UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

February 29, 2016 

MEMORANDUM 

SUBJECT: Petition No.: IN- I 0777; Salicylaldehyde. Human Health Risk Assessment and 

Ecological Effects Assessment to Support Proposed Exemption from the Requirement of a 

Tolerance When Used as an Inert Ingredient in Pesticide Formulations. 

FROM: 

PC Code: 730944 

Decision No.: /A 

Petition No.: IN-1 0777 

Inert Tracking No.: N/A 

DP Ba rcode: /A 

Regulatory Action: Inert 

Tolerance Exemption; 40 

CFR 180.9 10 

CAS Reg. No.: 90-02-8 

/I " ' ' . G-/ I -- William Cutchin, Chemist f;._LD~- -t- f:{v--

THROUGH: 

Chemistry, lnerts and ToxicologY. Asses ent Branch (CIT AB) 

Registration Division (RD* (750 P) 

Kerry Leifer, Team Leade · Av L 

TO: 

CIT AB/RD (7505P) 

Pv Shah, Branch Chief 

CITAB/RD (7505P) 
EXECUTIVE SUMMARY 

Ag-Chem Consulting LLC, on behalf of Om ex Agritluids, submitted a petition 

requesting , pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a(d), that EPA amend 40 CFR part 180.9IO to establish an 

exemption from the requirement of a tolerance for residu es of salicylaldehyde (2-

hydroxybenzaldehyde; CAS Reg. No. 90-02-8) when used as an inert ingredient 

(penetration aid) in pesticide formulations applied to growing crops or to raw agricultural 

commodities after harvest at a concentration not to exceed I4% by weight of the pesticide 

formulation. 

The acute oral toxicity of salicylaldehyde was examined in male rats and mice. The 

general lethal amount of salicylaldehyde is estimated to be 500mg/kg in mice. The dermal 

LDso for sali cylaldehyde was determined to be greater than 23 g/kg. Dermal irritation 

studies found salicylaldehyde to be irritating, with eschar formation and scarring 14 days 

after administration. 

In a combined repeated dose toxicity study with the reproduction/developmental 

toxicity screening test, toxicity was not observed in parental animals nor in reproductive 

parameters at doses up to I60 mg/kg/day, the highest dose tested. Fetal susceptibility was 

observed. Reduced bodyweight and offspring mortality after 4 days of nursing were 

observed at 160 mg/kg/day. The NOAEL was 40 mg/kg/day. 

Salicylaldehyde was negative for mutageni city in the Ames test and gave a positive 

response in the chromosome aberrations test using Chinese hamster cells (in vitro). An in 

vivo micronucleus assay was negative. Since the in vivo study is more reliable than the in 

vitro assays, the weight of evidence suggests that salicylaldehyde is unlikely to be 

mutagenic. 

There are no cancer studies available for salicylaldehyde. According to a DEREK 

(Nexus) (structural activity relationship) report, there are no structural alerts for 

carcinogenicity. Based on predicted rapid metabolism and excretion, lack of specific target 

organ toxicity in the repeat dose toxicity study, lack of mutagenicity concerns, and lack of 

any structural alerts for carcinogenicity, salicylaldehyde is not expected to be carcinogenic 

to humans at anticipated dietary concentrations. 

The metabolism of salicylaldehyde in rabbits demonstrated that 75% of single dose 

of salicylaldehyde was excreted in the urine as glucuronic acid and sulfate conjugates of 

vanillic acid. 

The FQPA Safety Factor (as required by the Food Quality Protection Act of 1996) is 

intended to provide an additionallO-fold safety factor (I OX), to protect for special sensitivity 

in infants and children. Based on available information, the FQPA safety factor should be 

reduced to IX. 

3 
Occupational handler and post-application exposure may occur by the dermal and 

inhalation routes of exposure only. RD initially assessed handler exposure and risks for 

salicylaldehyde in pesticides at baseline personal protective equipment (PPE; long pants, 

a long- sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory 

protection) which the Agency considers to be the typical minimal worker clothing. 

Typically, the Agency characterizes the risk estimate in relation to the restricted entry 

interval (REI) for a particular active ingredient. While REis for specific products are not 

discussed in this risk assessment, occupational post-application scenarios assessed 

generally result in margins of exposure (MOEs) that do not indicate risks of concern on 

Day 0 (the day of application) except for ten postapplication scenarios. Typically, the 

Agency characterizes the risk estimate in relation to the restricted entry interval (REI) 

for a particular active ingredient. While REis for specific products are not discussed in 

this risk assessment, occupational post-application scenarios assessed result in MOEs 

that do not indicate risks of concern on Day 0 (the day of application). 

Salicylaldehyde has been tested for ecological toxicity. The chemical is readily 

biodegradable and not expected to have adverse ecological effects due to dilution factor 

and biodegradability potential 

Taking into consideration all available information on salicylaldehyde, EPA 

concludes that there is a reasonable certainty that no harm to any population subgroup 

will result from aggregate exposure to salicylaldehyde when considering occupation, 

dietary exposure and all other nonoccupational sources of pesticide exposure for which 

there is reliable information. Therefore, the Agency recommends for the establishment of 

an exemption from tolerance for residues of salicylaldehyde when used as a pesticide 

inert ingredient in pesticide formu lations under 40 CFR §180.910 with the limitation that 

the end-use concentration not to exceed 14%. 

I. BACKGROUND 

Ag-Chem Consulting LLC, 12208 Quinque Lane, Clifton VA 20124 on behalf 

ofOmex Agrifluids, 24730 Avenue 13, Madera CA 93637, submitted a petition 

requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a(d), that EPA amend 40 CFR part 180.910 to establish an 

exemption from the requirement of a tolerance for re si dues of salicylaldehyde (2-

hydroxybenzaldehyde; CAS Reg. No. 90-02-8) when used as an inert ingredient (soil 

penetrant) in pesticide formulations applied to growing crops or raw agricu1tLrral commodities at 

no more than I 4% of the pesticide formulation 

II. INERT INGREDIENT PROFILE 

A. Summary of Uses 

The proposed use of salicylaldehyde is as an inert ingredient in pesticide 

formulations which include use on crops fo r pre- and post-harvest to help the active 

ingredient properly penetrate and remain available to act in the soil at a maximun 

concentration in the pesticide formulation of 14% by weight. 

5 
five guinea pigs tested fo r allergic skin reactions exhibited a positive response (Letter 

from Eastman Kodak Company to USEPA submitting Toxicity and Hazard Summary 

and Toxicity Report on Salicyladehyde with Attachements, I 0/221199 1 ). 

Eye irritation tests were not done, however, based on the severe skin reaction, it is 

assumed that this compound wo uld produce severe eye irritation. 

Metabolism 

A single dose of 400 mg/kg/day salicylaldehyde was administered to a fasted 

rabbit. Approximately 75% of the dose was excreted in the urine collected over 24 hr. 

Urine analysis revealed mainly ether soluble acids, with 27% and 3% accounted for as 

glucuronic acid and sulfate conj ugates of vanillic acid, respectively (The FEMA GRAS 

assessment of hydroxy- and alkoxy-substituted benzyl derivati ves used as fl avor 

ingredients, T.B. Adams eta!., Food and Chemica l Toxicology 43(2005) 1241 127 1) 

A.2. Combined Repeated Dose Toxicity Study with the 

Reproductive/Developmental Toxicity Screening Test 

To perform the repeated dose toxicity and reproductive developmental toxicity 

combined test based on oral administration using salicylaldehyde rats (Crj: CO (SD) type 

SPF), we used dosages of 0 (contrast group), 2.5, I 0, 40, and 160 mg/kg/day to discover 

the general toxicological effects in male and fema le animals due to repeated doses, and 

also to discover the effects on gonadal performance, mating behavior, impregnation, and 

parturition and other reproductive development. 

Repeated Dose Toxicity 

No effects of administration of the tested substance to male rats were fo und in 

general conditions, weight, feed volume, hematological test values, blood chemistry test 

values, autopsy findings, and organ weight. In the tested substance administration groups 

of 40 mg/kg/day or more, the degree of lobular peripheral adiposity in the liver and the 

frequency of appearance was less than in the contrast group. This is not considered to be 

an adverse effect. 

In the test on female rats, aside from one mother in the 40 mg/kg/day 

administration group that was partway through parturition on pregnancy Day 22, and one 

mother in the 160 mg/kg/day administration group that died on pregnancy Day 22, no 

changes were observed in the general condition. In the 160 mg/kg administration group. 

the liver weight showed a high value ( 15.36 ± 1.02 g vs 13-13.6 g), and the ovaries a low 

value ( 4 7 ± 7 mg vs 50-63 mg). However, no effects of administration of the tested 

substance were found in weight, feed volume, and autopsy findings. In the tested 

substance administration groups of 40 mg/kg/day or more, a slight increase in the 

glycogen volume was observed inside liver cells. 

The parental NOAEL was 160 mg/kg/day, the highest dose tested. 

7 
clastogenicity in rat bone marrow cells. 

Chromosome Aberration 

The proliferation suppression concentration exceeding 50% for salicylaldehyde 

CHLIIU cells was 0.020 mg/mL in the continuous process (48 hours), and in the shorttime process (6 hours) under S9 mix existence and non-existence, 0.20 mg/mL for both. 

As a result, the concentrations of 0.020 mg/mL for the continuous process, and 0.20 

mg/mLI for the short-time process, were set as the maximum process concentration for 

this test. One-half and one-fourth concentrations of the ma'<imum process concentration 

were set as the medium concentration and low concentration, respectively. In the 

continuous process group, specimens after 24-hour and 48-hour processing were 

manufactured under S9 mix non-existence, and chromosome analysis performed. In the 

short-time process group, 6-hour processing was performed under S9 mix existence and 

non-existence, followed by 18 hours culturing in a fresh culturing solution to manufacture 

a specimen, and chromosome analysis was performed. 

As a result of 24-hour and 48-hour continuous processing, the CHL/IU cells 

showed a significant increase of cells having chromosome structural aberrations, in the 

24-hour process high-concentration group (0.020 mg/mL), and significance was 

obtained in the trend test as well. In addition, in the 48-hour process high-concentration 

group (0.020 mg/mLI), a significant increase of cultured cells was seen, and a 

significant difference in the trend test was obtained as well. Meanwhile, the groups 

with 6-hour processing under S9 mix existence and non-existence were both dependent 

on the concentration, with a significant increase in cells with structural aberrations. In 

addition, the group under S9 mix existence was dependent on the concentration, with a 

significant increase in polyploidy cells. 

Reverse Mutation 

For the assay bacteria, five bacterial strains were used, including Salmonella 

typhimurium TAIOO, TA1535, TA98, TA1537, and Escherichia coli WP2 uvrA, and a 

dosage setting test was performed for this test using the plate method with S9 mix noadditive and additive conditions. When the dosage setting test was performed at a dosage 

of 50 to 5000 ug/plate, in the S9 mix no-additive, antibiotic action was found at dosages 

of 1500 ug/plate or more (T A 100 at 500 ug/plate or more, and WP2 uvrA at 5000 

ug/plate or more), while in the S9 mix additive, it was found at 1500 ug/plate or more 

(TA 100 at 500 ug/plate or more). In this test, the S9 mix no-additive test was set at 

dosages in a range of 31.3 to I 000 ug/plate (TA 100 at 15.6 to 500 ug/plate, and WP2 

uvrA at 125 to 4000 ug/plate), and the S9 mix additi ve test was set at 62.5 to 2000 

ug/plate (TA 100 at 15.6 to 500 ug/plate, and WP2 uvrA at 125 to 4000 ug/plate), and 

the test was implemented. 

As a result, in both of the two rounds of tests, since no increase was found in the 

revertant colony numbers that were more than double the solvent contrast value in all 

dosages of the fi ve types of assay strain used, we concluded that salicylaldehyde does 

not have any mutagenicity (negative) in the test system used. 

B. Chronic Toxicity 

9 
exposure assessments 

Residual Uncertainty in the Exposure Database 

The dietary risk assessment for salicylaldehyde is based on conservative, highend assumptions and as such the exposure assessment is not likely to underestimate 

actual exposures 

Based on above considerations, the FQPA Safety Factor (SF) has been 

reduced to 1 X. The acute and chronic population-adjusted doses (aPAD and cPAD) 

would be equal to the acute and chronic RtDs, respectively. 

D. Toxicity Endpoint Selection 

No acute toxicological endpoint of concern has been identified for salicylaldehyde. 

On the basis of the repeated dose and reproductive/developmental toxicity 

screening study, a OAEL for offspring toxicity NOAEL for salicylaldehyde was 40 

mg/kg/day. The LOAEL was 160 mg/kg/day based on reduced bodyweight and increase 

mortality in pups at 160 mg/kg/day. The standard 1 OX factors for intra- and inter- species 

were applied. The chronic reference dose (cRtD) is therefore 0.4 mg/kg (40 mg/kg bw/day 

II 00). Since the FQPA SF has been reduced to 1 X, the chronic population adjusted dose 

(cPAD) equals the cRfD. 

The chronic NOAEL is also applicable to the dermal and inhalation exposure routes. 

The acceptable MOE for de1mal and inhalati on exposure routes is 100 or above. 

IV. DIETARY EXPOSURE ASSESSMENT 

In conducting the chronic dietary exposure assessment using the Dietary Exposure 

Evaluation Model DEEM-FCIDTM, Version 3. 18, EPA used food consumption 

information from the U.S. Department of Agriculture's (USDA's) 2003-2008 ational 

Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA). As to residue levels in food, no residue data were submitted for 

salicylaldehyde. In the absence of specific residue data, EPA has developed an approach 

whi ch uses surrogate information to derive upper bound exposure estimates for the 

subj ect inert ingredient. Upper bound exposure estimates are based on the highest 

tolerance for a given commodity from a list of high-use insecticides, herbicides, and 

fungicides. A complete description of the general approach taken to assess inert 

ingredient risks in the absence of residue data is contained in the memorandum entitled 

"Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and 

Drinking Water) Dietary Exposure and Risk Assessments fo r the lnerts: · (D36 1707, S. 

Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number 

EPA-HQ-OPP-2008-0738. 

In the dietary exposure assessment, the Agency assumed that the residue level of 

the inert ingredient would be no higher than the highest tolerance for a given 

commodity. Implicit in this assumption is that there would be similar rates of 

degradation (if any) between the active and inert ingredient and that the concentration of 

II 
population and all population subgroups. The chronic dietary exposure from food and 

water to salicylaldehyde is 13% ofthe cPAD for the U.S. population and also 49% of the 

cPAD for children 1-2 years old, the most highly exposed population subgroup. 

C. Cancer Dietary Exposure and Risk 

The Agency has not identified any concerns fo r carcinogenicity relating to 

salicylaldehyde; therefore, a cancer dietary exposure assessment was not performed. 

Table 4. Dietary Exposure Assessment for Salicylaldehyde 

Population Chronic Exposure 

Su bgro up Acute Exposure Dietary Exposure Total 

from DEEM 

mg/kg/day I %aPAD mg/kg/day %cPAD 

US Pop. NA 0.0530 16 13 

All Infants (< lyr) 0.110440 28 

Children l-2yr 0.197747 49 

Children 3-5yr 0.135978 34 

Children 6-1 2yr 0.0701 55 18 

Youth 13-19yr 0.037743 9.4 

Adult 20-49y r 0.040527 10 

Adult 50-99yr 0.04250 1 II 

Fema le 13-49yr 0.040973 10 

V. RESIDENTIAL EXPOSURE AND RISK ASSESSMENTS 

As with the proposed agricultural uses, there is uncertainty regarding the possibility 

of " residential" use of this inert. The Agency conducted a "screening" level assessment of 

pesticide application activities known to result in high exposures, relatively speaking. The 

" home-owner" pesticide handlers are assumed to wear short-pants, short-sleeved shirts and 

shoes plus socks but no protective gloves. The resulting estimates of risk are considered 

conservative, i. e. protective. The MOEs for residenti al handlers all exceed I 00. 

A. Residential Mixer/Loader/Applicator 

Table 5. Estimated Residential Pesticide Handler (Mixer/Loader/Applicator) Exposure 

and Risk 

Mixer/loader/ Unit Exposure Application Units Body Average Da ily Marg in of 

applicator mg/lb handled Rate lb/gal Treated weight Dose Exposure 

Acres/day kg mglkg/day 

Hose end Dermal 13.4 0.0105 5 gal/day 80 Derm 0.00308 12,927 

Sprayer lnha l. 0.022 Inha l 

0.0000 144 

Pump-up hand- Dermal 63 5 gal/day Derm 0.0144 2.774 

he ld sprayer lnhal 0.0 18 lnha l 0.0000 18 

Backpack Derma l 130 5 gal/day Derm 0.02 98 1.338 

Sprayer In ha l 0. 14 Inha l 0.000092 

Convention Used to Estimate Exposure = 

Unit Exposure * Application rate * Units Treated -:- Body weight 

13 
= 0.00085 lb inert in formulated solution/ day 

For trigger pump spray 

0.13 gallon formulated solution* (8.34 lb/gal) * (5 .0%) = 0.00085 lb inert in formulated 

solution/ day 

B. Residential Post-Application 

Table 7. Summary Recreational and Residential Post-Application Exposures and 

Risks 

Activity 

Exposure (Dose) MOE mg inert/kg/day 

Toddler short-term oral hand to 0.0036 I 1.111 mouth !Tom contacting treated turf 

Toddler oral object to mouth 0.00023 173.913 (turfgrass) 

Adult dermal post applic turf 

contact 

0.0172 2,325 

Toddler dennal post applic turf 0.033 1,2 12 contact 

Adult golfer post app turf contact 0.000119 336, 134 

Child golfer post app turf contact 0.00202 19,801 

0.037 = hand to mouth + object to 

Toddle r combined exposure mouth + turf post-application 1,08 I 

exposure 

MOE = NOAEL .;.. Dose. OAEL = 40 mg inert/kg/day. 

Adult and Adolescent Golfer Post-Application Dermal Exposure may be estimated 

using the convention stated in Science Advisory Council for Exposure draft OP regarding 

·'Golfer Exposure Assessment For Adults and Children·' (24 August 2000). The draft policy 

states that adult and adolescent golfer dermal post-application exposure may be calcul ated 

as DE(t) (mg a.i./kg bw/day) = (TTR(t) ().lg/cm2)) * TC (cm2/hr) * hr/day + (CF ( I 000 

).lg/mg)) * BW (body weight (kg)) Where: 

DE(t) = dermal exposure at time (t) attributable to golfing on previously treated turf (mg 

a.i./kg bw/day). 

TTR(t) = turf transferable residue at time 1 ().lg/cm2

) 

TC = Transfer Coefficient (500 cm2/hr) 

hr = exposure period (4 hours) 

CF = conversion factor to change ).lg to mg. 

BW = body weight (kg) (80 kg for adult; adjusted (multiplied) by a factor of 1.7 for child 

golfers) 

and where TTRt = AR * F * (1-DY * CF2 * CF3 

AR = application rate (lb inert/acre); 0.02 1 lb ai/acre (taken from Table 5 above where 

0.0105 lb is applied to Y2 acre) 

15 
Children's short-term oral hand-to-mouth exposure= 

TTRt *SA* EX* FQ * ET * CF l where: 

PORt = potential dose rate on day ·'t" (mg/kg bw/day) 

TTRt = turf transferable residue on day "t" 2 turf); 0.00056 ~g/cm2 

SA = surface area ofthe hand (cm2/event; palmer surface area of3 fingers = 20 cm2 

EX = extraction factor from the hand by saliva = 50% 

FQ = frequency of hand-to-mouth activity (events/hr); 20 events/hr 

ET = exposure time (hr/day); 2 hrs/day 

CFI = weight unit conversion fac tor to convert in the TTR value to mg for the daily 

exposure (0.00 1 mg/~g). 

0.136 ~g/cm2 * 20 cm2/event * 0.50 %extraction factor * 20 events/hr * 2 hr/day * 0.001 

mg ~g 7 15 kg bw = 0.0036 mg inert/kg/day. 

MOE = OAEL 7 Dose 40 mg inert/kg/day 7 0.0036 mg inert/day = 11 ,111 . 

Children's object-to-mouth (turfgrass) = Grt * IgR * CF1 

PORt = potential dose rate on day "t" (mg/kg bw/day) 

GRt = grass (and plant matter) residue on day "t" ; 0.00056 ~g cm2 

IgR = mouthing rate of grass (cm2/day); 25 cm2/day 

CF I = weight unit conversion fac tor to convert ~g units of residue on the grass to mg for 

the daily exposure (0.001 g/ g). 

0. 136 g/c 2 * 25 cm2/day * 0.00 I g/~g 7 15 kg bw = 0.00023 mg inert/kg/day 

MOE = NOAEL 7 Dose and 40 mg inert/kg/day 7 0.00023 mg inert/kg/day = 173,9 13. 

VI. AGGREGATE RISK AND DETERMINATION OF SAFETY 

A. Acute Risk 

There was no hazard attributable to a single exposure seen the in the toxicity 

database for salicylaldehyde; therefore, an acute aggregate risk assessment is not 

required. 

A. Chronic Risk. 

Using the exposure assumptions described in Section III for chronic dietary 

exposure, EPA has concluded that chronic exposure to salicylaldehyde from food and 

water is conservatively estimated to utilize 49% of the cPAD for children l-2 yrs old, the 

population group receiving the greatest exposure. Chroni c residential exposure to residues 

of salicylaldehyde not expected. 

B. Short- and Intermediate-term Risk 

17 
durations. Active ingredient application rates were corrected for the maximum amount of 

the inert ingredient likely to be in the fi nal formulations to determine exposure and risk 

from exposure salicylaldehyde. A summary of the occupational assessment is presented 

below. 

A. Handler Risk 

Exposure Scenarios 

Exposure to pesticide handlers is likely during the occupational use of pesticides 

containing salicylaldehyde as an inert ingredient. Dermal and inhalation exposure was 

estimated using the Pestic ide Handlers Exposure Database (PHED) and Outdoor 

Residential Exposure Task Force (ORETF) data. The quantitati ve exposure/risk 

assessment developed for occupational handlers to support the requested tolerance 

exemption for salicylaldehyde is based on the following scenarios. RD notes that these 

scenarios were selected to represent the scenari os with the highest potential exposure. 

The scenarios are summarized in Table 6 below. Assessments are conducted using 

standard operating procedure developed by the Health Effects Division, Office of 

Pesticide Programs. The metric used to calculate exposure and risk is: 

Unit Exposure * 

mg inert/lb handled 

Application Rate * Units Treated/day + Body weight 

lb inert/unit Acres etc 80 kg 

Risk estimates were calculated using the Margin of Exposure (MOE) which is a ratio 

of the toxicological POD (mg/kg/day) to the daily dose (mg/kg/day). 

The point of departure is 40 mg/kg/day. Dermal and inhalation absorption are 

assumed to be I 00%. Short-term exposures ( 1-30 days) were estimated. For these uses. 

intermediate-term exposures ( 1-6 months) are not expected and are typically lower thus are 

not presented. The Agency assumes occupationally exposed individuals wear protective 

gloves. To assess handler risks, the Agency used surrogate unit exposure data from the 

PHED, and ORETF data. 

Risk Characterization: 

Table 9. Exposure and Risks for Occupational Handlers of Salicylaldehyde in Pesticide Products (All 

Exposure Durations) with Baseline Plus Gloves for High Acreage Mixer/ Loader Scenarios and Turf 

Area Dermal Inhalation Baseline+ Baseline Baseline Baseline Total 

Exposure Scenario Appl. Ratc1 Treated Unit Unit Gloves Inhalation + Gloves Inhalation MOE8 

(Formulation! (lb inen/ Daily2 Exposure Exposure Dennal Dose Dcm1al MOE7 

Application/ Crop) A) (acres) (mgllb (ugllb Dose (mg/kgl Mor:6 

inen)3 inert)3 (mg!ko day)5 

/day)4' 

Mixer/Loader Scenarios 

Liquids/ Aerial 

1.456 0.57408 0.029952 70 1300 66 Application/ l ligh ' ,.., ICTI 1200 0.023 1.2 

Liquids/ Aerial 

0.28 0. 11 04 0.00576 360 6900 340 Application/ lligh .. . ,.., ,,,., Liquids/ 1.456 200 0.09568 0.004992 420 8000 400 r.rnu nrlh"""'' II' o h 

19 
• Tall field/row crops (including scouting, weeding, hand harvesting sweet corn) 

• Turf (golf course/sod farm) (including mowing, transplanting, hand weeding) 

• Vine/Trellis crops (including scouting, training, tying, thinning, and grape girding 

and cane turning) 

Exposure Data and Assumptions are listed in the foot notes of Table 8.0 below which are 

standard operating procedure and developed by the Health Effects Division, Office of 

Pesticides Programs .. 

• Calculations of postapplication exposures are completed using maximum 

application rates of pesticide products for short-term exposures and average 

application rates of pesticide products for intermediate-term exposures. 

• No postapplication data were submitted for salicylaldehyde; a default 50% of 

the application rate (for agricultural crops) and 10% (for turf) is considered 

available as a transferrable residue with a l 0% default daily dissipation rate. 

• Dermal absorption is assumed to be 100%. 

Risks were calculated using the MOE approach, which is a ratio of the exposure to 

the toxicological PoD. 

Risk Characterization 

A variety of pesticide formulations may contain salicylaldehyde. PPE is usually 

not required for worker re-entry, and therefore these postapplication risk estimates are 

based on the baseline exposure scenario (i.e., typical work clothing but no gloves). 

Typically, the Agency characterizes the risk estimate in relation to the restricted entry 

interval (REI) for a particular active ingredient. While REis for specific products are not 

discussed in this risk assessment, occupational post-application scenarios assessed 

generally result in MOEs that do not indicate risks of concern on Day 0 (the day of 

application) except for ten postapplication scenarios. The results are summarized in Table 

8.0. 

l) The short-term worker postapplication activities involving herbicides on corn, 

specifically the hand-harvesting harvesting/ detassling scenario. That scenario resulted in 

a short-term MOE of 7 on the day of application (Day 0). Assuming an herbicide 

application at the maximum application rate, the short-term MOE would exceed 100 for 

this scenario at day 25 after application. The Agency notes that it is not expected to be 

typical agricultural practice to apply herbicides on the same day workers would be 

conducting hand harvesting and detassling activities. As noted earlier in this assessment, 

herbicides are typically applied relatively early in a growing season. 

2) The short-term worker postapplication activities involving herbicides on grape, 

table, specifically the harvest, pull, thin, prune, train, tie scenario. That scenario resulted 

in a short-term MOE of 53 on the day of application (Day 0). For the short-term, 

assw11ing an herbicide application at the maximum application rate, the MOE would 

exceed 100 for this scenario at day 6 after application. The Agency notes that it is not 

expected to be typical agricultural practice to apply herbicides on the same day workers 

would be conducting harvest, pull, thin, prune, train, tie activities. As noted earlier in this 

assessment, herbicides are typically applied relatively early in a growing season. 

21 
typical agricultural practice to apply fungicides on the same day workers would be 

conducting hand harvesting and detassling activities. As noted earli er in this assessment, 

fungicides are typically applied relatively early in a growing season. 

9) The short-term worker postapplication activities involvi ng fungicides on grape, 

table, specifica ll y the cane turning, girdling scenario. That scenario resulted in a shortterm MOE of 64 on the day of application (Day 0). For the short-term, assuming a 

fungicide application at the maximum application rate, the MOE would exceed I 00 for 

this scenari o at day 4 after application. The Agency notes that it is not expected to be 

typical agricultural practice to apply fungicides on the same day workers would be 

conducting hand cane turning, girdling activities. 

I 0) The short-term worker postapplication activities involving fungicides on turf, 

specifically the transplant, weed, harvest scenario. That scenario resulted in an MOE of 

94 on the day of application (Day 0). Assuming a fungicide application at the maximum 

application rate, the MOE wo uld exceed I 00 fo r this scenario at day I after application. 

The Agency notes that it is not expected to be typical agricultural practice to apply 

fungicides on the same day workers would be conducting transplant, weed, harvest 

activities. As noted earlier in this assessment, insecticides are typically applied relatively 

early in a growing season. 

All other insecticide postapplication scenarios result in MOEs that do not 

demonstrate risks of concern on the day of application (Day 0). 

A variety of pesticide formulations may contain salicylaldehyde. PPE is usually 

not required for worker re-entry, and therefore these postapplication risk estimates are 

based on the baseline exposure scenario (i.e., typical work clothing but no gloves). 

Typicall y, the Agency characterizes the risk estimate in relation to the restricted entry 

interval (REI) for a particular active ingredient. While REis for specific products are not 

discussed in this risk assessment, occupational post-application scenarios assessed result 

in MOEs that do not indicate risks of concern on Day 0 (the day of application). 

Table 10. Short-Term Occupational Postapplication Dermal Exposures and Risks for 

Salicylaldehyde 

Crop & Application Transfer Day after DFR, Daily Dose Exposure Ra te Wo rk Activity Coefficient 1 

Treatment2 (1-1g/cm2

)

3 day)~ MOE5 

Du ration (lb ine rt /A) (cm2/hr) 

Herbicide Product Scenarios 

Scout, weed 100 0 0.0327 1200 low foliage 

Scout, weed 400 0 0. 1306 3 10 

Corn high foliage 

(ST) 1.456 Scout, irrigate, 3.27 

weed high 1,000 0 0.3265 120 

fo liage 

Harvesting/ 17.000 0 5.55 13 7 detassling 

Hedge, irrigate, 

weed, scout, 500 0 0.0754 530 

train, tie 

Scout, train, tie 1,000 0 0. 1507 270 

23 
Table 10. Short-Term Occupational Postapplication Dermal Exposures and Risks for 

Salicylaldehyde 

Crop& Application Transfer Day after DFR, Exposure Rate Work Activity Coefficient' Trea tment1 (llg/cm1)J Duration (lb ine rt /A) (cm1/hr) 

Mowing 500 0 Turf/ sod 0.28 0.628 (ST) Transplant, 6,800 0 weed, harvest* 

1 . The rc from th1 s exposure scenano uses /\RTF data - study /\RF-035 (MRID 45432303) . 2 Day after Treatment set to 0 by default 

Daily Dose 

(mg ay)~ 

0.03 14 

0.4270 

3 Dislodgable Foliar Residue (Jlg/cm2) = AR * F * ( 1-0)' • CF I • CF2. Where: AR = Application Rate (lb 

inert/acre), F = fraction of ai retained on fo liage or 20% for foliar crop or 5% for turf (unitless), 0 = 

fraction of residue that dissipates daily or I 0% (unitless). t = number of days after application day (days), 

CF I = 4.54 x I 08 Jlg/lb, CF2 = 24.7 x I o-9 acre/cm2 

4 Daily Dermal Dose (mglkg/day) = DFR, * CF3 * Tc * DA * ET/BW (kg). Where: DFRt = dislodgable 

fo liar residue on day "t" (Jlg/cm2) , CF3 = I x I o3 mg/f..!g, Tc = transfer coefficient (cm2/hr), DA = dermal 

absorption factor 100% (unitless) defau lt with no data submitted, ET = exposure time 8 (hr/day), BW = 

body weight 80 (kg) (HED Hot Sheet 

#3 1, 1/ 17/ 12) 5 Margin of Exposure: MOE = POD (40 mglkg/day) I DOD (mglkg/day). MOE (unitless), POD = Point of 

Departure usually NOAEL = No Observed Adverse Effect Level: Dose level in a toxicity study. DOD = 

Dermal Daily Dose: the absorbed dose received from exposure to a pesticide in a given scenario. 

VIII. CUMULATIVE EXPSOURE 

Cumulative effectsfrom substances with a common mechanism of toxicity. Section 

408(b)(2)(D)(v) ofFFDCA requires that, when considering whether to establish, modify, 

or revoke a tolerance, the Agency consider "available information" concerning the 

cumulative effects of a particular pesticide's residues and "other substances that have a 

common mechanism oftoxicity." 

EPA has not found salicylaldehyde to share a common mechanism of toxicity 

with any other substances, and that salicylaldehyde does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has assumed that salicylaldehyde does not have a common mechanism of 

toxicity with other substances. For information regarding EPA's efforts to determine 

which chemicals have a common mechanism of toxicity and to evaluate the cumulative 

effects of such chemi cals, see EPA's website at 

http://www. epa.govlpesticides/cumulat ive. 

IX. ENVIRONMENTAL J USTICE STATEMENT 

Potential areas of environmental justice concerns, to the extent possible, were 

considered in this human health risk assessment, in accordance with U.S. Executive Order 

12898, "Federal Actions to Address Environmental Justice in Minority Populations and 

Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo 12898.pdf. 

As a part of every pesticide risk assessment, OPP considers a large variety of 

consumer subgroups according to well-established procedures. In line with OPP poli cy, 

RD estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup's food and water consumption, and activities in and around the 

25 

MOE5 

1300 

94 
XII. RISK CHARACTERIZATION 

Ag-Chem Consulting LLC, on behalf of Omex Agrifluids is proposing to amend 

40 CFR part 180.910 to establish an exemption from the requirement of a tolerance for 

salicylaldehyde (CAS# 90-02-8) in or on food crops at no more than 14% of the pesticide 

formulation to help the active ingredient properly penetrate and remain available to act in 

the soil. 

No adverse effects attributable to a single exposure to salicylaldehyde were seen 

in the toxicity databases; therefore, an acute dietary risk assessment is not a concern. A 

chronic dietary risk assessment takes into account exposure estimates from chronic 

dietary consumption of food and drinking water. Model estimates for oral exposure from 

the use of salicylaldehyde in pesticidal formulations (including exposure through 

drinking water) resulted in chronic dietary exposure estimates fo r food and drinking 

water below the Agency's level of concern (< 100% cPAD) for the US population and all 

population subgroups. The chronic dietary exposure from food and water to 

salicylaldehyde is 13% of the cPAD for the U.S. population and also 49% of the cPAD for 

children 1-2 years old, the most highly exposed population subgroup. The Agency has not 

identified any concerns for carcinogeni city relating to salicylaldehyde; therefore, a cancer 

dietary exposure assessment was not performed. These assessments are conservative in 

nature and will not underestimate the potential dietary risks to salicylaldehyde 

The term " residential exposure" is used in this document to refer to nonoccupational, non- dietary exposure (e.g., for lawn and garden pest control, indoor pest 

control, termiticides, and flea and tick control on pets). While there are no current or 

proposed residential uses for salicylaldehyde, it is possible that salicylaldehyde may be 

used as an inert ingredient in pesticide products for which short-term and intermediateterm residential exposures may result. In the absence of specific residential exposure 

scenarios, risk estimates for residential exposures to salicylaldehyde can be modeled 

based on occupational exposure assessments for salicylaldehyde. Occupational exposure 

assessments for salicylaldehyde for occupational mixer/loader/applicator exposure and 

occupational post-application exposure for comparable use scenarios (e.g., low pressure 

handwand turf application) with only baseline personal protective equipment result in 

MOEs of 500 or greater (i.e., exposures are not of concern). Given the larger treatment 

areas and higher concentrations of salicylaldehyde used in these occupational use 

pesti cide products than would be seen in residential uses, MOEs for residential use 

scenarios would exceed I ,000 or more and therefore there are no concerns for residential 

exposures to salicylaldehyde. 

Short- and intermediate term aggregate exposure takes into account short-term 

residential exposure plus chronic exposure through food and drinking water (considered 

to be a background exposure level). Since it is possible that salicylaldehyde may be used 

as an inert ingredient in pesticide products for which short-term and intermediate-term 

residential exposures may result, the Agency has determined that it is appropriate to 

aggregate chronic exposure through food and water with short-term residential 

exposures to salicylaldehyde. Using the exposure assumptions described in this unit for 

short-term exposures, EPA has concluded the combined short-term food, water, and 

residential exposures result in aggregate MOEs of 430 for adults and 170 for children (1-

27 
application. The Agency notes that it is not expected to be typical agricultural practice to 

apply herbicides on the same day workers would be conducting hand cane turning, 

girdling activities. · 

4) The short-term worker postapplication activities involving herbicides on turf, 

specifically the transplant, weed, harvest scenario. That scenario resulted in an MOE of 

72 on the day of application (Day 0). Assuming an herbicide application at the maximum 

application rate, the MOE would exceed I 00 for this scenario at day 3 after application. 

The Agency notes that it is not expected to be typical agricultural practice to apply 

herbicides on the same day workers would be conducting transplant, weed, harvest 

activities. As noted earlier in this assessment, herbicides are typically applied relatively 

early in a growing season. 

5) The short-term worker postapplication activities involving insecticides on 

corn, specifically the hand-harvesting harvesting/ detassling scenario. That scenario 

resulted in an MOE of 20 on the day of application (Day 0). Assuming an insecticide 

application at the maximum application rate, the MOE would exceed 100 for this 

scenario at day 16 after application. The Agency notes that it is not expected to be 

typical agricultural practice to apply insecticides on the same day workers would be 

conducting hand harvesting and detassling activities. As noted earlier in this assessment, 

insecticides are typically applied relatively early in a growing season. 

6) The short- term worker postapplication activities involving insecticides on 

grape, table, specifically the cane turning, girdling scenario. That scenario resulted in a 

short-term MOE of 37 on the day of application (Day 0). For the short-term, assuming 

an insecticide application at the maximum application rate, the MOE would exceed 100 

for this scenario at day 1 0 after application. The Agency notes that it is not expected to 

be typical agricultural practice to apply insecticides on the same day workers would be 

conducting hand cane turning, girdling activities. 

7) The short-term worker postapplication activities involving insecticides on turf, 

specifically the transplant, weed, harvest scenario. That scenario resulted in an MOE of 

4 7 on the day of application (Day 0). Assuming an insecticide application at the 

maximum application rate, the MOE would exceed I 00 for this scenario at day 6 after 

application. The Agency notes that it is not expected to be typical agricultural practice to 

apply insecticides on the same day workers would be conducting transplant, weed, 

harvest activities. As noted earlier in this assessment, insecticides are typically applied 

relatively early in a growing season. 

8) The shm1-term worker postapplication activities involving fungicides on corn, 

specifically the hand-harvesting harvesting/ detassling scenario. That scenario resulted in 

a short- term MOE of 3 7 on the day of application (Day 0). Assuming a fungicide 

application at the maximum application rate, the short-term MOE would exceed I 00 for 

this scenario at day 9 after application. The Agency notes that it is not expected to be 

typical agricultural practice to apply fungicides on the same day workers would be 

conducting hand harvesting and detassling activities. As noted earlier in this assessment, 

fungicides are typically applied relatively early in a growing season. 

9) The short-term wo rker postapplication activities involving fungicides on grape, 

29 
Appendix 1. Dietary Exposure Assessment 

EPA Ver. 3.16, 03-08-d 

DEEM-FCID Chronic analysis for INERTS- SALICYLALDEHYDE NHANES 2003-2008 2-day 

Residue file name: J: \ IN-10777\ INERTS 57ACTIVE_ 100PPBH20REV.R08 

Adjustment factor #2 used. 

Analysis Date 10 - 09-2015/ 13:54:20 Residue file dated: 10-09 - 2015 / 13:53:41 

Reference dose (RfD, Chronic) = . 4 mg / kg bw/ day 

COMMENT 1: Inert 57 active ingredients +drinking water (100ppb) 

=============================================================================== 

Population 

Subgroup 

Total US Populati on 

Hispanic 

Non-Hisp-White 

Non-Hisp-Black 

Non-Hisp-Other 

Nursing Infants 

Non-Nursing Infants 

Female 13 + PREG 

Children 1-6 

Children 7-12 

Male 13-19 

Female 13-19/ NP 

Male 20+ 

Female 20+/ NP 

Seniors 55+ 

All Infants 

Female 13-50 

Children 1 - 2 

Children 3-5 

Children 6-12 

Youth 13-19 

Adults 20-49 

Adul ts 50-99 

Female 13-49 

Total exposure by population subgroup 

Total Exposure 

mg/ kg Percent of 

body wt/ day Rfd 

------------- ---------------- 0.053016 13.3% 

0.057893 14.5%-

0 . 052024 13.0%-

0.049266 12.3% 

0 . 062540 15.6%-

0.069497 17.4%-

0. 128725 32.2%-

0.046267 11.6%-

0.153068 38.3% 

0.063675 15. 9%-

0.037453 9.4%-

0.038061 9.5%-

0. 039479 9.9%-

0.042885 10.7%-

0.042752 10.7%-

0.110440 27 . 6%-

0.040993 10.2%-

0.197747 49.4\ 

0 . 135978 34.0%-

0.070155 17.5%-

0.037743 9.4%-

0.040527 10.1%-

0.042501 10.6%-

0.040973 10.2%-

31 
Submitted Compound - Structure 

Average Mol Mass 

122.12 

Predictions 

0 

Smiles: C1 = CC=CC( =C1C( =O)[H])O 

Exact Mol Mass 

122.0368 

Log Kp 

-2.18 

Knowledge Base: Derek KB 2014 1.0 

Certified by 

Log P 

1.81 

Version 

1.0 

Last Modified Date 

23/ 01/2014 07:14:42 Lhasa Limited, Leeds, Yorkshire, UK 

Reasoning Summary 

+ Cardiotoxicity in mammal is EQUIVOCAL 

• Alert matched: RapidPrototype167 Substituted benzaldehyde 

+ Hepatotoxicity in mammal is EQUIVOCAL 

• Alert matched: RapidPrototype019 Aromatic aldehyde 

+ Mutagenicity in vitro in bacterium is INACTIVE 

• No misclassified or unclassified features 

+ Skin sensitisation in mammal is PLAUSIBLE 

• Alert matched: 439 Substituted phenol or precursor 

Endpoints not firing any alerts at the selected reasoning level (53) 

Adrenal gland toxicity 

alpha-2-mu-Giobulin nephropathy 

Anaphylaxis 

33 

Mitochondria I dysfunction 

Mutagenicity in vivo 

Nephrotoxicity 
Alert Descriptions 

CD Alert: 439 Substituted phenol or precursor 

(from KB: Derek KB 2014 1.0) 

Alert Description Image 

R2 R3 

R1-<l* R4 

H R5 

R1 =H. CH3 

R2·R5 =ant. except n,drox)l ethers. arnnes. suphonJC aod. sul!1lol'lc esters 

carbox)liC aoos acyl halides. add anh)drides. ttlioesters. esters 

and their alpha beta-l.llsaturated den1atrYes 

In addtJon R2-R5 camot alll:le h) drooen or a!K)I groups up ~ carbons 

idrO JCy Quno~~s and phena are excllded 

Comments 

Match with query compounc 

0 

The activity of phenols has been demonstrated in various skin sensitisation 

assays including the guinea pig maximisation test [Cronin and Basketter, Goh] 

and the human maximisation test [Opdyke]. Phenol itself is corrosive but not a 

sensitiser [Itoh, Basketter et al 1999a]. 

Oestradiol-type steroidal structures lacking substitution on, and carbon double 

bond conjugation of, the A ring are excluded from the alert on the following 

basis : 

1. Limited proprietary data provided by Bayer Schering Pharma AG indicate no 

evidence of skin sensitisation potential for compounds of this type in animal 

experiments. 

2. Oestradiol itself is in w ide-spread human use in transdermally administered 

hormone replacement therapy. Although isolated case reports have described 

allergic contact dermatitis to oestradiol (or in some cases are suggestive of it) 

following use of hormone replacement therapy [Boehncke and Gall, Carmichael 

and Foulds, Goncalo et al, Quirce et al], clinical trial data indicate that in general 

dermal exposure to oestradiol under such conditions has no sensitising potential 

[Rozenbaum et al] . 

3. For simple phenols, skin sensitisation is thoug ht to arise as a result of 

formation of a phenolic radical which subsequently reacts with skin proteins, 

primarily at positions ortho to the phenol group [Barratt and Basketter]. QSAR 

studies have shown that for other toxic pathways also involving phenolic radical 

formation, the activity of oestrogens such as oestradiol appears to be 

adequately modelled by approximating the structure to a dialkyl-substituted 

phenol [Zhang et al]. In thi s respect, it is therefore worthy of note that si mple 

alkyl phenols (such as 4-tert-butylanisole [Cronin and Basketter], 1,1,3-tri-[2-

35 
• Carmichael AJ and Foulds IS. (1992) 

Allergic contact dermatitis from oestradiol in oestrogen patches., Contact 

Dermatitis, 26, 194-195 

DO!: 10.1111/j.1600-0536.1992.tb00293.x 

• Goncalo M, Oliveira HS, Monteiro C, Clerins I and Figueiredo A. ( 1999) 

Allergic and systemic contact dermatitis from estradiol., Contact Dermatitis, 40 , 

58-59 

DOl: 10.1111/j. 1600-0536.1999.tb05989.x 

• Quirce S, Garde A, Baz G, Gonza lez P and Alonso Diaz de Durana MD. (1996) 

Allergic contact dermatitis from estradiol in a transdermal therapeutic system. , 

Allergy, 51 , 62-63 

DOl: 10.1111/j.1398-9995.1996.tb00014.x 

Rozenbaum H, Birkhauser M, De Nooyer C, Lambotte R, Pornel B, Schneider H, 

Studd J and Thebault J. (1996) 

Comparison of two estradiol transdermal systems (Oesclim 50 and Estraderm 

TTS 50). II. Local ski n tolerability., Maturitas, 25, 175-185 

DOl: 10.1016/S0378-5122(96)01074-2 

• Zhang L, Gao H, Hansch C and Selassie CD. (1998) 

Molecular orbital parameters and comparative QSAR in the analysis of phenol 

toxicity to leukemia cells., Journal of the Chemical Society: Perkin Transactions 

II, I 2553-2556 

DOl: 10.1039/a801684d 

• Zimerson E, Bruze M and Goossens A. (1999) 

Simultaneous p-tert-butylphenol-formaldehyde resin and p-tert-butylcatechol 

contact allergies in man and sensitizing capacities of p-tert-butylphenol and ptert-butylcatechol in guinea pigs., Journal of Occupational and Environmental 

Medicine, 41 , 23-28 

DOl: 10.1097/00043764-199901000-00005 

• Basketter DA, Flyvholm MA and Menne T. (1999) 

Classification criteria for skin-sensitizing chemicals : a commentary., Contact 

Dermatitis, 40, 175-182 

DOl: 10.1111/j.1600-0536.1999.tb06029.x 

• Basketter DA, Lea U , Cooper K, Stocks J, Dickens A, Pate I, Dearman RJ and Kimber 

I. (1999) 

Threshold for classification as a skin sensitizer in the local lymph node assay: a 

statistical evaluation., Food and Chemical Toxicology, 37, 1167-1174 

DOl: 10.1016/S0278-6915(99)00112-X 

• Opdyke DU. (1979) 

Fragrance raw materials monographs: alpha-methylanisalacetone., Food and 

Cosmetics Toxicology, 17 , 863 

DOl: 10.1016/SOOlS-6264(79)80072-3 

• Andersen A. (2006) 

Final amended report on the safety assessment of oxyquinoline and 

oxyquinoline sulfate as used in cosmetics., International Journal of Toxicology, 

25 (supplement 1) , 1-9 

DOl: 10.1080/10915810600716570 

• Yamano T, Ichihara M, Shimizu M, Noda T and Tsujimoto Y. (2007) 

Immunomodulatory effects of mono-, di-, and trimethylphenols in mice., 

Toxicology, 232, 132-137 

DOl: 10.1016/j.tox.2006.12.021 

• Fiedler H, Novak M and Schwank R. (1971) 

Investigations on group sensitization to new hydroxychinoline derivatives 

(German)., Dermatologica, 143 , 298-304 

DOl: 10.1159/000252221 

37 
- Mammalian skin sensitisation predictions in Derek associated with a reasoning 

level of equivocal or above have been considered positive; 

- Predictions do not take into account (i) the tautomeric forms of compounds or 

(ii) the individual components of mixtures; 

- Compounds have been considered positive for skin sensitisation if they have 

been classified as extreme, strong or moderate sensitisers; 

- Compounds classified as weak sensitisers have been excluded from the 

analysis; 

- No account has been taken of other skin sensitisation alerts which may also be 

present in some compounds; 

- Informat ion from the data sets may have been used previously as supporting 

evidence for the derivation of some alerts; 

-Some compounds may be present in more than one of the data sets analysed. 

@ Examples for Alert 439 Substituted phenol or precursor 

Example 1: 4-styryl-phenol 

0 

CAS Number: 3839-46-1 

39 
1) 

1) 

Test Data ( 4-allyl-anisole) 

Species 

guinea pig 

References 

Assay 

maxi misation test 

• Cronin MTD and Basketter DA. { 1994) 

Endpoint(s) 

Skin sensitisation 

Result 

moderate 

Multivariate QSAR analysis of a skin sensitization database., SAR and QSAR in 

Environmental Research, 2 , 159-179 

DOl: 10.1080/10629369408029901 

Example 4: phenol 

CAS Number: 108-95-2 

Test Data (phenol) 

Species 

mouse 

References 

Assay 

local lymph node assay 

Endpoint(s) 

Skin sensitisation 

Result 

negative 

• Basketter DA, Lea U, Cooper K, Stocks J, Dickens A, Pate I, Dearman RJ and Kimber 

I. {1999) 

Threshold for classification as a skin sensitizer in the local lymph node assay: a 

statistical evaluation., Food and Chemical Toxicology, 37, 1167-1174 

DOl: 10.1016/50278-6915{99)00112-X 

Example 5: alpha-methylanisalacetone 

:J 

/ 

CAS Number: 104-27-8 

41 
Q) Alert: RapidPrototype167 Substituted 

6enzaldehyde (from KB: Derek KB 2014 1.0) 

Alert Description Image 

F 

F· 

F 

Rl -RS = H, OH, "'OC (alky l) 

At least one of Rl -RS must be OH or OC (al kyl) 

Comments 

This alert describes the cardiotoxicity of substituted benzaldehydes. This is a 

rapid prototype alert derived using a proprietary data set of 1515 chemicals, 

classified on the basis of the presence or absence of histopathologic lesions in 

the heart in oral rat repeat dose studies mostly of 28-days duration. Two 

chemicals in this data set activated this rapid prototype alert and both of these 

were toxic to the heart. 

Reasoning Details 

Cardiotoxicity in mammal is EQUIVOCAL (from KB: 

Derek KB 2014 1.0) 

The parameters that have influenced your prediction are: substructures in the input 

structure, which have a potential for cardiotoxicity, your selected species which is 

mammal. 

Rule 266: If [species mammal] is [certain] then [Species dependent variable 

8] is [equivocal] 

• species mammal is CERTAIN 

In mammals the variable "Species dependent variable 8" is equivocal. 

43 
0 

H 

Details 

The query structure does not match any structural alerts or examples for (bacterial in 

vitro) mutagenicity in Derek. Additionally, the query structure does not contain any 

unclassified or misclassified features and is consequently predicted to be inactive in the 

bacterial in vitro (Ames) mutagenicity test. 

Skin sensitisation in mammal is PLAUSIBLE (from KB: 

Derek KB 2014 1.0) 

The parameters that have influenced your prediction are : substructures in the input 

structure, which have a potential for skin sensitisation, your selected species which is 

mammal. 

Rule 243: If [species mammal] is [certain] then [Species dependent variable 

22] is [plausible] 

• species mammal is CERTAIN 

In mammals the variable "Species dependent variable 22" is plausible. 

Rule 914: If [alert 439] is [certain] then [Skin sensitisation] is [Species 

dependent variable 22] 

• alert 439 is CERTAIN 

• Species dependent variable 22 is PLAUSIBLE 

If a chemical contains alert 439 then it is considered plausible that the chemical wil l 

cause skin sensitisation in mammals and impossible in bacteria. The variation in rule 

outcome with species is achieved via use of the variable "Species dependent variable 

22". 

45