ~ · - 1 · - :>' ~O · - tQ O ~a x ~u ~ c 0 4 ~- ~ - C 0 0 ~C 1 ~ ~ ~ · - X ~· - ~ ~ · - O 1 ~i 1 C, 0- - 4 ~ S ~ · - :>' 1 :^ U · - :^ ~ ~ ~ ~ ~ ~ ~ ~ ~ C C :>. ~ · - C JJ ~ U ~ ~ C 1 ~ ~ O ~ O ~0 JJ · - C (V · - ~ ~ C C I ~ N · - J~ · - U · - C} O ~ U :^ ~ le ~ ~ ~ · - rA ~· - U · - ~ 0- - ~ ~ ·. 6 ~ C C ·- X ~ C X ~ ~ ~ ^-- O ·- C O U · - O ~ ee O ~ O ~ ~-^ ~ ~ ~ ~ ~ ~ U ~ · - ~ ~ ~ ~ ~ ~ ~ C O C ~ ~ ~ ~ ~ ~ ~ ~ ~ · - O U ~ ~ U 0 4 O ~ 54 0 C · - C U rl Ll C P, C O. O, C ·,4t}--l C- -JJ S ~ ~ C ~ JJ' - ~ O ~ U ~ C ~ ~ C L4 ~X ~ ~ ~C ~ ~ · - ~ ~- - ~ ~O ~ S O~ ~ ~ Y E~ x:~ t~ ~) C)C!) U] U)u ~; cn ~ ;3; u ·~ ~ · ·· · · ~ ~ ~ o~ ~ ~ ~ ~ ~ O . ~ ~ ~ C~C~ C~ ~C~ 93 4 o Q. £ ~n Q U] Q tn Q cn C ·,. U] al C ~n Q U] o o C o a 8 0 U] E~ q" o CO C" ·,4 4 ~; .,.4 ~o o c o . - 4) D .,, 4 JJ ~n ·,4 o E~ O 0 ~ ~ 4 0 O E Q ~S ~ E~ ;~ 0 O ~ 4 0~ - cn ~4 o 5 ~ C ~ ·,1 Z ~; O · - a, ~ C ~ S · - ~n U] ~ U) u~ E~ U] ~ ~ E o £ · - o ~ O S ·,. 0 ·.- JJ · - O O ~ ~: 0 0 0 4 ~· - 4~ 0 ~ 4 :' =-^ ~ £ X C C) ~-- ~ Cq 4~ · - ._. a 0 ;U ~ 0~ ~ 0 =- - O JJ C o- - ~ ~ a,. - .,. ~ · - ~ C ~ 0, - ·~1 H ~J 4 P. ~ U) ~ ~ 4 ~ ~ ~ O P4 ~ ~ O ~ o ·,. ·,' U U] a) c ·~- -~ :, ~ o ~ >- - o pl ~ c) oo ~o' u ~u ~r a ' u' ~r~ ao ~o ~ ;o v ~c ~ ~c ~ ~o o ~oD ~o 0 a ~:4~ · -o ~c ~ ·,43, ~Q O 0 ~ ~Q ~ C ~ ~O · - ~ O C ~ ~3 ~ C ~ c ~ 4 ~ 01 4 --~1 ~- - ~ · - ~ ~ ~o 0 ~mm ~n a, ~ ~== 4 C S 4 ;.- C, ~ ~C~ 94 These data are presented for the purpose of evaluating the testing protocols; the focus is on the tests, not on the substances tested. Because the counts in Table 9 and Table 10 are not weighted to account for the different sampling rates over the seven categories, inferences as to the completeness of information on the whole select universe are not justified. Interpretation of Table 9 and Table 10 is based on the assumption that, after a decision to apply a specific test type to a specific substance, the quality of the test is independent of the reasons for doing it. The two committees also assumed that for their purpose inaccessible or unreported information did not exist. Furthermore, some studies might have been conducted according to standards higher than those indicated by a given rating, but that would not have been apparent in the reporting of those studies. The quality of design, execution, and reporting was not uniform among the various types of tests. For some types (e.g., acute oral administration in rodents, acute dermal application, acute eye irritation and corrosivity, guinea pig skin sensitization, and subchronic dermal application for 90 d), the majority of tests were deemed not to require repetition. Tests that were more complex (e.g., teratology in rodents and rabbits, multigeneration reproductive effects in rodents, and genetic toxicity) were frequently absent and therefore were often not a part of the determination of ability to conduct a health-hazard assessment. The relationships between the year in which rated studies were conducted and their quality ratings were not determined. The number of test types suitable for detecting substances harmful to in utero development is limited, and these few tests were rarely found for the substances examined. In general, the data most likely to exist on a substance are from tests for acute oral toxicity in adults. Tests designed to detect more chronic effects are also represented, including those involving cancer and gene mutations. Teratology studies in rodents and rabbits and multigeneration reproduction studies in rodents had been conducted infrequently, even when deemed necessary by the committee. Overall, the information available regarding toxicity to the conceptus is very limited. Committee evaluation of an individual study protocol always included reasons for the particular rating given to the study. For the most part, these reasons were statements of a given study's specific adequacies or inadequacies with respect to its reported protocol. They were collectively tabulated for analysis to assess which deficiencies were most prevalent and which ones could be overridden in assessing the overall value of a study. The Committee on Toxicity Data Elements did not identify every reason for every test evaluation, because the development of such tabulations was an evolutionary process in the documentation of the activity. In most cases of protocol evaluation, no more than three reasons for a given rating were necessary to support the quality rating. The committee did not consider its tabulations of reasons to be appropriate for detailed quantitative analysis; nevertheless, they provide an important overview of factors that affect the quality of tests. 95 As the evaluations proceeded, four kinds of reasons for assigning particular ratings evolved: · Deviations from reference protocol guidelines that, because they were minor, did not prevent a study from being used in a health-hazard assessment. · Reasons for judging test protocols to be adequate despite their deviations from reference protocol guidelines. · Reasons for judging test protocols to be inadequate. · Reasons for not needing to repeat a study that had been judged to have an inadequate protocol. The committee used this information to assess which deficiencies were most prevalent, which ones could be overridden, and which ones caused studies to be of little or no value for conducting a health-hazard assessment. Some of the more common minor deviations from reference protocol guidelines that nevertheless resulted in a rating of adequate included the use of too few animals per dosage group, the use of only one sex, the use of too few or improper dosages, and the absence of various kinds of observations (e.g., clinical chemistry or histopathology). Reasons for judging such tests to have been conducted adequately even though they were not performed according to reference protocol guidelines included the expectation that more information would not alter the conclusions, the sufficiency of data to evaluate toxicity or calculate an acceptable LD50, and the use of dosages high enough to give positive results or exceed the limit test now prescribed in the guidelines. Tests that were rated as inadequately conducted were often missing required observations (e.g., test-animal description, diet analysis, chemical analysis, clinical chemistry, and histopathology), had too few dosages, or lacked sufficiently detailed end points, such as data tabulation or statistical analysis of data. Occasionally, the committee recommended that these studies not be repeated, either because toxicity was sufficiently well established or because more information would have only limited value. The first three of the six quality ratings are collectively a measure of testing that need not be repeated because its quality is adequate for conducting a health-hazard assessment, the breadth of existing information is sufficient for conducting a complete health-hazard assessment, or repetition of inadequate tests would not add much to existing information. When these first three classifications are combined, it is clear that much of the past testing has been productive. For both G and A ratings, tests were done according to reference protocol 96 guidelines or in an otherwise acceptable fashion. Tests with G. A, or IN ratings need not be repeated. For four acute tests indicated in Table 9 (acute oral administration in rodents, acute dermal application, acute dermal irritation and corrosivity, and acute eye irritation and corrosivity), the sums of G. A, and IN ratings as a measure of testing not needed were about 83, 87, 81, and 76%, respectively. As indicated in Table 11, the percentages of four principal chronic tests (multigeneration reproduction in rodents, carcinogenicity in rodents, chronic toxicity, and combined carcinogenicity and chronic toxicity in rodents) that did not need to be repeated were consistently and substantially lower. These findings should be viewed in perspective: (1) the comparison is of simple acute tests with more complex chronic tests, (2) as indicated in Table 11, the numbers of chronic tests acutally performed were far smaller than the numbers of acute tests, and (3) the percentages are derived from small numbers of evaluated tests, particularly in the case of the chronic studies. TEST I NG NEEDS The data summarized in Table 9 are presented in detail in Tables 12 through 18 for each test performed in each category of substances examined. In these tables, one may find the percentage of the times each test was run (by substracting the value under X from 100%) for each category, as well as the percentage of the times, when the test was run, that it was given each of the five quality ratings. Upper and lower 90% confidence limits are presented with these data. Among the 18 tests deemed by the Committee on Toxicity Data Elements to be required for pesticides and inert ingredients of pesticide formulations (see Appendix F), the proportion of substances with tests performed inadequately and needing repetition (IR + C) or not performed at all (X) ranged from 0% to 73~. For cosmetic ingredients, the corresponding range was 67-100%; for drugs and excipients in drug formulations, 25-601; for food additives, 33-80~; and for chemicals in commerce, 45-100~. This indicates that, for each category of intended use, substantial testing and retesting remain to be performed if information gaps are to be filled. The major portion of testing need results from failure to do required tests, rather than from conducting tests in a manner inappropriate for the purpose of health-hazard assessment. If the unknown amount of information that was not available to the committee had been available, the "untested" category would be somewhat smaller than reported here. To some extent, the apparent inadequacy of genetic-toxicity data reflects the facts that some of the test strains now required were not available until after 1976 and that the testing required involves a tier system of evaluation developed only recently. The apparent lag in testing of food additives may reflect the fact that many food additives were not generally deemed to require extensive testing until they were removed from the GRAS list in recent years. 97 TABLE 11 Comparison of Aggregate Quality Ratings (Al1 G. A, and IN) for Selected Acute Test Types and Selected Chronic Test Types No. Substances Having Test Typea at Least One Test Proportion with Ratings Evaluated of G. A, or IN,b % Acute: Acute oral in rodents 63 74-83-90 Acute dermal 30 76-87-95 Acute dermal irritation 37 70-81-91 and corrosivity Acute eye irritation 33 63-76-88 and corrosivity Chronic: Multigeneration reproduction 12 12-33-61 in rodents Carcinogenicity in rodents 23 34-52-70 Chronic toxicity 29 23-38-50 Combined carcinogenic~ty 8 20-50-80 and chronic toxicity in rodents a These tests were selected for illustrative purposes. b Values are aggregate proportions of tests having quality ratings of G. A, or IN, not number of substances having these ratings. The 90% confidence limits shown are rough approximations based on the Bernoulli distribution. These proportions are based on the study of highest quality, even when other studies of the same test type were done. 98 Table 19 contains relative comparisons of test types that, although considered essential, were not conducted, conducted inadequately, or reported in a manner inadequate for use in a health-hazard assessment. These tests need to be conducted or repeated. In general, chronic studies, inhalation studies, and the more complex studies with specific end points (e.g., neurotoxicity, genetic toxicity, and effects on the conceptual are most frequently needed. The gaps in toxicity information differ from one category of substances to another. To some extent, these differences may reflect the spectrum of individual tests that the Committee on Toxicity Data Elements prescribed as necessary to meet its criteria for adequacy of information in each category. The relative comparisons in Table 19 are based on estimates for the select universe based on the sample of 675 substances and the subsample of 100 substances. Because each subsample category is small, the order is subject to substantial random errors and might change on repeating the determination of toxicity-testing needs with a new random sample. The three greatest testing needs for pesticides and inert ingredients of pesticide formulations were in teratology, subchronic neurotoxicity, and genetic toxicity. For cosmetic ingredients, the greatest testing needs were for subchronic eye toxicity and neurobehavioral toxicity. A large variety of test types (14 test types indicated in Table 19) are needed most for drugs and excipients in drug formulations. For food additives, seven test types are needed most. For the three production categories of chemicals in commerce, eight (at least 1 million pounds per year), seven (less than 1 million pounds per year), and four (unknown or inaccessible production) test types were determined to he most needed. HEALTH-HAZA~ ASSESSMENT The determination of toxicity-testing needs was based not only on evaluation of testing quantity and quality by the expert scientific committees. After careful review, it also involved their collective decision on the ability to conduct a health-hazard assessment with available information and on the need for additional studies or for retesting in the case of inadequate studies. If requirements for testing were rigidly adhered to, it would be necessary to say that, in light of intended use, not one of the 100 substances in the subsample met the requirements according to the strictest standards set by the protocols chosen by the Committee on Toxicity Data Elements. However, less rigid standards permitted the committees to determine whether enough testing had been done and was of sufficiently good quality for at least a partial health-hazard assessment. me ability to conduct complete, partial, or no health-hazaru assessments of substances in each of the seven categories of the select universe is summarized in Table 20 and Figure 4. For purposes of interpretation, a complete health-hazard assessment is Refined as one that provides a full estimate of hazard associated with the safe use of 99 v) Q o ,1 c ·~( .-' Q a' P4 o 0 i_ -a' a' c al c .,. -.4 u' a' to in o c .,' ha En o .,' In a) At: i: En :D -A ~ sac H 3 a U a ~ Z ·> In ~ ~ ~L in 5: C a L X a, al U] · to ~ a, ~as ~ ID a~ ~ ~ ~ ~ oo tS) ~d ~D ~? ~u ~> 1 ~C~ , ~ tn ~ 1 ~ ~ 1 ~ ~ ~) ~1 c ~u ~1 o 1 ~1 1 ~) 1 t- 1 1 0 1 1 1 1 1 a:, 1 1 1 1 t- ~ 0 1 ~ ~ 1 O _I O ~ _I O O O ~0 ~1 0 0 0 0 _4 1 ~ O _t t~ O 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~ 1 1 1 1 1 O ~ O O ~ O O O O O ~O O O O ~ ~ 0 ~ ~ O a~ o C~ ~ ~ ~ ~7 ~C ~e ~tD ~ Lt~ 1 tD d' ~1 ~) ~1 C ~1 ~t ~In 1 ~ ~0 1 1 1 1 1 1 1 o 1 o 1 1 1 1 1 1 ~1 1 1 1 ~u ~r- 01 O CO O 0 ~1 0 ~1 0 0 0 0 0\ 0 ~1 0 0 0 0 1 c ~_t C~ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~1 1 1 O O O O ~0 ~0 0 0 0 0 0 ~O 0 0 0 ~U. O O O O O O C~ ~ ~ O Lt. 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a' r~ m N . - U) e U] C 0 JJ - :' c ·~4 c o u u 0 ·~4 ~.o~ CO 4J u U Y .. - ~ ~P. C) 0 ~ C ~ .~ .. - C 0 _ ;o 0 _ U 0 C d~ c :, E" O~ ~ 0 0 . - ~n c- ~ 0 ·. - .-, p4 oo C o^ 0 . - C - ~ 0 -. x: ·e 1 ,, O ·= >, ;>, >, ~ >, I ~ C D U ~4J ~· - ~C #4 .- ·~4 ·.~ ~ ·.- I X ~C) V ~^~- ~ ~I 1 0 ~·~1 ·r4 ~'3 J~ X ·r. 1 C J~ 1 4 ~X X X' ~O · - O X a:, O C O O O ~O ~ ~ O ~·- ~,C O ~L~ ~ C Ll I ·~- ~·- U ' . - ~1 ~1 ~ 1 X ~ 4 r~ O ~C I ~ ~O ~ ' - O 'Ld ~ ·r~ ~ ~ ~ J' O O C to ·~- ~J~ 4 ~· - ·rr4~ C N~ ~ ~ u ~ r ~ L1 t~ 0 u c) ·'- ~ ~ I ~~ ~ c ~ ~ ·~-~ ~ ~ 0 · - 0 0 0 I JJ · - ~ ·~- U ~ ·~ 0 ~ ~ t ~ · - ~ ~ X ~ ~ I ~ ~ ~ X ·r4~ ~. - . - ~ .,- ·- ~ C) ~ :> 0 u u c ~ ~ ~ 0 c ~ ~ u ~e .> 0 0 ~ 0 0 ·- RJ J ~·- ·- ·r~ ~ ~ ~ C ~ ~-- ·- ~ ·r ~ ·~- 4 ~ ~ e 'C ~ C ~ ~C ~ C ~ O ~ C ~ ·~- ~ ~ C V ~ ~ Ul ~ C) c 0 0 ~ ~ ~ oY u 0 ~ ~o c ~ 0 ~ 0 e C 4 Q ·~- ~ ~ ~ ~ O D ~ ~ O ~C 4 ~ S · - S I O JJ aC O S C ~ D rl Q4 o C · - ~ ~ S ~ ~ ~ ~ ~ ~ ~ c ~ ~ ~ ~u 0 u 0 ~ ~ ~ ~ ~ 0 ~ ~ ~ 0 ~ 0 ~ 0 ~ co a 0 ·,' 7 ~ ~ ~ C D ~ ~ C ~ ~, - ~ X ~ ~ ~ ~ U ~ ~ ~ D U Y ~ ~O cn u ~Z c ~u ~cn E ~x: ~ U ~ ~ u ~ ~ 0 ~ L u O ·.~ O E C CO U] ~ · - .C ~ · - ~ Ll .. Ll C I :>' I I O1 0 E 1 ~ 1 1 1 ~4J ~ ~C O ~ ~ ~ .r ~·r4 J-1 C I. - U- - '- 0 4 0 ~ IV U ~C ~I X t~ U ~ U ^ - I ~ ~S I · ~r ~(V ~C ° X · - 1 -4 ~ J ~I Q 4) I X X -~ O O JJ ' O X CO X ·~ ~ ~ ~ C O O O ~· ~dJ O ~ O U dJ ~ ~ U, :- C 0 4 ~p ~4 1 ~-~C ~ V ·~1- - · - (V ·~1 Q ·.- ~ I I .~ >' GS ~C ~X 4 U C ~ ) _I O ~ C I :>' JJ JJ ~0 · - 0 ~0 4 ·r~ ~ ~ C ~ ~ ~ O C ~ · - · - ·~- 4 0 ~ · - ~ ~ ~=-~- X N 4 4 ·r" O · - U ~ ~ ~4 U ~ ~ 1 4 1 ~O a~ o ·~ o ~ .,~ ~ .^ ·.- ~ ~ ~ I I ·~ ~ O ~ O O'-~ ~·~- C JJ ~ dJ · - ~ ~- - X X.^ . - ~ I · - Q. U C .> 4 U C O O·> ~ ~ ~ U U e E ~, - aJ ~ ~ ~ ~ ~ ~ · - ·.- ~C S- - ·-- - ·. 4 4 ·." C t0 C ~ S C r~ ~ U] C 4 0 ~·~1 C C 4~ C ~J O O U]4 JJ o .,- ~ ~J O ~ ~ ~ O O U U~ O O O ~ ·~- Y ·H O C O C ~ ~ O O C 4 0 C 4 ~ D ~ 4 C · - · -4 ~ O D 0 4 ~ ~ ~4 ·'-/ ,C C O · - 04-t- C JJa) 4 S I dJ D ~O S ~ S ~0U ~ ~ ~ ~ h C ~ U 0 4 JJ ~ U O ~ O U . - ~ ~ ·r ~ U O O ~ ~ O ~ O O ~ ~ ~ ·~ - ~ D C ~ ~4 4 4 C ~U D ~4 4 X ~ D 4 . ~ ~U ~ 13 Q' mY ~Z x: ~ os ~,3 ~o ~ ~X ~4 ~ C "a4 t~ Ul ~J O ~ ~] oC C S ._t ~ V 0 CO C~ ~ U C ~e ~ ~ _ .. 4 0 ~V 1 1 :>' 1 ~V O U C :~ ~>, .,,, ~>,, ~I 4 ~ U ·rF4 4 ~J ~V 4 ~C U · - ·'- ·'- · - J ~·'- C I O U) · ~ V ·- U U X U C :>' U ~41 1 ·~1 1 ~ ~ U) O X · ~·'- O · ~ I · - I ~C ~I 0 ~ ~ C 0 x x J ~x ' ~.~- I X a' 0 0 ~:~ ~ ~ ~ J ~O U C O C ~4 .- JJ ~4J C {0 ~J~ ~ ~C 4 er~ O ~1 JJ ·~- ·- tJ 05 C I ~I .^ X ·.- ~I :~ ~S 4 U -~_1 C '~ O . - .~1 0 ~ ~C I ~O ~ O ~ ~4 ·'- ·~1 ~ ~10 ~ ) ~t0 0 0 C ~rr ~V ~00 dJ--I r ~·- X ~ 4~ 4 1 4 ~ ~4 ~·~- O U N 4 1 U ·- U 4 ~O ~ ' ~0 ~ O O O ·. ~ I O I ~ ·^ ·r" ~ ·r" ~ O ~ · - U-- 4 ~ ~. - _/ (~ J~ -- - 1 18 J~ X ~ 4J ·r~ _~ 4~ '- X ·~-- ~ ·- 0 4 ~ U U C U ~ ~ :> ~ U O ~ ~ ~ V ~ C O ~E .> ~U m-~- S ·~ ·- ~.~ ~ ·- ~ ~(V :~ dJ ~ U~ ·~ C ~ J ~ · - 4 ·- ~C ~ ~ C C J~ C ' ~ C 4S O ~ C'1 ~ C ~ C ~ ·- ~ ~ ~ ~ ~ 4 ~ S -- ~S O C O ~ O O ~ - -- ~ U ~ ~ ~ O C ~ O U ~ O '~ O O C U ~ ~ V 4 ~ 4 ~ ~ ~ O ~ ~ ~ ~ C 4 ~ O C'- ~ 4 ~ ~ ~ 4 S ~ S C S I O ~ D . - ~ C ~ · - S ~ U ·~ - ~ ~ 4 ~ ~ ~ ~ ~ U S O U O V ~ 4 ~ ~ V ~ O ~ C ~ U 0 ~ U ~ ~ O ~ O ~ O ~ ~ V :' ~ 4 D C Q ~ :3 4 ~ _I ~ 4 ~ ' - CR Q ~ X 4 C :, U :1 U ~ ~ C ~ ~ -~ - U :D :~ ~ ~ 411 :~ S U Y ~ O ~ dJ ~ U U ~ C C S u: u: u~ Z E~ :E ~ .~ U] u~ E;~ C) '~ #t f d¢ 116

a) in L' ·~- a) On o 0 ·-' 4 o U] 0 0 U] o U] U] In 0 4 N ; 1 a: 4 a: o ·,4 ·,' to ~3 V to C 3 to c 4~ ~3 ~ o at .,' .,, x e o ~ 0 0 Z ~ c o c s · - c) ~ en · - 0 U) X ~ p ~ o ~4 o .. - .~' x Ed . .~. 1 s JJ 0 to ~ U) N U) U] 0 ~ In 0 Z 3: At: . - 1 ~ ~ Id S ~ 0 Q · - 4) 4 U] · - 4 L4 t15 N U] U] O 3 A5 ~ ~ ~ 0 _~ ~ i.d U) ·~ Q. N 0 ~ O ~ ~ 0 0 C) 3: :: ¢¢ ~q a, 0 Q )- ~ O U] >' o 4J 0 ~ r~ U, \0 ~CO ~ ;~ 1 1 1 1 1 1 1 u ~a, 1 1 1 1 1 1 1 ~o ~a) ~ 0 ·~ C~ 1 1 1 1 ~D O0 \0 ~ ·~ C~ _' m ~1 1 1 1 1 1 1 0 0 0 0 ~LO ~1 1 1 C ~O O O CO O - 1 t- ~1 1 1 0 1 1 ~1 ~ 1 CO 1 1 1 1 1 1 1 O ~O O '~ 1 ~ ~1 1 1 1 1 1 1 d. o0 ~ ~ O 1 ~1 ~1 '4 ~1 c ~1 1 1 1 1 1 o0 ~ U~ U' 1 ~- 1 ~1 ~ ~- 0 1 a' 1 1 1 1 O O O 1 1 1 1 1 1 1 O ~O O O O O U ~0 _~ ~1 11 CD ~ ~ ~ .. a, . tQ ~ 1 ~tl1 U] ~Q O ~ C ~· - ~V·- C O C4 ~ ·- ·,'05 · - ~6 ~ >1 ~ O  V ·~1 ~U] V ~ "a v C O ~V ~ ~ ~ X 6 ~C C U] ~10 ~J ~· - · - C ~ · - U] ~O ~O O C ~C ~ ~· - 0 · - · - =V ~C ,1 ·- ,~·~- ·~4 ~ ~ ~ ~ O ~ ~ C)J~ ~V ·~1 a~ C ._' ~ .,-~ ~ ~· - ~ ~ Y J~ L4 ~ ~ ~6 C U] ~ U~0 ~: ~O ~ ~ ~ ~ o48 ~ ~04 ,, ^ lV 117 Q ·_' U] tn Q c o ..~, o 4~ c ..- · - U o 6 C ·_' 6 S 0 0 0 CV Q U] S C) - oc ·.- 6 o C ·,4 ·. - V ._' X o ·,. C ·,. 6 0 .,' .e cV ·_. C o U dP o 3 o C Q. :~ ~ ~ O ·- O 3 C ·,' cr a, 0 C V h4 .,. eQ 6 C O 0 q~ a) ~ U] 6 :, U] V] 0 U] L. N S S a~ S ·,. P4 tTS Q 0 C V a' ~q o 0 ·. - U] Q o V

Category Size of Estimated Mean Percent Category in the Select Universe Pesticides and Inert Ingredients of Pesticide Formulations Cosmetic Ingredients Drugs and Excipients Used in Drug Formulations Food Additives 3,350 3,410 1 ,815 8,627 Chemicals in Commerce: 12,860 At Least 1 Million Pounds/Year Chemicals in Commerce: 13,91 1 Less than 1 Million Pounds/Year Chemicals in Commerce: 21,752 Production Unknown or I naccessible Complete Health Hazard Assessment Possible 10 24 2 26 38 _ ////1 1 ////f- I ////- 1 _ ////F ~I 10 18 1 2 14 56 11 11 12 ...22 :~:~:~:~:~: /// ·:~:~:~:~:. '/ 10 8 36 25 46 78 76 82 // Minimal Toxicity Partial Health Hazard Assessment Available Possible Some Toxicity Information Available (But below Minimal) No Toxicity Information Available FIGURE 2 Ability to conduct health-hazard assessment of substances in seven categories of select universe. 118

It is evident that, even in categories in which the greatest amount of testing has been done, there is still a great deal to do. For the chemicals in commerce, this arises in part from the facts that regulation of these substances has come about only recently and that the regulatory requirements for testing have generally been less than those for substances in the other categories. The three categories of chemicals in commerce also do not specifically reflect the substances of greatest commercial use. Exposure information may be present to a greater degree on such substances than on those selected for the sample. INTERPRETATION AND ANALYSIS OF PHYSICOCHEMICAL AND EXPOSURE DATA The committees attempted to relate the quantity and quality of toxicity testing to several factors that seem to be logical determinants of testing, such as breadth of known exposure, expected trends in exposure, physicochemical properties and chemical fate of the substances, and strength of evidence of toxicity in humans, including the severity of reported chronic human toxicity. In audition, the committees sought information on occupational and environmental exposure and attempted to relate this information to the extent and quality of toxicity testing. These efforts were limited to substances in the subsample. As the dossiers for the 100 substances in the subsample were examined, it became evident that characterization of the substances with respect to each of these factors, if it was possible at all, was based on sparse information. Most available information was on the physicochemical properties of the substances; the least was on exposure. However, no comprehensive method of gathering the needed information could be identified, and, in the end, the principal basis for characterizing exposure information was the knowledge and expertise of the committee members. For example, a judgment about widespread exposure was made on the basis of available information--such as the number of persons exposed in occupational or environmental settings, production volumes, environmental stability, or number of drug prescriptions sold--or on the individual experience and personal knowledge of committee members. It is possible that exposure information is more complete on substances of greatest commercial importance than on other substances. Information on physicochemical properties and potential exposure was tabulated and tallied as present or absent, but its quality and quantity were not assessed. Therefore, conclusions drawn from these data should be interpreted conservatively. A multiple-choice summary checklist (see Appendix L) for each substance in the subsample of 100 was completed by the Committee on Toxicity Data Elements after review of all information in the dossier. These data were then examined for correlations among amount and quality of testing, potential for exposure, knowledge of physicochemical properties, and concern for potentially adverse human health effects. 120

to o an A u In u] o o · - o H V "rl .,' C) al Pa U) o a. Ed U] ~1 U] W to ~ O dP A a. A V I,' O eQ 8 In Q U] O O . - ~ A ,1 EN - - U] In a' V ~ O ·rl O C) O V U] CQ a, ~ ., A A {Q.- ' DO H ·~1 ~ ~ JJ ~ ~ O ~Q ~ O ~-,1 0'~ ~n bq "1 H .~1 0 ~ ~ ~-- =- - ~ "1 .,1 =~1 ·,. = ~n eQ ~ ~ O ~ O P' O C) ~ ~ o Q. E~ O O O O O O O O _' _I ~t- 1 1 1 1 1 1 O ~O O O O d' O O O O O O O O O O O _I o 1 1 1 1 1 1 1- ~l- t- ~ \9 ~kD O ~.- Q O ~ 0 ~ O . - ~ - o ~a~ · - ~u ~ ~ c- - · - ~ ~ · - ~ =- - ~o ~ ~ o ~ ~ ~ o H P' U] ~ U .~: 122

Of all the types of chemical information sought, data on the overall availability of analytic methods were least available (0-27~. Analytic methods were considered to be available if there was any information on the pure substance only in nonbiologic systems, on chemical reactions in biologic systems, or on evaluation in environmental media (air, water, and food) or direct human substrates (urine, blood, other body fluids, and tissues). Data elements concerning use, production processes and volumes, chemical bioavailability, and exposure related to the workplace, the general environment, and intended use are necessary to assess the relation between exposure potential and overall health hazard. Data on intended-use exposure or, where appropriate, indications of uses other than those intended (e.g., drug abuse) were more readily available for pesticides and inert ingredients of pesticide formulations (67~), drugs and excipients in drug formulations (100~), cosmetic ingredients (67%), and food additives (608) than for chemicals in commerce (0-30~. Data elements involving bioavailability were available for 73% of pesticides and inert ingredient of pesticide formulations and for 20% of the low-volume chemicals in comme rce . Information on bioavailability was considered available if there was any information on environmental stability and turnover rates; biodegradation; excretion and elimination; occurrence in air, water, tissues, or food chains; or bioaccumulation. Data related to occupational and environmental exposure potentials frequently were absent, ranging from 45% to 100% absent in the seven categories. The availability of data concerning occupational or intended-use exposure had little or no relation to whether the literature contained information on bioavailability or environmental exposure. Pertinent data concerning the determination of exposure were scanty, even though exposure assessment is inherent in any approach to health-hazard assessment. Although the committees' standards for judging the presence of various types of physicochemical charateristics were liberal, the proportions of substances without such data are high. The hazards associated with human exposure to chemicals depend on the nature, frequency, and intensity of exposure, as well as on the toxicity of the chemicals. The major activity of the committees, however, was devoted to an analysis of the quality and quantity of the toxicity data base, and the bulk of this report describes the analytic process and the results of the analysis. Although the committees acknowledge the importance of both exposure and toxicity data in hazard evaluation, they recognized that it would not be possible to use an approach that assembles an exposure data base amenable to the kinds of systematic analysis applied to the toxicity data base. The following are among the many factors that limit the application of such an approach: · There are few legal reporting requirements for human exposure to chemicals. Even data on production volumes of substances and numbers of people involved in manufacture, distribution, use, and waste disposal are limited. 123

· There is little incentive for voluntary reporting of either production or exposure data in the open literature or in accessible agency files, and the few data available are often reported in forms that limit their comparability. · Environmental-concentration data collected for compliance monitoring--such as coal-mine dust content, ambient-air concentrations of criteria pollutants, and concentrations of pesticide residues in foods--are for specific substances that were not in the random sample selected for this study. Furthermore, data collected for compliance monitoring may be of limited value in evaluating population exposures. ~ Little is known about physical processes and procedures that affect the exposure potential for uses other than those intended. For example, the intensity of occupational exposure is strongly influenced by the choice of process and control equipment, and the intensity of environmental exposure is strongly influenced by the selection of waste-disposal technique, chemical reactivity, and degree of biodegradability. In view of the great importance of exposure data and indexes of hazard assessment and the nearly complete absence of such data, the committees recommend that planning begin for the development of much more 'I than now exist for exposure The committees recognize that this will require a substantial effort and allocation of resources. It will also depend on further interagency collaboration and communication. extensive, detailed, and accurate data bases assessments. 124

Next: 6. SUMMARY AND CONCLUSIONS »
Toxicity Testing: Strategies to Determine Needs and Priorities Get This Book
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Prepared at the request of the National Toxicology Program, this landmark report reveals that many chemicals used in pesticides, cosmetics, drugs, food, and commerce have not been sufficiently tested to allow a complete determination of their potential hazards. Given the vast number of chemical substances to which humans are exposed, the authors use a model to show how research priorities for toxicity testing can be set.

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