# Presentation: 371863

## NICEATM			ICCVAM
National Toxicology Program  Interagency 	Interagency Coordinating Committee Center for the Evaluation Of Alternative 	on the Validation of Alternative 	 Toxicological Methods 			Methods

**NICEATM****	****	****	****ICCVAM**
**National Toxicology Program  Interagency ****	****Interagency Coordinating Committee Center for the Evaluation Of Alternative ****	****on the Validation of Alternative ****	**** Toxicological Methods ****	****	****	****Methods**
**	****	****	****	**

**Proposed Reference Substances: **
**BRD Summary**

**Expert Panel Meeting**
**January 11-12, 2005**
**Bethesda, Maryland**

## Reference Substances for Validation Studies

**According to the ICCVAM Submission Guidelines (ICCVAM, 2003), to the extent possible, reference substances should:**
**Be representative of the range of responses for which the proposed test method is expected to cover (i.e., nonirritants and mild, moderate, or severe eye irritants)**
**Represent the classes of chemicals for which the proposed test method is expected to be used.**
**Have produced high quality results (i.e., produced in a GLP compliant study) in the reference test method and/or the species of interest**
**Have well-defined chemical composition**
**Be readily available**
**Not be associated with excessive hazard or prohibitive disposal costs**

## Proposed Reference Substances (I)

**Coverage of the  Range of Anticipated Responses:**

| Classification (GHS) | Total Database | Commercially Available | Recommended for Validation |
| --- | --- | --- | --- |
| Category 1  | 123 | 48 | 48 |
| Category 2A | 24 | 11 | 11 |
| Category 2B | 68 | 27 | 15 |
| Nonirritant | 277 | 111 | 15 |
| Total | 492 | 197 | 89 |

## Proposed Reference Substances (II)

**Coverage of the range of anticipated responses within Category 1 substances (commercially available):**
**CO = Corneal Opacity; IR = Iritis**

| Subcategory | Criteria | Number |
| --- | --- | --- |
| 4 | CO = 4 at any time (1/3 animals) | 24 |
| 3 | Positive response based on mean for first 3 days (2/3 animals with CO>3 or IR>1.5) and a persistent (>21 days) lesion  | 2 |
| 2 | Positive response based on mean for first 3 days (2/3 animals), not persistent | 4 |
| 1 | Positive response based on a persistent lesion and not severity (1/3 animals) | 18 |
|  | Total | 48 |

## Proposed Reference Substances (III)

***In vivo***** data source**

| GHS Category | CTFA | ECETOC | EPA-TSCA | FDA | NIHS | Total |
| --- | --- | --- | --- | --- | --- | --- |
| Category 1 | 7 | 26 | 5 | 2 | 8 | 48 |
| Category 2A | 0 | 10 | 1 | 0 | 0 | 11 |
| Category 2B | 1 | 13 | 1 | 0 | 0 | 15 |
| Nonirritant | 2 | 12 | 0 | 1 | 0 | 15 |
| Total | 10 | 61 | 7 | 3 | 8 | 89 |

**CTFA: Cosmetic, Toiletry, and Fragrance Association **
**ECETOC: European Centre for Ecotoxicology and Toxicology of Chemicals **
**EPA-TSCA: U.S. Environmental Protection Agency – Toxic Substances Control Act **
**FDA: U.S. Food and Drug Administration**
**NIHS: National Institute of Health Sciences - Japan**

## Chemical Classes Represented Among the Reference List

**	*****Other Classes Include (n = 1): Acyl halide, Aldehyde, Alkali, Amine, Isocyanate, Methacrylate, Oil/Water formulation, Organophosphate, Polychlorinated**** **

| Class | Total | Cat 1 | Cat 2A | Cat 2B | NI |
| --- | --- | --- | --- | --- | --- |
| Surfactant | 13 | 8 | 2 | 1 | 2 |
| Alcohol | 13 | 3 | 3 | 6 | 1 |
| Surfactant Formulation | 9 | 7 | 0 | 1 | 1 |
| Acid | 7 | 7 | 0 | 0 | 0 |
| Miscellaneous | 5 | 4 | 0 | 0 | 1 |
| Sulfur-Containing | 4 | 2 | 0 | 1 | 1 |
| Inorganic | 4 | 2 | 0 | 1 | 1 |
| Heterocycle | 4 | 3 | 0 | 0 | 1 |
| Organic Salt | 4 | 3 | 0 | 1 | 0 |
| Alcoholic Formulation | 3 | 2 | 0 | 0 | 1 |
| Hydrocarbon | 3 | 0 | 0 | 1 | 2 |
| Ketone | 3 | 0 | 1 | 1 | 1 |
| Acetate | 2 | 0 | 1 | 1 | 0 |
| Acrylate | 2 | 1 | 0 | 0 | 1 |
| Nitrile | 2 | 1 | 0 | 1 | 0 |
| Silane/Siloxane | 2 | 2 | 0 | 0 | 0 |
| Other* | 9 | 3 | 4 | 0 | 2 |
| Total | 89 | 48 | 11 | 15 | 15 |

## Chemical Classes Represented Among Category 1 Subcategories

**	**
**	*****Other Classes Include (n = 1): Acrylate, Alkali, Amine, Isocyanate, Nitrile**** **

| Class/Cat 1 Subcategory | Total | 4 | 3 | 2 | 1 |
| --- | --- | --- | --- | --- | --- |
| Surfactant | 8 | 3 | 0 | 2 | 3 |
|      Anionic Surfactant | 1 | 0 | 0 | 0 | 1 |
|      Cationic Surfactant | 6 | 3 | 0 | 2 | 1 |
|      Nonionic Surfactant | 1 | 0 | 0 | 0 | 1 |
| Acid | 7 | 4 | 0 | 1 | 2 |
| Surfactant Formulation | 7 | 0 | 0 | 0 | 7 |
| Miscellaneous | 4 | 2 | 2 | 0 | 0 |
| Alcohol | 3 | 1 | 0 | 1 | 1 |
| Heterocycle | 3 | 3 | 0 | 0 | 0 |
| Organic Salt | 3 | 3 | 0 | 0 | 0 |
| Alcoholic Formulation | 2 | 0 | 0 | 0 | 2 |
| Inorganic | 2 | 1 | 0 | 0 | 1 |
| Silane/Siloxane | 2 | 1 | 0 | 0 | 1 |
| Sulfur-Containing | 2 | 1 | 0 | 0 | 1 |
| Other* | 5 | 5 | 0 | 0 | 0 |
| Total | 48 | 24 | 2 | 4 | 18 |

## Product Classes Represented Among the Reference List

**	*****Other Classes Include (n = 1): Acyl halide, Aldehyde, Alkali, Amine, Isocyanate, Methacrylate, Oil/Water formulation, Organophosphate, Polychlorinated**** **

| Class | Total | Cat 1 | Cat 2A | Cat 2B | NI |
| --- | --- | --- | --- | --- | --- |
| Solvent | 12 | 1 | 3 | 7 | 1 |
| Industrial Chemical | 10 | 6 | 2 | 1 | 1 |
| Unclassified | 10 | 5 | 0 | 1 | 4 |
| Disinfectant/Germicide | 8 | 7 | 1 | 0 | 0 |
| Soaps/Surfactants | 7 | 6 | 0 | 0 | 1 |
| Cosmetic | 6 | 4 | 1 | 0 | 1 |
| Chemical Intermediate | 5 | 2 | 1 | 1 | 1 |
| Herbicide/Pesticide | 5 | 3 | 1 | 1 | 0 |
| Shampoos | 5 | 4 | 0 | 1 | 0 |
| Detergent | 4 | 0 | 1 | 1 | 2 |
| Pesticide/Pharmaceutical Intermediate | 4 | 1 | 0 | 2 | 1 |
| Anti-fungal/Anti-infective | 3 | 2 | 1 | 0 | 0 |
| Pharmaceutical | 3 | 2 | 0 | 0 | 1 |
| Cleaner | 2 | 2 | 0 | 0 | 0 |
| Lotions/Sunscreens | 2 | 1 | 0 | 0 | 1 |
| Other* | 3 | 2 | 0 | 0 | 1 |
| Total | 89 | 48 | 11 | 15 | 15 |

## Product Classes Represented Among Category 1 Substances

**	*****Other Classes Include (n = 1): Acrylate, Alkali, Amine, Isocyanate, Nitrile**** **

| Class/Cat 1 Subcategory | Total | 4 | 3 | 2 | 1 |
| --- | --- | --- | --- | --- | --- |
| Disinfectant/Germicide | 7 | 4 | 0 | 2 | 1 |
| Industrial Chemical | 6 | 4 | 0 | 0 | 2 |
| Soaps/Surfactants | 6 | 0 | 0 | 0 | 6 |
| Unclassified | 5 | 5 | 0 | 0 | 0 |
| Cosmetic | 4 | 3 | 0 | 0 | 1 |
| Shampoos | 4 | 0 | 0 | 0 | 4 |
| Herbicide/Pesticide | 3 | 3 | 0 | 0 | 0 |
| Anti-fungal/Anti-infective | 2 | 1 | 1 | 0 | 0 |
| Chemical Intermediate | 2 | 0 | 0 | 1 | 1 |
| Cleaner | 2 | 1 | 0 | 0 | 1 |
| Pharmaceutical | 2 | 0 | 1 | 0 | 1 |
| Other* | 5 | 3 | 0 | 1 | 1 |
| Total | 48 | 24 | 2 | 4 | 18 |