HPV Challenge Program Overview

Introduction

On October 14, 1999, EPA Deputy Assistant Administrator Susan H. Wayland provided a test plan development framework for manufacturers and importers participating in the HPV Challenge Program (http://www.epa.gov/oppt/chemrtk/pubs/general/ceoltr2.htm). This framework outlined 10 animal welfare principles that sponsors were asked to observe in all Test Plans submitted under the HPV Challenge Program; although sponsors may determine the need to deviate from the principles based on testing needs not associated with the HPV Challenge Program, but a rationale should be provided. In essence, the principles address the development of a well-considered plan for testing HPV chemicals that accounts for all available scientifically sound information, and uses categories of chemicals and Structure Activity Relationships (SAR) where appropriate. By developing the plans in this way, unnecessary animal testing will be eliminated while the need for the development of scientifically defensible health and environmental effects information on high production volume chemicals will be fulfilled.

Methodology

This report consists of individual tables for the first 40 Test Plans for HPV Challenge Program chemicals/categories. Their order of presentation in this report is the same as the order of appearance on the EPA HPV Challenge Program website (http://www.epa.gov/oppt/chemrtk/pubs/summaries/viewsrch.htm). The individual tables are structured in the following way. The first column presents a short summary of the principles under review (Table 1 contains the complete text of the principles from the October 14, 1999 letter and the summary text used in the individual tables). The middle column contains an assessment of the Test Plan for each principle, and the right column contains an evaluation of compliance. A table is presented at the end which provides a summary of the individual reviews. It should be noted that this assessment was limited to the October 14, 1999 letter. EPA is providing comments on these issues as well as on the technical/scientific aspects of the Test Plans directly to the sponsors.

The assessment column contains explanatory information about each Test Plan and should be used in conjunction with the compliance information. For example, the second principle requires submitters to analyze available, scientifically valid data so that further testing will be minimized. Although a Test Plan may appear to have adequately reported available data, commentors may identify additional studies not presented in the Test Plan. In this case, the individual table would indicate that the Test Plan appeared to present all available studies, but commentors have noted otherwise. The four levels of compliance used are: (1) compliance, (2) noncompliance, (3) equivocal or unclear compliance, and (4) not applicable. "Equivocal or unclear" compliance is used, for example, when a submitter notes that some of the chemicals under consideration are GRAS, but does not use this information in any of the justification for testing. "Not applicable" compliance is used, for example, where compliance with principle 3 ("[w]ere categories of related chemicals and structure activity relationships used to minimize further testing?") is evaluated for a single chemical. It should be noted that for some of the principles, compliance is achieved with either a "Yes" or "No" answer. For example, if a chemical under consideration is GRAS, then compliance with principle 8 is "Yes," while compliance is achieved with a "No" answer for non-GRAS chemicals.

As noted above, the October 14, 1999 letter contained 10 principles. For this review, however, principle 1, which requires the submission of a "thoughtful" Test Plan, was reviewed for categories only. Assessing "thoughtfulness" for single chemical submissions, many of which provide only tabular Test Plans, was difficult (the amount of thought that was devoted to a tabular Test Plan could not be determined). Principle 1 for single chemicals, therefore, is assigned an "unclear or equivocal" designation in the tables as a place holder. Finally, this report considers those HPV Challenge Program submissions posted on EPA's Challenge program website as of March 22, 2001 (40 Test Plans). It therefore represents only a "snapshot" in time.

Conclusion

The overall conclusion of the assessment, as depicted in the Summary Table, is that HPV Challenge Program sponsors are following the guidance in the October 14, 1999 letter to a significant degree.

Table 1. Summary Text Used in the Individual Tables

Text from the 14 October 1999 Letter	Summary Text
1. In analyzing the adequacy of existing data, participants shall conduct a thoughtful, qualitative analysis rather than use a rote checklist approach. Participants may conclude that there is sufficient data, given the totality of what is known about a chemical, including human experience, that certain endpoints need not be tested.	Was the analysis thoughtful and qualitative?
2. Participants shall maximize the use of existing and scientifically adequate data to minimize further testing. To reinforce this approach, EPA will consider information contained in the databases identified in the enclosure, or in databases maintained by the organizations identified in the enclosure, to have been known to the Agency within the meaning of Section 8(e) of the Toxic Substances Control Act (TSCA), 42 U.S.C. 2607(e). This policy is limited to information reported by participants under the HPV Challenge program and generated for or contained in these databases as of the date of this letter. In addition, any other potential liability under TSCA Section 8(e) for existing data on HPV Challenge program chemicals will be limited according to the terms of the "Registration Agreement for TSCA Section 8(e) Compliance Audit Program (56 Fed. Reg. 4128, Feb. 1, 1991)." This policy does not affect prior 8(e) enforcement actions.	Were available data used to minimize further testing?
3. Participants shall maximize the use of scientifically appropriate categories of related chemicals and structure activity relationships.	Were categories of related chemicals and structure activity relationships used to minimize further testing?
4. Consistent with the Screening Information Data Set (SIDS) program of the Organization for Economic Cooperation and Development (OECD), participants shall not conduct any terrestrial toxicity testing.	Was any terrestrial toxicity testing proposed (e.g., OECD Testing guidelines 206, 207, 208, 213, and 214)?
5. Participants are encouraged to use in vitro genetic toxicity testing to generate any needed genetic toxicity screening data, unless known chemical properties preclude its use.	Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?
6. Consistent with the OECD/SIDS program, participants generally should not develop any new dermal toxicity data.	Was any dermal toxicity testing proposed?
7. Participants shall not develop sub-chronic or reproductive toxicity data for the HPV chemicals that are solely closed system intermediates, as defined by the OECD/SIDS guidelines.	For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?
8. In analyzing the adequacy of screening data for chemicals that are substances Generally Recognized as Safe (GRAS) for a particular use by the Food and Drug Administration (FDA), participants should consider all relevant and available information supporting the FDA's conclusions. Participants reviewing the adequacy of existing data for these chemicals should specifically consider whether the information available makes it unnecessary to proceed with further testing involving animals. As with all chemicals, before generating new information, participants should further consider whether any additional information obtained would be useful or relevant.	Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA's conclusions) used to obviate the need for SIDS-level testing?
9. Because validated non-animal tests for some SIDS endpoints may be available soon, participants shall make the following revisions to the sequence of testing: (a) Testing of closed system intermediates, which present less risk of exposure, shall be deferred until 2003; (b) Individual chemicals (i.e., those HPV chemicals not proposed for testing in a category) that require further testing on animals shall be deferred until November 2001. These revisions should not be construed to suggest that delay or deferral is appropriate with respect to testing of scientifically appropriate categories of related chemicals.	Was testing delayed for closed-system intermediates and single chemicals?
10. Companies shall allow 120 days between the posting of test plans and the implementation of any testing plans.	Was a 120 day waiting period implemented?

Dicarboxylic Acids Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Dicarboxylic Acids is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	Yes. However, it is unclear if information supporting FDA’s conclusions were incorporated into the Test Plan. The GRAS status of this chemical was not directly used in the justification for limiting the testing needs of the category, even though no health effects testing was proposed.
9. Was testing delayed for closed-system intermediates and single chemicals?	Not Applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan, but the submitters indicated that they would wait until the comment period was over and had received any submitted remarks before beginning any action.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Dinitrile Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, dinitriles is a category. The use of structure activity relationships were referenced, however, no specific information was presented.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	Yes, dermal and eye irritation studies are planned.
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

1,1-Difluoroethane

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable; 1,1-difluoroethane is a single chemical.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Yes
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Glycolic Acid

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable; glycolic acid is a single chemical.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Yes
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Acetoacet-o-Anisidide

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable; acetoacet-o-anisidide is a single chemical	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No new testing is proposed. The submitted suggests that acetoacet-o-anisidide is a closed-system intermidiate; however, little supporting information is presented.
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

†Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Methanol

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable; methanol is a single chemical.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	Not Applicable	NA
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Tall Oil and Related Substances Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, tall oil and related substances is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Dipropylene Glycol Dibenzoate

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable, dipropylene glycol dibenzoateis a single chemical.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

p-Methylstyrene

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable, p-methylstyrene is a single chemical	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No health effects testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Cyclohexyl isocyanate

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable, cyclohexylisocyanate is a single chemical	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No information was presented in the submission.	†
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

C6-C10 Aliphatic Aldehydes and Carboxylic Acids Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, C6-C10 Aliphatic Aldehydes and Carboxylic Acids is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	Yes
9. Was testing delayed for closed-system intermediates and single chemicals?	Not Applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Tall Oil Fatty Acids and Related Substances Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Tall Oil Fatty Acids and Related Substances is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not Applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Alkylphenols Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, alkylphenols is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not Applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

†Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Ethanol

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable, ethanol is a single chemical	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Cyclic Anhydrides

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, cyclic anhydrides is a category
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

FYROL FR-2 [Tris(1,3-dichloro-2-propyl) phosphate]

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not Applicable, FYROL FR-2 is a single chemical	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No health effects testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Terpenoid Primary Alcohols and Related Esters Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, although the discussion is not always presented in a straightforward manner.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Terpenoid Primary Alcohols and Related Esters is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	Yes, 3 of the 4 members of the proposed category are considered GRAS by FDA. Nonetheless, the GRAS status of these chemicals was not directly used in the justification for limiting the testing needs of the category, even though no health effects testing was proposed. It is unclear if information supporting FDA’s conclusions were incorporated into the Test Plan.	†
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Spent Pulping Liquor and Cooking Liquors Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, based on a preliminary review.
2. Were available data used to minimize further testing?	Yes, according to the submission, however, very little data are available; available data appear to have been used appropriately.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable, categories are not appropriate for this substance.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Terpenoid Tertiary Alcohols and Related Esters Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes. The Test Plan, however, was difficult to follow and failed to support some of the conclusions made.
2. Were available data used to minimize further testing?	Yes, although the discussion is not always presented in a straightforward manner.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Terpenoid Tertiary Alcohols and Related Esters is a category; however, the category justification was difficult to follow.
4. Was any terrestrial toxicity testing proposed?	No
5.Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	Yes, 10 of 13 chemicals in the proposed category are considered GRAS by FDA. Nonetheless, the GRAS status of these chemicals was not directly used in the justification for limiting the testing needs of the category, even though no health effects testing was proposed. It is unclear if information supporting FDA’s conclusions were incorporated into the Test Plan.	†
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

2,3 Dihydro-2,2-dimethyl-7-benzofuranol

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	Yes (chromosomal aberrations), no rationale was provided in the Test Plan.
6. Was any dermal toxicity testing proposed?	Yes (acute dermal), no rationale was provided in the Test Plan.
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No information was presented in the submission.	†
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Methallyl Chloride

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No information was presented in the submission.	†
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Alkyl Acetate C6-C13 Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, although the Test Plan includes the C11-C14 branched alkyl acetate esters in the category; these esters do not appear to have the same pattern of toxicity as the other members of the group
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Alkyl Acetate C6 - C13 is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Cinnamyl Derivatives Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, although some additional explanation of the justification for the ecotoxicity testing was needed.
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Cinnamyl Derivatives is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	Yes, 3 of 4 chemicals in the proposed category are listed as GRAS chemicals by FDA. The GRAS designation was only mentioned in Section 2.2 "Background Information" of the Test Plan and does not appear to be part of the reasoning used to eliminate health effects tests. It is unclear if information supporting FDA’s conclusions were incorporated into the Test Plan.	†
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

1,3,5-Trioxane

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this chemical.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

1,3-Dioxolane

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this chemical.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

C5 Noncyclics Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, although there were errors in the Test Plan.
2. Were available data used to minimize further testing?	Yes; however, commentors suggest that the test plan does not fully use existing data, particularly in the area of toxicokinetics.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, C5 Non-cyclics is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	Yes, a mouse chromosomal aberration test has been proposed in the Test Plan. The inhalation route of exposure was chosen because inhalation is the most relevant exposure route for the C5 Non-Cyclics streams. The mouse micronucleus test was chosen for chromosomal effects testing because isoprene is negative in in vitro tests of genotoxicity but positive in the mouse micronucleus test. 2-Methyl-2-butene is also positive in the mouse micronucleus test. These data indicate that in vivo tests would be more likely to identify genotoxic effects from this group of chemicals.
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No (all test streams are commercial products or isolated intermediates)
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Dimethyl Ether

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this chemical.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Petroleum Gas Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, but the Test Plan did not adequately support the proposed category.
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that the American Petroleum Institute failed to review the current toxicologic literature for available test information. No specific additional toxicologic studies were cited in the comment that support this conclusion.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes; however, according to comments, additional data exist for related chemicals. It is unclear if these are scientifically appropriate.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	Yes. A limited rationale (i.e., the inability of the existing in vitro tests to detect genetic activity and the lack of any in vivo data) was used to support the proposed in vivo testing in the mouse micronucleus test (OECD 474).	†
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No. While most of the "petroleum gases are intermediate process streams that do not leave the refinery", the components proposed for testing are present in finished commercial products.
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

AMPS® Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, data are available for at least one member of the category for every end point.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, AMPS® is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this category.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Silane, [3-(2,3-epoxypropoxy)propyl]trimethoxy

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, physical and chemical properties that precluded certain testing were discussed.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	No, although structure activity relationships were considered in the Silicones Environmental, Health and Safety Council response to EPA comments.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Solubility in water was the only study proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Tris(2,4-di-(tert)-butylphenyl)phosphite

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal.	†
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that this chemical is listed as an FDA food contact substance and suggests that this indicates that a toxicologic profile exists. No indication of what specific data may be available from FDA was provided.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Stability in water was the only study proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Octadecyl 3,5-di(tert)-butyl-4-hydroxyhydrocinnamate

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that this chemical is listed as an FDA food contact substance and suggests that this indicates that a toxicologic profile exists. No indication of what specific data may be available from FDA was provided. Additional studies on mutagenicty and induction of microsomal enzymes were cited.	†
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this chemical.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Tetrakis-(methylene-(3,5-ditertbutyl-4-hydrocinnamate)methane

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that this chemical is listed as an FDA food contact substance and suggests that this indicates that a toxicologic profile exists. No indication of what specific data may be available from FDA was provided. Additional studies on acute toxicity and genotoxicity were cited (unpublished government reports) along with a study on the "inhibition of metabolic cooperation" from the open literature.	†
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No testing was proposed for this chemical.	NA
10. Was a 120 day waiting period implemented?	No testing was proposed for this chemical.	NA

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Tris (Nonylphenol) Phosphite

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that this chemical is listed as an FDA food contact substance and suggests that this indicates that a toxicologic profile exists. No indication of what specific data may be available from FDA was provided.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	No; according to commentors, however, some SAR comparison opportunities exist, although no carefully constructed scientific assessment was included in the comments.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	In vivo genetic toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
6. Was any dermal toxicity testing proposed?	Dermal toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

p-Cumylphenol

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes, a commentor, however, states that this chemical is listed as an FDA food contact substance and suggests that this indicates that a toxicologic profile exists. No indication of what specific data may be available from FDA was provided.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Not applicable. Test data were presented for this chemical only by the sponsor; no SAR comparisons were necessary.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	In vivo genetic toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
6. Was any dermal toxicity testing proposed?	Dermal toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Phosphorous Acid, Cyclic NeoPentanetetrayl Diphenyl Ester

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Unclear or equivocal	†
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	No, according to commentors, however, some SAR comparison opportunities exist, although no carefully constructed scientific assessment was included in the comments.	NA
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	In vivo genetic toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
6. Was any dermal toxicity testing proposed?	Dermal toxicity testing was proposed in the Test Plan, but no rationale supporting the testing was provided.
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	No
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Alkyl Sulfide Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, although some supporting data were missing from the Test Plan.
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, although EPA comments suggest that the justification for the category based on health effects is weak.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	Yes

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

High Butadiene C4 Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes, although there were some inconsistencies in the Test Plan.
2. Were available data used to minimize further testing?	Yes
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, High Butadiene C4 is a category.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	Yes, a mouse chromosomal aberration test (apparently to be administered by inhalation) has been proposed in the Test Plan. The mouse micronucleus test (OECD 474) was chosen for chromosomal effects testing because there are no in vivo genetic toxicity data available for the low (~10%) 1,3 butadiene stream. These data indicate that in vivo tests would be more likely to identify genotoxic effects from this group of chemicals.
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	Unclear. The low butadiene stream was chosen for a combined repeat dose/reproductive effects/neurotoxicity screen. It is unclear from the Test Plan if this stream is a closed-system intermediate. Nonetheless, this test is proposed in order to support the sponsors’ premise that butadiene is the dominant toxicant in this category.	†
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Aminosilanes Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, a commentor, however, states that there are existing data on hydrolysis products of related chemicals, but specific data were not provided.
4. Was any terrestrial toxicity testing proposed?	No
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Petroleum Coke Category

Question	Assessment	Compliance
1. Was the analysis thoughtful and qualitative?	Yes
2. Were available data used to minimize further testing?	Yes, based on a preliminary review.
3. Were categories of related chemicals and structure activity relationships used to minimize further testing?	Yes, Petroleum Coke is a category.
4. Was any terrestrial toxicity testing proposed?	Yes, earthworms and plants will be tested to better understand the impact of petroleum coke in soil. This is consistent with OECD guidance.
5. Was in vivo genetic toxicity testing proposed to generate genetic toxicity screening data?	No
6. Was any dermal toxicity testing proposed?	No
7. For chemicals that are solely closed-system intermediates, was subchronic or reproductive toxicity testing proposed?	No
8. Are any GRAS chemicals proposed for testing? If so, was this information (or other available information supporting the FDA’s conclusions) used to obviate the need for SIDS-level testing?	No
9. Was testing delayed for closed-system intermediates and single chemicals?	Not applicable	NA
10. Was a 120 day waiting period implemented?	No information on this element was presented in the cover letter or test plan.	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

Summary

Test Submission Name	Principles Discussed in October 14, 1999 Letter from Deputy Assistant Administrator Susan H. Wayland to Manufacturers/Importers
Test Submission Name	1	2	3	4	5	6	7	8	9	10
Dicarboxylic Acids Category									NA	†
Dinitrile Category									NA	†
1,1-Difluoroethane			NA
Glycolic Acid			NA
Acetoacet-o-anisidide			NA						NA	†
Methanol			NA				NA		NA	†
Tall Oil and Related Substances Category									NA	†
Dipropylene Glycol Dibenzoate	†		NA						NA	†
p-Methylstyrene	†		NA						NA	†
Cyclohexyl Isocyanate	†		NA						†
C6-C10 Aliphatic Aldehydes & Carboxylic Acids Category									NA	†
Tall Oil Fatty Acids and Related Substances Category									NA	†
Alkylphenols Category									NA	†
Ethanol	†		NA						NA	†
Cyclic Anhydrides									NA	†
Fyrol FR-2	†		NA						NA	†
Terpenoid Primary Alcohols and Related Esters Category								†	NA	†
Spent Pulping Liquor and Cooking Liquors Category			NA						NA	†
Terpenoid Tertiary Alcohols and Related Esters Category								†	NA	†
2,3-Dihydro-2,2-dimethyl-7-benzofuranol	†		NA						†	†
Methallyl Chloride	†		NA						†	†
Alkyl Acetate C6 - C13 Category									NA	†
Cinnamyl Derivatives Category								†	NA	†
1,3,5-Trioxane	†		NA						NA	NA
1,3-Dioxolane	†		NA						NA	NA
C5 Noncyclics Category									NA	†
Dimethyl Ether	†		NA						NA	NA
Petroleum Gas Category					†				NA	†
AMPS® Category									NA	NA
Silane,[3-(2,3-epoxypropoxy)propyl]trimethoxy	†								NA	†
Tris(2,4-di-(tert)-butylphenyl)phosphite	†		NA						NA	†
Octadecyl 3,5-di(tert)-butyl-4-hydroxyhydrocinnamate	†	†	NA						NA	NA
Tetrakis-(methylene-(3,5-ditertbutyl-4-hydrocinnamate)methane	†	†	NA						NA	NA
Tris (Nonylphenol) Phosphite	†		NA
p-Cumylphenol	†		NA
Phosphorous Acid, Cyclic NeoPentanetetrayl Diphenyl Ester	†		NA
Alkyl Sulfide Category									NA
High Butadiene C4 Category							†		NA	†
Aminosilanes Category									NA	†
Petroleum Coke Category									NA	†

Compliant with 14 October 1999 letter to manufacturers and importers

Non-compliant with 14 October 1999 letter to manufacturers and importers

† Compliance with 14 October 1999 letter to manufacturers and importers is unclear or equivocal

NA Not applicable

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