![](media/image1.wmf){width="1.2in" height="1.2in"}

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION,

PESTICIDES AND

TOXIC SUBSTANCES

[MEMORANDUM]{.underline}

DATE: September 29, 2005

SUBJECT: **Para-tertiary amylphenol (4-t-amylphenol) and its sodium and
potassium salts** Evaluation of Toxicology Database for the
Reregistration Eligibility Decision Document Disciplinary Chapter.
Chemical Nos. 064101, 064111, 064112. Case No. 3016. DP Barcode: D316279

FROM: Myron Ottley, Ph.D., Toxicologist

And

Deborah Smegal, MPH Toxicologist

Antimicrobials Division (7510C)

TO: Killian Swift, Risk Manager Reviewer

Team 36, Reregistration

Antimicrobials Division (7510C)

**TABLE OF CONTENTS**

[**1.0 BACKGROUND 3**](#background)

[2.0 HAZARD CHARACTERIZATION 3](#hazard-characterization)

[3.0 REQUIREMENTS 4](#requirements)

[4.0 DATA GAP(S) 5](#data-gaps)

[5.0 HAZARD ASSESSMENT 5](#hazard-assessment)

[5.1 Acute Toxicity 5](#acute-toxicity)

[**5.2** **Subchronic Toxicity** 6](#__RefHeading___Toc116186548)

[**5.3** **Developmental Toxicity** 7](#__RefHeading___Toc116186549)

[**5.4** **Reproductive Toxicity** 8](#__RefHeading___Toc116186550)

[**5.5** **Chronic Toxicity** 8](#__RefHeading___Toc116186551)

[**5.6** **Carcinogenicity** 8](#__RefHeading___Toc116186552)

[**5.7** **Mutagenicity** 9](#__RefHeading___Toc116186553)

[**5.8** **Neurotoxicity** 10](#__RefHeading___Toc116186554)

[**5.9** **Metabolism** 10](#__RefHeading___Toc116186555)

[**5.10** **Special/Other Studies** 10](#__RefHeading___Toc116186556)

[6.0 TOXICITY ENDPOINT SELECTION 11](#__RefHeading___Toc116186557)

[**6.1** **ACUTE DIETARY (Acute Reference Dose)**
11](#__RefHeading___Toc116186558)

[**6.2.** **CHRONIC DIETARY (Chronic Reference Dose) General
Population** 13](#__RefHeading___Toc116186559)

[**6.3. INCIDENTAL ORAL EXPOSURE** 13](#__RefHeading___Toc116186560)

[**6.4 OCCUPATIONAL / RESIDENTIAL EXPOSURE**
14](#__RefHeading___Toc116186561)

[**6.5** **Margins of Exposure** 17](#__RefHeading___Toc116186562)

[**6.6** **Recommendation for Aggregate Exposure Risk Assessments**
18](#__RefHeading___Toc116186563)

[**6.7** **Classification of Carcinogenic Potential**
18](#__RefHeading___Toc116186564)

[7.0 FQPA CONSIDERATIONS 18](#__RefHeading___Toc116186565)

[**7.1** **Adequacy of the Data Base** 18](#__RefHeading___Toc116186566)

[**7.2** **Neurotoxicity Data** 18](#__RefHeading___Toc116186567)

[**7.3.** **Developmental & Reproductive Toxicity**
18](#__RefHeading___Toc116186568)

[**7.4** **Determination of Susceptibility**
19](#__RefHeading___Toc116186569)

[**7.5** **Determination of the Need for Developmental Neurotoxicity
Study** 19](#__RefHeading___Toc116186570)

[**7.6.** **Database Uncertainty Factor**
19](#__RefHeading___Toc116186571)

[8.0 OTHER ISSUES 19](#__RefHeading___Toc116186572)

[9.0 REFERENCES 20](#__RefHeading___Toc116186573)

[10.0 APPENDICES 21](#__RefHeading___Toc116186574)

[**10.1** **Toxicity Profile Summary Tables**
21](#__RefHeading___Toc116186575)

#   {#section .unnumbered}

# 1.0 BACKGROUND

4‑tertiary‑amylphenol (C5H11C6H4OH, PC code 64101) is a white to pale
yellow flaky substance soluble only in alcohols and ethers while its
sodium and potassium salts (C5H11C6H4Na+ and C5H11C6H4K+, PC codes 64111
and 64112, respectively) are soluble in water. 4‑tert‑amylphenol and its
salts are active ingredients in pesticides, including bacteriostats,
microbicides, microbistats, nematicides, fumigants, and bacteriocides
used in manufacturing, reformulating, and repackaging facilities. It is
also used in wood protection and adhesive coatings, human bedding and
clothing, diapers, laundry equipment, and air treatment systems.

4‑tert‑Amylphenol and its salts are applied in the following food uses,
which may result in indirect food contact: commercial egg washing,
handling, hatchery, and processing facilities; milking equipment; farm
and agricultural equipment and structures/ premises; mushroom house
equipment and houses; canneries and frozen food plants; feed mills and
stores; meat processing plants; beverage processing plants; eating
establishment surfaces, equipment, and utensils; food storage and
distribution equipment and utensils; and food dispensing equipment.

4‑tert‑Amylphenol is used in the following public and private
facilities: indoor and outdoor use on domestic dwelling and its
contents; recreation areas; transit vehicles, including ships, railway
cars, aircrafts, automobiles, and taxis; hospitals; veterinary
facilities; barbers and beauty shops; morgues, mortuaries, and funeral
equipment and premises; solid waste sites and containers; and bathroom
premises.

# **2.0 HAZARD CHARACTERIZATION**

The toxicology database for 4-t-amylphenol, in terms of guideline
studies, is largely incomplete. Studies from the open literature provide
limited information, and more data are needed to put together a complete
profile.

4-t-Amylphenol is a primary dermal irritant (Category I) and is in
Category III for acute oral toxicity based on guideline studies. It also
appears to be an eye irritant (Category I), and may be in Category III
for acute dermal toxicity according to data from the open literature.
However, acceptable guideline acute studies are not available for
dermal, inhalation, primary eye irritation or dermal sensitization, and
the literature data protocols were inadequate. In short-term studies,
4-t-amylphenol produced clinical signs along with decreased food
consumption and body weight in a developmental toxicity study, but no
systemic effects in a 13-week dermal study. The structural abnormalities
and developmental delays that occurred in the developmental study,
occurred at higher dose levels than the maternal effects, suggesting
that increased quantitative susceptibility concerns are not warranted;
however, the minimal maternal effects (reversible clinical signs) seen
in the presence of the developmental effects increases concern for
qualitative susceptibility. Neither a developmental study in rabbits nor
a reproduction study was available to provide confirmation.

Available data suggest that 4-t-amylphenol has endocrine disrupter
capabilities (uterotrophic and estrogenic effects) and increased
bilirubin production in babies. In addition, this chemical is listed on
a European list of "Chemicals purported to be endocrine disruptors".
When taken with the lack of available developmental and reproductive
toxicity data, concerns for FQPA issues are heightened.

No dermal penetration studies were available for 4-t-amylphenol, and an
extrapolation between the 91-dermal study and the oral developmental
study does not seem possible, for the purposes of estimating dermal
absorption.

4-t-Amylphenol was negative for carcinogenicity in a subchronic skin
painting study from the open literature. However, guideline studies for
carcinogenicity are not available. All mutagenicity tests were negative.

# 3.0 REQUIREMENTS 

The toxicity data requirements for indirect food uses of 4-t-amylphenol
and its salts, and additional studies requested by Agency's ADTC
committee (2005) are indicated in Table 1.

**Table 1.**

+-----------------------------------------+-------------+--------------+
| **Test**                                | **          |              |
|                                         | Technical** |              |
+=========================================+=============+==============+
|                                         | *           | *            |
|                                         | *Required** | *Satisfied** |
+-----------------------------------------+-------------+--------------+
| 870.1100 Acute Oral Toxicity            | Y           | Y            |
|                                         |             |              |
| 870.1200 Acute Dermal Toxicity          | Y           | N            |
|                                         |             |              |
| 870.1300 Acute Inhalation Toxicity      | Y           | N            |
|                                         |             |              |
| 870.2400 Primary Eye Irritation         | Y           | N            |
|                                         |             |              |
| 870.2500 Primary Dermal Irritation      | Y           | Y            |
|                                         |             |              |
| 870.2600 Dermal Sensitization           | Y           | N            |
|                                         |             |              |
| 870.6100 Acute Delayed Neurotox. (Hen)  | N           |              |
|                                         |             |              |
| 870.6200a Acute Neurotox. Screening     | N           |              |
| Battery (Rat)                           |             |              |
+-----------------------------------------+-------------+--------------+
| 870.3100 Oral Subchronic (Rodent)       | Y           | N            |
|                                         |             |              |
| 870.3150 Oral Subchronic (Non-Rodent)   | N           | N            |
|                                         |             |              |
| 870.3200 21-Day Dermal                  | N           | Y            |
|                                         |             |              |
| 870.3250 90-Day Dermal                  | Y           | N            |
|                                         |             |              |
| 870.3465 90-Day Inhalation              | Y (28 days) |              |
|                                         | (a)         |              |
+-----------------------------------------+-------------+--------------+
| 870.3700a Developmental Toxicity        | Y           | Y            |
| (rodent)                                |             |              |
|                                         | Y (b)       | N            |
| 870.3700b Developmental Toxicity(       |             |              |
| non-rodent)                             | Y ©         | N            |
|                                         |             |              |
| 870.3800 Reproduction                   |             |              |
+-----------------------------------------+-------------+--------------+
| 870.4100a Chronic Toxicity (Rodent)     | N           | N            |
|                                         |             |              |
| 870.4100b Chronic Toxicity (Non-rodent) | N           | N            |
|                                         |             |              |
| 870.4200a Oncogenicity (Rat)            | N           | N            |
|                                         |             |              |
| 870.4200b Oncogenicity (Mouse)          | N           | N            |
|                                         |             |              |
| 870.4300 Chronic/Oncogenicity           | N           | N            |
+-----------------------------------------+-------------+--------------+
| 870.5100 MutagenicityCGene Mutation -   | Y           | Y            |
| bacterial                               |             |              |
|                                         | Y           | Y            |
| 870.5300 MutagenicityCGene Mutation -   |             |              |
| mammalian                               | Y           | Y            |
|                                         |             |              |
| 870.5395 MutagenicityCMammalian         | N           | N            |
| erythrocyte micronucleus                |             |              |
|                                         |             |              |
| 870.5xxx MutagenicityCOther Genotoxic   |             |              |
| Effects                                 |             |              |
+-----------------------------------------+-------------+--------------+
| 870.6100 90-Day Neurotoxicity (hen)     | N           |              |
|                                         |             |              |
| 870.6200b 90 Day Neuro. Screening       | N           |              |
| Battery (Rat)                           |             |              |
|                                         | N           |              |
| 870.6300 Develop. Neuro                 |             |              |
+-----------------------------------------+-------------+--------------+
| 870.7485 General Metabolism             | N           |              |
|                                         |             |              |
| 870.7600 Dermal Penetration             | N           |              |
+-----------------------------------------+-------------+--------------+
| 870.7200 Companion Animal Safety        | N           |              |
+-----------------------------------------+-------------+--------------+
| Special Studies for Ocular Effects      | N           |              |
|                                         |             |              |
| > Acute Oral (Rat)                      |             |              |
| >                                       |             |              |
| > Subchronic Oral (Rat)                 |             |              |
| >                                       |             |              |
| > Six-month Oral (Dog)                  |             |              |
+-----------------------------------------+-------------+--------------+

**Y** - Yes; **N** -- no

\(a\) Requested by the ADTC (2005) because 4-t-amylphenol is an air
deodorizer, and thus the committee was concerned about the hazard
associated with inhalation exposure.

\(b\) Requested by the ADTC (2005) because the rat developmental
toxicity study showed qualitative evidence of increased susceptibility.

© Requested by the ADTC (2005) because available data suggest the
potential for endocrine disruptor capabilities.

# 4.0 DATA GAP(S)

There are several data gaps for 4-t-amylphenol. The existing acute
toxicity data are unacceptable and four acute toxicity studies using the
technical grade active ingredient must be conducted. In addition, the
use sites for this chemical involve indirect food contact. Therefore, a
90 day rat oral toxicity study must be submitted to support this use. In
addition, the ADTC (2005) identified potential qualitative
susceptibility concerns in the existing rat developmental study, and
thus requested a developmental toxicity study in another species
(rabbits). In addition, because of the potential concerns for endocrine
disruption of 4-t-amylphenol in the literature, the ADTC (2005)
requested a reproduction toxicity study be submitted. Because
4-t-amylphenol is an air deodorizer, the ADTC (2005) was concerned about
the hazard associated with inhalation exposure, and thus requested a
repeat 28-day inhalation study.

# 5.0 HAZARD ASSESSMENT

The acid p-t-amylphenol (PTAP) is the active ingredient and the salt
products (potassium and sodium) are the end use formulations. There is
no technical grade active PTAP salt.

## 5.1 Acute Toxicity

[Adequacy of data base for acute toxicity]{.underline}: 4-t-Amylphenol
is a primary dermal irritant (Category I) and is in Category III for
acute oral toxicity based on guideline studies. It also appears to be an
eye irritant (Category I), and may be in Category III for acute dermal
toxicity according to data from the open literature. However, acceptable
guideline acute studies are not available for dermal, inhalation,
primary eye irritation or dermal sensitization, and the literature data
protocols were inadequate. The additional studies required are listed in
Table 1 and in Section 3, Data Gaps.

  ------------------------- ---------- ------------------------- ------------
  Guideline No./ Study Type MRID No.   **Results**               **Toxicity
                                                                 Category**

  870.1100 Acute oral       46616601   LD50 \>2000 mg/kg for     III
  toxicity                             males and females         

  870.1200 Acute dermal     NA         No adequate acute         \[ \]
  toxicity                             toxicity studies were     
                                       provided or identified in 
                                       the open literature.      

  870.1300 Acute inhalation NA                                   \[ \]
  toxicity                                                       

  870.2400 Acute eye        NA                                   \[ \]
  irritation                                                     

  870.2500 Acute dermal     46616602   Corrosive following 4     I
  irritation                           hour application; scar    
                                       tissue noted 14 days      
                                       after treatment           

  870.2600 Skin             NA                                   
  sensitization                                                  
  ------------------------- ---------- ------------------------- ------------

NA=Not available

[]{#__RefHeading___Toc116186548 .anchor}**5.2 Subchronic Toxicity**

[Adequacy of data base for subchronic toxicity]{.underline}: A
subchronic oral rodent toxicity test is required for the indirect food
uses of 4-tert-amylphenol.

**870.3250 90-Day Dermal Toxicity B Rat**

[Executive Summary:]{.underline} In a subchronic dermal toxicity study
(MRID 42470301), Nipacide Amylphenol (Amenphenol, Batch No. L18K) was
administered to the clipped skin of Sprague Dawley Crl: CD BR VAF/Plus
rats (10 males and 10 females/group) at dose levels of 0, 2.5, 10 and 25
mg/kg, 6 hr/day, five days/week for 13 weeks. The test substance was
dissolved in a 50% v/v solution of ethanol (200 proof) in distilled
water; all doses were administered at a constant volume of 6.0 ml/kg.

No treatment-related deaths or clinical signs were observed.

Dermal irritation was not observed in controls or at 2.5 mg/kg/day. At
10 and 25 mg/kg/day, both sexes exhibited dose-related dermal
irritation, such as erythema and desquamation which progressed to eschar
formation with subsequent eschar exfoliation. The incidence and severity
of the dermal irritation were increased in the 25 mg/kg/day group where
the eschar formation progressed to cover 50 - 75% of the application
site in two males and five females. Ulcerations were also observed
within the exposure site of three males and five females in the 25
mg/kg/day group. Eschar formation in the 10 mg/kg/day group progressed
to cover 10 - 25 of the application site in one male and three females.

No biologically significant changes in body weight or body weight gain
were observed at any dose level. No biologically significant changes in
food consumption were observed. A transient increase (p\<0.05) in food
consumption was noted during study days 8 - 15, but was small (+8%), and
not accompanied by a corresponding change in body weight.

No treatment-related ocular effects were noted in test animals.

Hematological parameters showed no biologically significant changes due
to the test substance. Clinical chemistry parameters were affected
significantly by treatment to the test substance

Organ weights were not affected by treatment to the test substance. No
other gross pathological findings were made. Histopathological
observations were limited to the treated skin of rats in the 10 and 25
mg/kg/day groups. These changes included minimal to marked acanthosis,
minimal to mild chronic or acute dermatitis, inflammatory exudate on the
epidermal surface and occasional ulcers. The incidence and severity of
the dermal changes were dose dependent.

**The systemic NOAEL is 25 mg/kg/day. The LOAEL has not been
established.**

**The dermal NOAEL is 2.5 mg/kg/day. The LOAEL is 10 mg/kg/day based on
histopathological changes, dermal irritation characterized by erythema,
desquamation, eschar formation and subsequent eschar exfoliation.**.

[]{#__RefHeading___Toc116186549 .anchor}**5.3 Developmental Toxicity**

[Adequacy of data base for developmental toxicity]{.underline}: The data
base for developmental toxicity is adequate only for non-food uses of
amylphenol. Additional data are required for indirect or direct food
uses.

The one study provided, a prenatal developmental toxicity study in rats,
indicated a lower NOAEL and LOAEL for maternal toxicity (i.e., 50 and
200 mg/kg-day) than for developmental toxicity (i.e., 200 and 500
mg/kg-day), and the developmental effects were not frankly teratogenic.
Thus, there is no indication that the fetus is more susceptible than the
pregnant female.

**870.3700a Prenatal Developmental Toxicity Study - Rat**

[Executive Summary]{.underline} : In a developmental toxicity study
(MRID 41920002) Nipacide Amylphenol ( a.i. not specified; Batch L18K)
was administered by gavage to pregnant Sprague-Dawley rats (25/dose)
from gestation days (GD) 6 to GD 15 at dose levels of 0, 50, 200, and
500 mg/kg/day. Animals were sacrificed on GD 20, and dams and litters
were examined for signs of toxicity.

Maternal toxicity, observed at 200 and 500 mg/kg/day was manifested as
increased incidences of clinical signs (mucoid/soft stools, urine stains
rales, hair loss, salivation). Decreased body weight (p\<0.05, p\<0.01)
and decreased body weight gain of 10 - 50% (p\<0.05, p\<0.01) were
observed at several periods during gestation in the 200 and 500
mg/kg/day groups, respectively. Similarly, mean food consumption was
decreased 9 - 58% respectively during gestation at 200 and 500
mg/kg/day.

No adverse maternal effects were observed at 50 mg/kg/day.

**The maternal NOAEL is 50 mg/kg/day, and the LOAEL is 200 mg/kg/day,
based on clinical signs, decreases in body weight and body weight gain,
and decreases in food consumption.**

Effects in the conceptus observed at 500 mg/kg/day were decreased fetal
body weight (-5.6%, p\<0.05, measured as fetal weight/litter) and an
increased incidence of bent ribs (p\<0.05).

No adverse developmental effects were observed at 50 or 200 mg/kg/day.

**The developmental NOAEL is 200 mg/kg/day, and the LOAEL is 500
mg/kg/day, based on an decreased fetal body weight and an increased
incidence of bent ribs.**

[]{#__RefHeading___Toc116186550 .anchor}**5.4 Reproductive Toxicity**

[Adequacy of data base for reproductive toxicity]{.underline}: The data
base for reproductive toxicity is inadequate for indirect or direct food
uses of amylphenol. To support those uses of amylphenol, a reproductive
toxicity test must be submitted.

[]{#__RefHeading___Toc116186551 .anchor}**5.5 Chronic Toxicity**

[Adequacy of data base for chronic toxicity]{.underline}. The data base
for chronic toxicity is adequate for indirect food uses of amylphenol.

[]{#__RefHeading___Toc116186552 .anchor}**5.6 Carcinogenicity**

[Adequacy of data base for carcinogenicity]{.underline}: The data base
for carcinogenicity is adequate for indirect food uses of amylphenol.

[]{#__RefHeading___Toc116186553 .anchor}**5.7 Mutagenicity**

[Adequacy of data base for mutagenicity]{.underline}: The data base for
mutagenicity is considered adequate based on EPA=s 1991 mutagenicity
guidelines and indicates that p-tert-amylphenol is not mutagenic or
genotoxic. In a submitted bacterial study (MRID No. 414384-01) and a
study identified in the published literature (Zeiger et al. 1988),
p-tert-amylphenol was not mutagenic to the bacteria in the presence or
absence of mammalian metabolic activation. An assay using cultured mouse
lymphoma cells also proved negative (MRID No. 415727-01). Finally, a
mouse micronucleus test using male and female CD-1 mice also was
negative (MRID No. 417108).

**Gene Mutation**

+-----------------------+----------------------------------------------+
| Guideline 870.5265,   | Nipacide PTAP (\> 98.5% a.i.) was tested for |
| 870.5100, The         | its ability to induce reverse mutations in   |
| *Salmonella           | selected *Salmonella typhimurium* strains.   |
| typhimurium* reverse  | Five dose levels were tested both with and   |
| mutation assay        | without metabolic activation: 1, 3.2, 10,    |
|                       | 31.6, and 100 g/plate. Results were         |
| MRID No. 414384-01    | negative at all doses, with and without      |
|                       | activation. At 100 g/plate, inhibition of   |
| Classification:       | growth, observed as thinning of the          |
| Acceptable            | background lawn of non-revertant cells and   |
|                       | reduction in revertant colony numbers,       |
|                       | occurred in all strains following exposure.  |
|                       | There was no indication of a mutagenic       |
|                       | response in any strain at any dose level     |
|                       | with or without S9 activation.               |
+-----------------------+----------------------------------------------+
| Guideline 870.5300,   | Technical Nipacide PTAP was tested in the    |
| In vitro mammalian    | mouse lymphoma cell mutation system, both    |
| cell gene mutation    | with and without metabolic activation, at    |
| test                  | the following dose levels: non-activated     |
|                       | conditions - 5, 10, 20, 30, and 40 g/ml;    |
| MRID No. 415727-01    | activated conditions - 2, 4, 6, 8, and 10    |
|                       | g/ml. The few positive results in single    |
| Classification:       | cultures were inconsistent and not related   |
| Acceptable            | to dose. Historical control data provided in |
|                       | showed that mutation frequencies of the      |
|                       | controls in this study were slightly lower   |
|                       | than the historical controls, indicating     |
|                       | that the mutation frequencies in the         |
|                       | controls of this experiment were more        |
|                       | similar to historical controls. Thus, the    |
|                       | results are negative for gene mutations      |
|                       | under the conditions of the study.           |
+-----------------------+----------------------------------------------+

**Cytogenetics**

+-----------------------+----------------------------------------------+
| Guideline             | Nipacide PTAP was tested in a micronucleus   |
| 870.5395,Mammalian    | test in male and female CD-1 mice at the     |
| erythrocyte           | following dose levels: 62.5 (M), 250 (M+F),  |
| micronucleus test     | 1000 (M+F), and 4000 mg/kg (F). There was no |
|                       | evidence that Nipacide induced chromosomal   |
| MRID No. 41710801     | or other damage leading to micronucleus      |
|                       | formation in polychromatic erythrocytes.     |
| Classification:       | Although inadequate in demonstrating any     |
| Acceptable            | interaction in target cells, the negative    |
|                       | results are acceptable for reregistration    |
|                       | purposes.                                    |
+-----------------------+----------------------------------------------+

**Other Genotoxicity**

  ------------------------ ----------------------------------------------
  No studies in this       
  category                 

  ------------------------ ----------------------------------------------

[]{#__RefHeading___Toc116186554 .anchor}**5.8 Neurotoxicity**

[Adequacy of data base for Neurotoxicity]{.underline}: These studies are
not required at this time.

[]{#__RefHeading___Toc116186555 .anchor}**5.9 Metabolism**

[Adequacy of data base for metabolism:]{.underline} These studies are
not required at this time.

[]{#__RefHeading___Toc116186556 .anchor}**5.10 Special/Other Studies**

> **5.10.1 Skin Sensitization and Depigmentation**

P-tert-amylphenol has been reported to be a skin sensitizer and
depigmenting agent (BIBRA Working Group, 1990). Stevenson (1984),
however, reported p-tert-amylphenol to have a Alow depigmenting
potential@ because none of 129 men who had been exposed to the compound
during its manufacture exhibited depigmentation.

> **5.10.2 Endocrine Disruption**

4-t-Amylphenol is listed on a European list of "Chemicals purported to
be endocrine disruptors" (IEH 2005).

Soto et al. (1995) have found p-tert-amylphenol to be estrogenic in the
E-SCREEN assay, which assesses the estrogenicity of a compound by
measuring its proliferative effect on estrogen-sensitive cells. The cell
number achieved by similar inocula of MCF-7 cells (estrogen-sensitive
human breast cancer cells) in the absence of estrogens (negative
control) and in the presence of 17β-estradiol (positive control) is
compared with the number of cells achieved with a range of
concentrations of the test chemical. For 4-tert-pentylphenol, a
concentration of 10 M was the lowest concentration needed for maximal
cell yield. For the positive control 17β-estradiol, the lowest
concentration needed was 30 pM. The relative proliferative effect (RPE)
is calculated as 100 x (PE-1) of the test compound divided by (PE-1) of
17β-estradiol. A value of 100 indicates that the compound tested is a
full agonist of the estradiol; a value of 0 indicates that the compound
lacks estroenicity at the doses tested. Intermediate values suggest that
the compound is a partial agonist of 17β-estradiol. For
4-tert-pentylphenol, and RPE of 105 was estimated.

Routledge and Sumpter (1997) demonstrated estrogenic activity of
4-tert-amylphenol using an estrogen-inducible strain of yeast
(*Saccharomyces cerevisiae*) that expresses the human estrogen receptor.
Using the natural estrogen 17β-estradiol for comparison, the data
indicated that both the position (para \> meta \> ortho) and branching
(tertiary \> secondary = normal) of the alkyl group affect
estrogenicity. In this assay, 4-tert-amylphenol was found to be
100,000-fold less potent than17β-estradiol.

+----------+----------------+--------+------+----------+-------------+
| **Ref    | **Model**      | **     | **   | **       | *           |
| erence** |                | Estrog | IC50 | Relative | *Relative** |
|          |                | enic** | (    | Binding  |             |
|          |                |        | M)** | Affinity | **Potency   |
|          |                | **LO   |      | (RBA)    | (%)**       |
|          |                | EC\*** |      | (%)**    |             |
|          |                |        |      |          | *           |
|          |                | **(log |      |          | *Comments** |
|          |                | M)**   |      |          |             |
+----------+----------------+--------+------+----------+-------------+
| Blair    | Rat uterine ER |        | 1.   | 0.0005   |             |
| 2000     | competitive    |        | 6x10 |          |             |
|          | binding        |        | ^-4^ |          |             |
+----------+----------------+--------+------+----------+-------------+
| Miller   | Yeast          |        |      |          | 1/200000 of |
| 2001     | recombinant    |        |      |          | E~2~        |
|          |                |        |      |          |             |
|          | Human ERα      |        |      |          | PTAP        |
|          |                |        |      |          | IC~50~/E2   |
|          | t              |        |      |          | IC~50~      |
|          | ranscriptional |        |      |          |             |
|          | activation     |        |      |          |             |
+----------+----------------+--------+------+----------+-------------+
| Schultz  | Yeast          |        | 4.   |          | 0.0008      |
| 2000     | recombinant    |        | 8x10 |          |             |
|          |                |        | ^-6^ |          | \~ 70% of   |
|          | Human ERα      |        |      |          | max E~2~    |
|          |                |        |      |          |             |
|          | t              |        |      |          |             |
|          | ranscriptional |        |      |          |             |
|          | activation     |        |      |          |             |
+----------+----------------+--------+------+----------+-------------+

\*LOEC=lowest observed effects concentration

E~2~=17β-estradiol

[]{#__RefHeading___Toc116186557 .anchor}**6.0 TOXICITY ENDPOINT
SELECTION**

[]{#__RefHeading___Toc116186558 .anchor}**6.1 ACUTE DIETARY (Acute
Reference Dose)**

> **6.1.1.** **Acute RfD** **Subpopulation: Females 13+**
>
> [Study Selected:]{.underline} Developmental Toxicity B Rat \'83‑3a
>
> [MRID No.]{.underline}: 41920002
>
> [Executive Summary]{.underline} : In a developmental toxicity study
> (MRID 41920002) Nipacide Amylphenol ( a.i. not specified; Batch L18K)
> was administered by gavage to pregnant Sprague-Dawley rats (25/dose)
> from gestation days (GD) 6 to GD 15 at dose levels of 0, 50, 200, and
> 500 mg/kg/day. Animals were sacrificed on GD 20, and dams and litters
> were examined for signs of toxicity.
>
> Maternal toxicity, observed at 200 and 500 mg/kg/day was manifested as
> increased incidences of clinical signs (mucoid/soft stools, urine
> stains rales, hair loss, salivation). Decreased body weight (p\<0.05,
> p\<0.01) and decreased body weight gain of 10 - 50% (p\<0.05, p\<0.01)
> were observed at several periods during gestation in the 200 and 500
> mg/kg/day groups, respectively. Similarly, mean food consumption was
> decreased 9 - 58% respectively during gestation at 200 and 500
> mg/kg/day.
>
> No adverse maternal effects were observed at 50 mg/kg/day.
>
> **The maternal NOAEL is 50 mg/kg/day, and the LOAEL is 200 mg/kg/day,
> based on clinical signs, decreases in body weight and body weight
> gain, and decreases in food consumption.**
>
> Effects in the conceptus observed at 500 mg/kg/day were decreased
> fetal body weight (-5.6%, p\<0.05, measured as fetal weight/litter)
> and an increased incidence of bent ribs (p\<0.05).
>
> No adverse developmental effects were observed at 50 or 200 mg/kg/day.
>
> **The developmental NOAEL is 200 mg/kg/day, and the LOAEL is 500
> mg/kg/day, based on an decreased fetal body weight and an increased
> incidence of bent ribs.**
>
> [Dose Selected for Risk Assessment:]{.underline} 200 mg/kg/day based
> on skeletal effects and decreased fetal body weight gain observed at
> the LOAEL of 500 mg/kg/day
>
> [Comments about Study/Endpoint Uncertainty Factor]{.underline}: The
> effects observed at the developmental LOAEL, skeletal abnormalities,
> can occur in the conceptus following a single exposure to pregnant
> females.
>
> **This risk assessment IS required.**

**Acute RfD =** [200 mg/kg/day (NOAEL)]{.underline} = **0.67 mg/kg/day**

300 (UF)

> **6.1.2. Acute RfD** **(General Population including Infants and
> children)**
>
> [Study Selected :]{.underline} None Guideline #: \'83‑3
>
> [MRID No.:]{.underline} None
>
> [Dose Selected for Risk Assessment:]{.underline} None
>
> [Comments about Study/Endpoint Uncertainty Factor]{.underline}: A
> study appropriate for this endpoint was not identified.
>
> **This risk assessment is NOT required.**

[]{#__RefHeading___Toc116186559 .anchor}**6.2. CHRONIC DIETARY (Chronic
Reference Dose) General Population**

> [Study Selected:]{.underline} Developmental Toxicity B Rat \'83‑3a
>
> [MRID No.]{.underline}: 41920002
>
> [Executive Summary:]{.underline} See Acute Dietary, Females 13+
>
> [Uncertainty Factor]{.underline}: 300 ( 10 x for inter-species
> variation, 10x for intra-species extrapolation, 3x for database
> inadequacies).
>
> [Dose Selected for Risk Assessment:]{.underline} 50 mg/kg/day based on
> clinical signs, decreases in body weight and body weight gain,
> decreased food consumption at the LOAEL of 200 mg/kg/day.
>
> [Comments about Study/Endpoint Uncertainty Factor]{.underline}: This
> study represents the best available data to assess chronic toxicity.

**Chronic RfD =** [50 mg/kg/day (NOAEL)]{.underline} = **0.17
mg/kg/day**

300 (UF)

> [Comments about Study/Endpoint Uncertainty Factor]{.underline}: The
> ADTC concluded this study can be used to establish a chronic RfD
> because it is the best oral study available. An extra uncertainty
> factor to compensate for the lack of a chronic study was deemed
> necessary.

[]{#__RefHeading___Toc116186560 .anchor}**6.3. INCIDENTAL ORAL
EXPOSURE**

**6.3.1. Short-Term**

> [Study Selected:]{.underline} Developmental Toxicity ‑ Rats
> Guideline#:\'82‑3
>
> [MRID No.:]{.underline} 41920002
>
> [Executive Summary:]{.underline} See Acute RfD, Females 13+
>
> [Dose Selected for Risk Assessment:]{.underline} 50 mg/kg/day based on
> clinical signs, decreases in body weight and body weight gain,
> decreased food consumption at the LOAEL of 200 mg/kg/day.
>
> [Comments about Study/Endpoint:]{.underline} The maternal toxicity
> seen at the LOAEL can be attributed to short-term exposure.

**This risk assessment is required.**

**6.3.2. Intermediate-Term**

> [Study Selected:]{.underline} Developmental Toxicity ‑ Rats
> Guideline#:\'82‑3
>
> [MRID No.:]{.underline} 41920002
>
> [Executive Summary:]{.underline} See Acute RfD, Females 13+
>
> [Dose Selected for Risk Assessment:]{.underline} 50 mg/kg/day based on
> clinical signs, decreases in body weight and body weight gain,
> decreased food consumption at the LOAEL of 200 mg/kg/day.
>
> [Comments about Study/Endpoint:]{.underline} The maternal toxicity
> seen at the LOAEL can be attributed to short-term exposure.

**This risk assessment is required.**

[]{#__RefHeading___Toc116186561 .anchor}**6.4 OCCUPATIONAL / RESIDENTIAL
EXPOSURE**

> **6.4.1. DERMAL ABSORPTION**
>
> [Study Selected:]{.underline} None Guideline #: \'85‑2
>
> [MRID No.:]{.underline} None
>
> [Executive Summary:]{.underline} None. An appropriate study was not
> available
>
> **Dermal Absorption Factor: 100%**
>
> [Comments about Dermal Absorption Factor:]{.underline} Since a dermal
> absorption study was not available, a dermal absorption factor of 100%
> is assumed.
>
> **6.4.2. SHORT‑TERM DERMAL (1 ‑ 30 days)**
>
> [Study Selected:]{.underline} Dermal Subchronic Toxicity ‑ Rats
> Guideline#:\'82‑3
>
> [MRID No.:]{.underline} 42470301
>
> [Executive Summary:]{.underline} In a subchronic dermal toxicity study
> (MRID 42470301), Nipacide Amylphenol (Amenphenol, Batch No. L18K) was
> administered to the clipped skin of Sprague Dawley Crl: CD BR VAF/Plus
> rats (10 males and 10 females/group) at dose levels of 0, 2.5, 10 and
> 25 mg/kg, 6 hr/day, five days/week for 13 weeks. The test substance
> was dissolved in a 50% v/v solution of ethanol (200 proof) in
> distilled water; all doses were administered at a constant volume of
> 6.0 ml/kg.
>
> No treatment-related deaths or clinical signs were observed.
>
> Dermal irritation was not observed in controls or at 2.5 mg/kg/day. At
> 10 and 25 mg/kg/day, both sexes exhibited dose-related dermal
> irritation, such as erythema and desquamation which progressed to
> eschar formation with subsequent eschar exfoliation. The incidence and
> severity of the dermal irritation were increased in the 25 mg/kg/day
> group where the eschar formation progressed to cover 50 - 75% of the
> application site in two males and five females. Ulcerations were also
> observed within the exposure site of three males and five females in
> the 25 mg/kg/day group. Eschar formation in the 10 mg/kg/day group
> progressed to cover 10 -- 25% of the application site in one male and
> three females.
>
> No biologically significant changes in body weight or body weight gain
> were observed at any dose level. No biologically significant changes
> in food consumption were observed. A transient increase (p\<0.05) in
> food consumption was noted during study days 8 - 15, but was small
> (+8%), and not accompanied by a corresponding change in body weight.
>
> No treatment-related ocular effects were noted in test animals.
>
> Hematological parameters showed no biologically significant changes
> due to the test substance. Clinical chemistry parameters were affected
> significantly by treatment to the test substance
>
> Organ weights were not affected by treatment to the test substance. No
> other gross pathological findings were made. Histopathological
> observations were limited to the treated skin of rats in the 10 and 25
> mg/kg/day groups. These changes included minimal to marked acanthosis,
> minimal to mild chronic or acute dermatitis, inflammatory exudate on
> the epidermal surface and occasional ulcers. The incidence and
> severity of the dermal changes were dose dependent.
>
> **The systemic NOAEL is 25 mg/kg/day. The LOAEL has not been
> established.**
>
> **The dermal NOAEL is 2.5 mg/kg/day. The LOAEL is 10 mg/kg/day based
> on histopathological changes, dermal irritation characterized by
> erythema, desquamation, eschar formation and subsequent eschar
> exfoliation.**.
>
> [Dose Selected for Risk Assessment:]{.underline} 25 mg/kg/day, which
> is the systemic NOAEL and the highest dose level tested.
>
> [Comments about Study/Endpoint:]{.underline} None.
>
> **This risk assessment is required.**
>
> **6.4.3. INTERMEDIATE‑ TERM DERMAL (One month to Several Months)**
>
> [Study Selected:]{.underline} Subchronic Dermal ‑ Rats Guideline#: \'
> 82‑3
>
> [MRID No.:]{.underline} 42470301
>
> [Executive Summary:]{.underline} See Short-Term Dermal.
>
> [Dose Selected for Risk Assessment:]{.underline} 25 mg/kg/day, which
> is the systemic NOAEL and the highest dose level tested.
>
> [Comments about Study/Endpoint:]{.underline} None.
>
> **This risk assessment is required.**
>
> **6.4.4. LONG‑TERM DERMAL (Several Months to Lifetime)**
>
> [Study Selected:]{.underline} Subchronic Dermal ‑ Rats Guideline#: \'
> 82‑3
>
> [MRID No.:]{.underline} 42470301
>
> [Executive Summary:]{.underline} See Short-Term Dermal.
>
> [Dose Selected for Risk Assessment:]{.underline} 25 mg/kg/day, which
> is the systemic NOAEL and the highest dose level tested.
>
> [Comments about Study/Endpoint:]{.underline} None.
>
> **This risk assessment is required.**
>
> **6.4.5. INHALATION (All Durations).**
>
> [Study Selected:]{.underline} Developmental Toxicity ‑ Rats
> Guideline#:\'82‑3
>
> [MRID No.:]{.underline} 41920002
>
> [Executive Summary:]{.underline} See Acute RfD, Females 13+
>
> [Dose Selected for Risk Assessment:]{.underline} 50 mg/kg/day based on
> clinical signs, decreases in body weight and body weight gain,
> decreased food consumption at the LOAEL of 200 mg/kg/day.
>
> [Comments about Study/Endpoint:]{.underline} The maternal toxicity
> seen at the LOAEL can be attributed to short-term exposure.
>
> **This risk assessment is required.**

[]{#__RefHeading___Toc116186562 .anchor}**6.5 Margins of Exposure**

> **Acute and chronic dietary**: 10x interspecies extrapolation, 10x
> intraspecies variation, 10x FQPA safety factor, 3x database
> uncertainty factor.
>
> **Incidental oral**: Target MOE=3000 (10x interspecies extrapolation,
> 10x intraspecies variation, 10x FQPA safety factor, 3x database
> uncertainty factor).
>
> **Short- and Intermediate Term Dermal Residential**: Target MOE=1000
> (10x interspecies extrapolation, 10x intraspecies variation, 10x FQPA
> safety factor)
>
> **Short- and Intermediate Term Dermal Occupational**: Target MOE=1000
> (10x interspecies extrapolation, 10x intraspecies variation)
>
> **Long-Term Dermal Residential**: Target MOE=3000 (10x interspecies
> extrapolation, 10x intraspecies variation, 10x FQPA safety factor, and
> 3X for subchronic to chronic exposure)
>
> **Long-Term Dermal Occupational**: Target MOE=300 (10x interspecies
> extrapolation, 10x intraspecies variation and 3X for subchronic to
> chronic exposure)
>
> **Inhalation Residential**: Target MOE=3000 (10x interspecies
> extrapolation, 10x intraspecies variation, 10x FQPA safety factor, 3x
> database uncertainty factor)
>
> **Inhalation Occupational**: Target MOE=300 (10x interspecies
> extrapolation, 10x intraspecies variation, 3x database uncertainty
> factor)

[]{#__RefHeading___Toc116186563 .anchor}**6.6 Recommendation for
Aggregate Exposure Risk Assessments**

> Food and water exposures of amylphenol should be aggregated. An acute
> aggregate assessment is required for Females 13+; however it is NOT
> required for the General Population including Infants and Children
> because there is no dietary endpoint identified.
>
> Residential exposures of amylphenol resulting in incidental oral and
> inhalation exposures should be aggregated with average food exposures.
> However, this aggregation should take into consideration the different
> uncertainty factors applied to the various endpoints. Dermal exposures
> are not aggregated with the other scenarios based on the use of a
> different study and endpoint for dermal risk assessments.

[]{#__RefHeading___Toc116186564 .anchor}**6.7 Classification of
Carcinogenic Potential**

> Amylphenol has not been assigned a cancer classification.
> 4-t-Amylphenol was negative for carcinogenicity in a subchronic skin
> painting study from the open literature. However, guideline studies
> for carcinogenicity are not available. All mutagenicity tests were
> negative.

[]{#__RefHeading___Toc116186565 .anchor}**7.0 FQPA CONSIDERATIONS**

[]{#__RefHeading___Toc116186566 .anchor}**7.1 Adequacy of the Data
Base**

> The toxicology data base is not complete with respect to assessing the
> increased susceptibility to infants and children as required by FQPA
> for Amylphenol. An acceptable rat developmental study is available,
> but a guideline study in the rabbit is not available, nor is a
> guideline reproduction study.

[]{#__RefHeading___Toc116186567 .anchor}**7.2 Neurotoxicity Data**

> There are currently no guideline neurotoxicity studies available for
> 4-t-amylphenol.

[]{#__RefHeading___Toc116186568 .anchor}**7.3. Developmental &
Reproductive Toxicity**

**7.3.1. Developmental Toxicity:**

> An executive summary for a prenatal developmental study is provided
> under Acute Dietary, Females 13+. This study showed no quantitative
> evidence of increased susceptibility (i.e., developmental
> NOAELs/LOAELs were the higher than those for maternal effects).
> However, there was qualitative evidence of increased susceptibility
> (i.e., fetal effects (skeletal abnormalities, decreased body weight
> gain) were considered to be more severe than the maternal toxicity
> (reversible clinical signs) observed at the same dose level).
>
> **7.3.2. Reproductive Toxicity:**
>
> A two-generation reproduction study in rats is not available for
> Amylphenol.

[]{#__RefHeading___Toc116186569 .anchor}**7.4 Determination of
Susceptibility**

> Quantitative evidence of increased susceptibility was not demonstrated
> in the rat developmental study; however, a possible increase in
> qualitative susceptibility was demonstrated in this study. In
> addition, there is an absence of developmental toxicity data in the
> rat, and an absence of reproductive toxicity data.
>
> In the open literature (Yamasaki et al. 2003), an increase in
> non-pregnant uterine weight was observed in rats following Amylphenol
> exposure. Another study (Soto et al. 1995) suggested that
> 4-t-amylphenol may have estrogenic effect. Wysowski et at. (1978)
> reported elevated blood levels of bilirubin in children exposed to
> 4-t-amylphenol and other phenols in disinfectant. These studies, while
> not indicative, are suggestive of a basis for increased concern for
> reproductive and/or developmental effects due to exposure to
> Amylphenol.
>
> The ADTC has determined that the FQPA Safety Factor should be Ten
> (10).

[]{#__RefHeading___Toc116186570 .anchor}**7.5 Determination of the Need
for Developmental Neurotoxicity Study**

> The ADTC committee has not identified a basis for requesting a
> developmental neurotoxicity study at this time. However, the Committee
> is recommending that when the 90-day rat subchronic study is
> conducted, the protocol be modified to assess endocrine disruptor
> effects and uterotropic effects. Protocols are available from HED.

[]{#__RefHeading___Toc116186571 .anchor}**7.6. Database Uncertainty
Factor**

> The ADTC has assessed an additional Uncertainty Factor of 10 at this
> time, due to the number and significance of the data gaps.

[]{#__RefHeading___Toc116186572 .anchor}**8.0 OTHER ISSUES**

There are no outstanding issues at this time.

[]{#__RefHeading___Toc116186573 .anchor}**9.0 REFERENCES**

MRID No. 41438401

May, K. 1990. Nipacide PTAP (para-tertiary amylphenol): Assessment of
Mutagenic Potential in Histidine Auxotrophs of *Salmonella typhimurium*.
Prepared by Life Science Research Ltd., Suffolk, UK. Study No. 90/0109.
Submitted by Nipa Laboratories, Inc., Wilmington, DE.

MRID No. 41572701

Lloyd, J.M. 1990. Investigation of Mutagenic Activity in the TK+/- Mouse
Lymphoma Cell Mutation System. Prepared by Life Science Research Ltd.,
Suffolk, UK. Study No. 90/NLL034/0395. Submitted by Nipa Laboratories,
Inc., Wilmington, DE.

MRID No. 41710801

Edwards, C.N. 1990. Assessment of Clastogenic Action on Bone Marrow
Erythrocytes in the Micronucleus Test. Prepared by Life Science Research
Ltd., Suffolk, UK. Study No. 90/NLL033/0533. Submitted by Nipa
Laboratories, Inc., Wilmington, DE.

MRID No. 41920002.

Siglin, J.C. 1991. Nipacide PTAP, Teratology Study in Rats. Prepared by
Springborn Laboratories, Inc., Spencerville, OH. Study No. 3227.3.
Submitted by Nipa Laboratories, Inc., Wilmington, DE.

MRID 42470301

Siglin 1992. Ninety-One Day Dermal Toxicity Study in Rats with Nipacide
PTAP. Springborn Laboratories.

MRID No. 46616601. Tuffnell, P.P. Phenol, 4-(1,1-dimethylpropyl)- Acute
Oral Toxicity in the Rat. Safepharm Laboratories Ltd., Derby U.K.,
Laboratory Test No. 47/2097. July 23, 1992. Unpublished.

MRID No. 46616602. Tuffnell, P.P. Phenol, 4-(1,1-dimethylpropyl)- Acute
Dermal Irritation Test in the Rabbit. Safepharm Laboratories Ltd., Derby
U.K., Laboratory Test No. 47/2098. July 25, 1992. Unpublished.

Antimicrobials Toxicology Endpoint Selection Committee (ADTC). 2005.
4-t-Amylphenol. Report of the Antimicrobials Toxicology Endpoint
Selection Committee. From Myron Ottley and Tim McMahon to Mark Hartman.
July 12, 2005.

BIBRA, Working Group (1990): Para-tertiary-Amylphenol. Toxicity Profile
BIBRA Toxicology International. 3 pp.

Blair, R.M., Fang, H., Branham, W., Hass, B., Dial, S., Moland, C.,
Tong, W., Shi, L.,

Perkins, R., and D. Sheehan. (2000). The estrogen receptor relative
binding affinities of 188 natural and xenochemicals: structural
diversity of ligands. *Toxicol Sci.* 54, 138-153.

Miller, D., Wheals, B., Beresford, N., Sumpter, J. (2001). Estrogenic
activity of phenolic additives determined by an *in vitro* yeast assay.
*Environ Health Perspect*. 109, 133-138.

Routledge, E. J. and Sumpter, J. P. (1997) Structural features of
alkylphenolic chemicals associated with estrogenic activity. J. Biol.
Chem. 272(6): 3280-3288.

Schultz, T., Sinks, G., Cronin, M. (2000) Effect of substituent size and
dimensionality on potency of phenolic xenoestrogens evaluated with a
recombinant yeast assay. *Environ Toxicol Chem* 19, 2637-2642

Soto, et al. (1995) The E-SCREEN assay as a tool to identify estrogens:
An update on estrogenic environmental pollutants. Environ. Health
Perspect. 103 (Suppl. 7): 113-122.

Stevenson,C.J. (1984): Environmentally induced vitiligo (leukoderma)
from depigmenting agents and chemicals. J. Toxicol. Cutaneous Ocul.
Toxicol. 3(3): 299-308.

Wysowski, D.K. et al. (1978) Epidemic neonatal hyperbilirubinemia and
use of a phenolic disinfectant detergent. Pediatrics 61: 165-170.

Yamasaki, K., et al. (2003) Immature rat uterotrophic assay of 18
chemicals and Hershberger assay of 30 chemicals. Toxicology 183: 93-115.

Zeiger,E., Anderson,B., Haworth,S., Lawlor,T., and Mortelmans,K. (198):
Salmonella mutagenicity tests. 4. results from the testing of 300
chemicals. Environ. Mol. Mutagen 11: 1-158.

[]{#__RefHeading___Toc116186574 .anchor}**10.0 APPENDICES**

[]{#__RefHeading___Toc116186575 .anchor}**10.1 Toxicity Profile Summary
Tables**

**10.1.1 Acute Toxicity Table**

  ------------------------- ---------- ------------------------- ------------
  Guideline No./ Study Type MRID No.   **Results**               **Toxicity
                                                                 Category**

  870.1100 Acute oral       46616601   LD50 \>2000 mg/kg for     III
  toxicity                             males and females         

  870.1200 Acute dermal     NA         No adequate acute         \[ \]
  toxicity                             toxicity studies were     
                                       provided or identified in 
                                       the open literature.      

  870.1300 Acute inhalation NA                                   \[ \]
  toxicity                                                       

  870.2400 Acute eye        NA                                   \[ \]
  irritation                                                     

  870.2500 Acute dermal     46616602   Corrosive following 4     I
  irritation                           hour application; scar    
                                       tissue noted 14 days      
                                       after treatment           

  870.2600 Skin             NA                                   
  sensitization                                                  
  ------------------------- ---------- ------------------------- ------------

NA=Not available

**10.1.2 Subchronic, Chronic and Other Toxicity Table**

+-------------+-----------------+-------------------------------------+
| **Guideline | **MRID No.      | **Results**                         |
| No./ Study  | (year)/         |                                     |
| Type**      | Classification  |                                     |
|             | /Doses**        |                                     |
+=============+=================+=====================================+
| 870.3250    | MRID 42470301   | NOAEL = 2.5 mg/kg/day               |
|             | (1993)          |                                     |
| 90-Day      |                 | LOAEL = 10 mg/kg/day based on       |
| dermal      | 0, 2.5, 10, 25  | dermal effects                      |
| toxicity    | mg/kg/day       |                                     |
|             |                 |                                     |
|             | not acceptable, |                                     |
|             | no systemic     |                                     |
|             | toxicity        |                                     |
|             | demonstrated    |                                     |
+-------------+-----------------+-------------------------------------+
| 870.3700a   | 41920002 (1991) | **Maternal** NOAEL = 50 mg/kg/day   |
|             |                 |                                     |
| Prenatal    | Acceptable      | LOAEL = 200 mg/kg/day based on      |
| de          |                 | clinical signs and decreased body   |
| velopmental | 0, 50, 200, 500 | weight, weight gain, and food       |
| in rodents  | mg/kg/day       | consumption                         |
|             |                 |                                     |
|             |                 | **Developmental** NOAEL = 200       |
|             |                 | mg/kg/day                           |
|             |                 |                                     |
|             |                 | LOAEL = 500 mg/kg/day based on      |
|             |                 | decreased fetal body weight and     |
|             |                 | increased incidence of bent ribs    |
+-------------+-----------------+-------------------------------------+
| Gene        | 414384-01       | Negative, with or without           |
| Mutation    | (1990)          | activation                          |
|             |                 |                                     |
| 870.5265    | Acceptable      |                                     |
|             |                 |                                     |
| *Salmonella | 1, 3.2, 10,     |                                     |
| t           | 31.6, and 100   |                                     |
| yphimurium* | g/plate        |                                     |
| reverse     |                 |                                     |
| mutation    |                 |                                     |
| assay       |                 |                                     |
+-------------+-----------------+-------------------------------------+
| Gene        | 415727-01       | Negative with and without metabolic |
| Mutation    | (1990)          | activation. The few positive        |
|             |                 | results in control plates are       |
| 870.5300    | Acceptable      | consistent with historical control  |
|             |                 | data for the laboratory and test    |
| *In vitro*  | non-activated   | system.                             |
| mammalian   | conditions - 5, |                                     |
| cell gene   | 10, 20, 30, and |                                     |
| mutation    | 40 g/ml;       |                                     |
| test        | activated       |                                     |
|             | conditions - 2, |                                     |
|             | 4, 6, 8, and 10 |                                     |
|             | g/ml           |                                     |
+-------------+-----------------+-------------------------------------+
| C           | 417108 (1990)   | Negative                            |
| ytogenetics |                 |                                     |
|             | Acceptable      |                                     |
| 870.5395    |                 |                                     |
|             | 62.5 (M), 250   |                                     |
| Mammalian   | (M+F), 1000     |                                     |
| erythrocyte | (M+F), and 4000 |                                     |
| mi          | mg/kg (F)       |                                     |
| cro-nucleus |                 |                                     |
| test        |                 |                                     |
+-------------+-----------------+-------------------------------------+

+----------+------------+---------------+---+----------------------------+
| Exposure | Dose Used  | Target MOE,   | S |                            |
|          | in Risk    | UF, Special   | t |                            |
| Scenario | Assessment | FQPA SF, for  | u |                            |
|          |            | Risk          | d |                            |
|          | (          | Assessment    | y |                            |
|          | mg/kg/day) |               | a |                            |
|          |            |               | n |                            |
|          |            |               | d |                            |
|          |            |               | T |                            |
|          |            |               | o |                            |
|          |            |               | x |                            |
|          |            |               | i |                            |
|          |            |               | c |                            |
|          |            |               | o |                            |
|          |            |               | l |                            |
|          |            |               | o |                            |
|          |            |               | g |                            |
|          |            |               | i |                            |
|          |            |               | c |                            |
|          |            |               | a |                            |
|          |            |               | l |                            |
|          |            |               | E |                            |
|          |            |               | f |                            |
|          |            |               | f |                            |
|          |            |               | e |                            |
|          |            |               | c |                            |
|          |            |               | t |                            |
|          |            |               | s |                            |
+----------+------------+---------------+---+----------------------------+
| Acute    | NOAEL= 200 | UF = 3000     | D |                            |
| Dietary  | mg/kg/day  | (10x          | e |                            |
|          |            | inter-species | v |                            |
| *        |            | e             | e |                            |
| *Females |            | xtrapolation, | l |                            |
| 13+**    |            | 10x           | o |                            |
|          |            | intra-species | p |                            |
| b.w. =   |            | variation)    | m |                            |
| 60kg     |            |               | e |                            |
|          |            | FQPA SF= 10   | n |                            |
|          |            |               | t |                            |
|          |            | DB UF = 3     | a |                            |
|          |            |               | l |                            |
|          |            | **Acute PAD** | t |                            |
|          |            | =0.067        | o |                            |
|          |            | mg/kg/day     | x |                            |
|          |            |               | i |                            |
|          |            |               | c |                            |
|          |            |               | i |                            |
|          |            |               | t |                            |
|          |            |               | y |                            |
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|          |            |               | r |                            |
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|          |            |               |   |                            |
|          |            |               | N |                            |
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|          |            |               | A |                            |
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|          |            |               | 2 |                            |
|          |            |               | 0 |                            |
|          |            |               | 0 |                            |
|          |            |               | m |                            |
|          |            |               | g |                            |
|          |            |               | / |                            |
|          |            |               | k |                            |
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|          |            |               | a |                            |
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|          |            |               | c |                            |
|          |            |               | t |                            |
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|          |            |               | d |                            |
|          |            |               | f |                            |
|          |            |               | e |                            |
|          |            |               | t |                            |
|          |            |               | a |                            |
|          |            |               | l |                            |
|          |            |               | b |                            |
|          |            |               | o |                            |
|          |            |               | d |                            |
|          |            |               | y |                            |
|          |            |               | w |                            |
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|          |            |               | i |                            |
|          |            |               | g |                            |
|          |            |               | h |                            |
|          |            |               | t |                            |
|          |            |               | a |                            |
|          |            |               | t |                            |
|          |            |               | 5 |                            |
|          |            |               | 0 |                            |
|          |            |               | 0 |                            |
|          |            |               | m |                            |
|          |            |               | g |                            |
|          |            |               | / |                            |
|          |            |               | k |                            |
|          |            |               | g |                            |
|          |            |               | / |                            |
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|          |            |               | a |                            |
|          |            |               | y |                            |
+----------+------------+---------------+---+----------------------------+
| Chronic  | NOAEL = 50 | UF = 3000     | D |                            |
| Dietary  | mg/kg/day  | (10x          | e |                            |
|          |            | inter-species | v |                            |
| **[All   |            | e             | e |                            |
| po       |            | xtrapolation, | l |                            |
| pulation |            | 10x           | o |                            |
| s]{.unde |            | intra-species | p |                            |
| rline}** |            | variation)    | m |                            |
|          |            |               | e |                            |
| b.w. =   |            | FQPA SF= 10   | n |                            |
| 70 kg    |            |               | t |                            |
|          |            | DB UF = 3     | a |                            |
|          |            |               | l |                            |
|          |            | **Chronic     | t |                            |
|          |            | PAD** =0.017  | o |                            |
|          |            | mg/kg/day     | x |                            |
|          |            |               | i |                            |
|          |            |               | c |                            |
|          |            |               | i |                            |
|          |            |               | t |                            |
|          |            |               | y |                            |
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|          |            |               | t |                            |
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|          |            |               | d |                            |
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|          |            |               | a |                            |
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|          |            |               | O |                            |
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|          |            |               | m |                            |
|          |            |               | a |                            |
|          |            |               | l |                            |
|          |            |               | s |                            |
|          |            |               | a |                            |
|          |            |               | t |                            |
|          |            |               | 2 |                            |
|          |            |               | 0 |                            |
|          |            |               | 0 |                            |
|          |            |               | m |                            |
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+----------+------------+---------------+---+----------------------------+
| In       | NOAEL =50  | MOE = 3000    | D |                            |
| cidental | mg/kg/day  | (10x          | e |                            |
| Oral     |            | interspecies  | v |                            |
|          |            | e             | e |                            |
| (short   |            | xtrapolation, | l |                            |
| and      |            | 10x           | o |                            |
| inte     |            | intraspecies  | p |                            |
| rmediate |            | variation,    | m |                            |
| term)    |            | 10x FQPA , 3x | e |                            |
|          |            | database UF)  | n |                            |
|          |            |               | t |                            |
|          |            |               | a |                            |
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|          |            |               | d |                            |
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|          |            |               | N |                            |
|          |            |               | O |                            |
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|          |            |               | o |                            |
|          |            |               | d |                            |
|          |            |               | c |                            |
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|          |            |               | n |                            |
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|          |            |               | u |                            |
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|          |            |               | p |                            |
|          |            |               | t |                            |
|          |            |               | i |                            |
|          |            |               | o |                            |
|          |            |               | n |                            |
|          |            |               | i |                            |
|          |            |               | n |                            |
|          |            |               | m |                            |
|          |            |               | a |                            |
|          |            |               | t |                            |
|          |            |               | e |                            |
|          |            |               | r |                            |
|          |            |               | n |                            |
|          |            |               | a |                            |
|          |            |               | l |                            |
|          |            |               | a |                            |
|          |            |               | n |                            |
|          |            |               | i |                            |
|          |            |               | m |                            |
|          |            |               | a |                            |
|          |            |               | l |                            |
|          |            |               | s |                            |
|          |            |               | a |                            |
|          |            |               | t |                            |
|          |            |               | 2 |                            |
|          |            |               | 0 |                            |
|          |            |               | 0 |                            |
|          |            |               | m |                            |
|          |            |               | g |                            |
|          |            |               | / |                            |
|          |            |               | k |                            |
|          |            |               | g |                            |
|          |            |               | / |                            |
|          |            |               | d |                            |
|          |            |               | a |                            |
|          |            |               | y |                            |
+----------+------------+---------------+---+----------------------------+
| Dermal   | NOAEL = 25 | MOE           |   | Subchronic dermal toxicity |
|          | mg/kg/day  | (             |   | in the rat                 |
| (short   | (HDT)      | occupational) |   |                            |
| and      |            | = 100         |   | No systemic effects        |
| in       |            |               |   | identified up to and       |
| termedia |            | MOE           |   | including the high dose of |
| te-term) |            | (residential) |   | 25 mg/kg/day               |
|          |            | =1000 (10x    |   |                            |
| (occu    |            | interspecies  |   |                            |
| pational |            | e             |   |                            |
| and      |            | xtrapolation, |   |                            |
| resi     |            | 10x           |   |                            |
| dential) |            | intraspecies  |   |                            |
|          |            | variation,    |   |                            |
|          |            | 10x FQPA)     |   |                            |
+----------+------------+---------------+---+----------------------------+
| Dermal   | NOAEL = 25 | MOE           |   | Subchronic dermal toxicity |
|          | mg/kg/day  | (             |   | in the rat                 |
| (lo      | (HDT)      | occupational) |   |                            |
| ng-term) |            | = 300         |   | No systemic effects        |
|          |            |               |   | identified up to and       |
| (occu    |            | MOE           |   | including the high dose of |
| pational |            | (residential) |   | 25 mg/kg/day               |
| and      |            | =3000 (10x    |   |                            |
| resi     |            | interspecies  |   |                            |
| dential) |            | e             |   |                            |
|          |            | xtrapolation, |   |                            |
|          |            | 10x           |   |                            |
|          |            | intraspecies  |   |                            |
|          |            | variation,    |   |                            |
|          |            | 10x FQPA, 3X  |   |                            |
|          |            | for           |   |                            |
|          |            | subchronic to |   |                            |
|          |            | chronic       |   |                            |
|          |            | duration)     |   |                            |
+----------+------------+---------------+---+----------------------------+
| In       | NOAEL = 50 | MOE           |   | Developmental toxicity     |
| halation | mg/kg/day  | (             |   | study in the rat           |
|          |            | occupational) |   |                            |
| All time |            | = 300         |   | NOAEL of 50 mg/kg/day,     |
| periods  |            |               |   | based on clinical signs,   |
|          |            | MOE           |   | decreased body weight and  |
| (occu    |            | (residential) |   | body weight gain, and      |
| pational |            | = 3000        |   | decreased food consumption |
| and      |            |               |   | in maternal animals at 200 |
| resi     |            | (10x          |   | mg/kg/day                  |
| dential) |            | interspecies  |   |                            |
|          |            | e             |   |                            |
|          |            | xtrapolation, |   |                            |
|          |            | 10x           |   |                            |
|          |            | intraspecies  |   |                            |
|          |            | variation,    |   |                            |
|          |            | 10x route     |   |                            |
|          |            | e             |   |                            |
|          |            | xtrapolation, |   |                            |
|          |            | 3x database   |   |                            |
|          |            | uncertainty)  |   |                            |
+----------+------------+---------------+---+----------------------------+
| Cancer   | No cancer  |               |   |                            |
|          | data       |               |   |                            |
|          | available  |               |   |                            |
|          | for 4-t    |               |   |                            |
|          | amylphenol |               |   |                            |
+----------+------------+---------------+---+----------------------------+

**10.1.3 Toxicity Endpoint Selection Table**