p-18-0320 hlth risk assessment final 05-13-20

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P‐18‐0320Chemical Name: CASRN:

Human Health Report Status: DATE COMPLETED

HAZARD DRAFT ‐ Pending Review 10‐05‐2018

HAZARD REVIEWED 11‐06‐2018

RISK DRAFT ‐ Pending review 11‐05‐2018

RISK QC 11‐07‐2018

RISK REVIEWED

RISK FINAL ‐ Uploaded 11‐07‐2018

UPDATE DRAFT ‐ Pending review 05‐11‐2020

UPDATE REVIEWED

UPDATE FINAL ‐ Uploaded 05‐12‐2020

dbrown

Typewritten Text

6/10/2020 DSB

asullivan

Typewritten Text

Verified by AMS 6/16/2020

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1 HUMANHEALTHSUMMARY

1.1 HazardSummaryEPA estimated the human health hazard of this chemical substance based on its estimated physical/chemical properties, available data on the new chemical substance, by comparing it to structurally analogous chemical substances for which there is information on human health hazard, and other structural information. Absorption is poor via all routes based on physical/chemical properties. For the new chemical substance, EPA identified hazards for skin, eye, and respiratory tract irritation, skin and respiratory sensitization, and lung effects based on data on the new chemical substance. The new chemical substance is expected to hydrolyze rapidly in water; however, no hazards were identified for the oral route of exposure for an analogue of the hydrolysis product up to 500 mg/kg‐bw/day. EPA identified a NOAEC of 2.1 mg/m3 based on lung effects, which was used to derive exposure route‐ and population‐specific points of departure for quantitative risk assessment. EPA qualitatively evaluated irritation and sensitization effects.

1.2 ExposureandRiskCharacterizationFor this assessment, EPA assessed worker exposures via the dermal and inhalation routes. Releases to water, air, and landfill were estimated. Exposures to the general population were assessed via drinking water, groundwater ingestion impacted by landfill leaching, fish ingestion, and fugitive air. Exposure to the general population via stack air inhalation was not assessed because releases to air were expected to be negligible (below modeling thresholds).Consumer exposures were not assessed because consumer uses were not identified as conditions of use. Risks to human health for the new chemical substance were evaluated using a route‐specific effect level (i.e., NOAEC). Based on the hazard determination and available quantitative and qualitative risk information, EPA concludes that there is risk for the new chemical substance.

1.2.1 WorkersRisks were identified for workers for lung effects via inhalation exposure based on quantitative hazard data for the new chemical substance (MOE = 2; Benchmark MOE = 100; Fold factor = 48). Irritation and sensitization hazards to workers via inhalation and dermal contact were identified based on data on the new chemical substance. Risks for these endpoints were not quantified due to a lack of dose‐response for these hazards. However, exposures can be mitigated by the use of appropriate personal protective equipment (PPE), including impervious gloves, eye protection, and respiratory protection. EPA expects that employers will require and that workers will use appropriate PPE consistent with the Safety Data Sheet (SDS) prepared by the submitter, in a manner adequate to protect them.

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1.2.2 GeneralPopulationRisks were not identified for the general population for lung effects via inhalation exposure based on quantitative hazard data for the new chemical substance (MOE = 393; Benchmark MOE = 100). No hazards were identified for a hydrolysis product of the new chemical subtance; therefore, risks were not calculated. Based on no identified hazards, risks are not expected via drinking water, groundwater ingestion impacted by landfill leaching, and fish ingestion. Irritation and sensitization hazards to the general population are not expected via drinking

water ingestion or fugitive air releases due to dilution of the chemical substance in the media.

1.2.3 ConsumersRisks to consumers were not evaluated because consumer uses were not identified as conditions of use.

1.3 AssumptionsandUncertainties Absorption of the new chemical substance is based on physical/chemical properties.

Health effects for the hydrolysis product were based on analogue data.

1.4 PotentiallyUsefulInformationNone.

1.5 HazardLanguageSkin Irritation, Serious Eye Damage, Respiratory Sensitization, Skin Sensitization, Specific Target

Organ Toxicity

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2 HUMANHEALTHHAZARD

2.1 ChemistrySummary

2.2 HazardSummary

2.2.1 AbsorptionAbsorption is poor via all routes based on physical/chemical properties.

2.2.2 StructuralAlertsIsocyanates

2.2.3 HumanHealthCategory(FromUSEPA2010document)Chemical Category: Diisocyanates Chemical Category Health Concerns: Skin and respiratory sensitization; lung toxicity Category Testing Strategy: Skin sensitization, 90‐day subchronic inhalation test

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2.2.4 OECDQSARToolbox

US EPA New Chemical Category Diisocyanates

Respiratory sensitization alert Acylation >>isocyanates and

related>>Diisocyanates

Protein binding alerts for skin

sensitization according to GHS

Skin sensitization Category 1A>>

Isocyanates

Oncologic Primary Classification Not classified

2.2.5 HazardMeetingSummaryThere are concerns for irritation to the skin, eyes, and respiratory tract, respiratory and dermal sensitization, and lung effects based on data on the new chemical substance. The isocyanates are expected to react rapidly with water to yield primary amines. Based on no effects observed at the highest tested dose of 500 mg/kg‐bw/day for an analogue of the hydrolysis product, there is a low hazard concern for drinking water exposures.

2.3 ToxicityData

2.3.1 NewChemicalSubstanceData Provided with P‐18‐0320 (Full study results were not provided for the summaries below and

could not be verified by EPA):

o Acute oral study (guideline not specified) – LD50 > 5000 mg/kg‐bw. Decreased motor

activity was observed in all rats and diarrhea in those treated at 5000 mg/kg‐bw,

within 2 or 4 hours of administration, respectively. These signs persisted for the

remainder of Day 1 (up to 6hr after dosing). Apart from ungroomed appearance

during days 2‐4, all rats made an uneventful recovery.

o Acute percutaneous toxicity (guideline not speicified) – LD50 > 2mL/kg‐bw. Very

slight or well‐defined erythema and loss of flexibility was observed at the dermal

sites of application of all rats for up to 10 days after dressing removal. Other less‐

frequently observed reactions comprised of over‐sensitivity to touch and slight

edema in the majority of rats and transient erosion, bleeding, eschar, and sloughing

of skin in single or small numbers of animals.

o In vivo skin irritation (guideline not specified) – Mild skin irritation. Mean irritation

score of 2.08.

o In vivo eye irritation (guideline not specified) – Positive for mild eye irritation based

on cornea opacity score of 1 in 3 out of 3 animals. Resolution of the irritation

reactions was first apparent on the third day of the study and treated eyes were

overtly normal by Day 7. GHS Category 2B

o Ames test – Negative, however the study report is likely incomplete and only a single

experiment was shown, without any dose‐finding study or replicate.

Submitted with (same‐as) Test data (Verified by EPA):

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o Bacterial Reverse Mutation Assay (OECD 471): negative in Salmonella with and without activation;

o Genetic Toxicity: Mouse micronucleus assay (OECD 474): Negative in mouse micronucleus assay

o Acute Oral Toxicity test (OECD 423): rat oral LD0 = 2000 mg/kg‐bw; o Acute Eye Irritation test in rabbits (OECD 405): Classified as causing Serious Eye

Damage based on corneal opacity and staining persisted for 21days o Acute Skin Irritation Test in rabbits (OECD 404): Irritating to skin, did not clear in 14

days (GHS Category 2) o Guinea Pig Maximization Test(OECD 406): strong skin sensitization in guinea pigs

[90%; 9/10] using Magnusson‐Kligman assay o Acute Inhalation Toxicity Test (OECD 403): rat 4hr inhalation LC50 = 60 mg/m3 with

evidence of lung damage; NOEL of 8.8 mg/m3 o Subacute inhalation toxicity study (OECD 412) 4‐week study with bronchoalveolar

lavage: 10 male and 10 female Wistar rats per group were examined in a subacute 4‐week inhalation study with aerosolized exposure: 6‐hr/day for five days for four consecutive weeks) to mean actual concentrations of 0.16, 0.52, 2.1, and 10.4 mg test substance/m3 under dynamic directed‐flow nose‐only exposure conditions. The aerosol was highly respirable to rats, i.e., the average mass median aerodynamic diameter (MMAD) was 0.7 µm, the geometric standard deviation (GSD) was in the range of 1.3‐1.9. Rats exposed under otherwise identical test conditions to the vehicle control (acetone) served as concurrent control group. The rats were sacrificed after the exposure period. In the 2.1 mg/m3 air group, a few rats experienced mild and transient signs of respiratory tract irritation. In the high‐level exposure group, the rats experienced transiently decreased body weights (first exposure week only). The signs observed in this group were predominantly related to respiratory distress which appears to attenuate during the course of study period. The major signs can be summarized as follows: Bradypnea, labored and unregular breathing pattern, piloerection, serous nasal discharge, nostrils with red encrustations. In the high level exposure male group experienced a mild decrease in the number of peripheral thrombocytes. This, however, is considered to be an incidental finding. There were no statistically significant changes in absolute or relative organ weights. The histopathological examination of rats revealed in rats of the 2.1 and 10.4 mg/m3groups a statistically significantly increased incidence of laryngeal squamous cell hyperplasia and metaplasia. Moreover, in the 10.4 mg/m3 group a keratosis of the laryngeal epithelium was found in both males and females. In the lower groups, this trend was more pronounced in females than in males. ln the lung the most significant finding was a marked alveolar duct fibrosis in both males and females of the 10.4 mg/m3 group. There was no effect on extrapulmonary organs. In rats exposed to 10.4 mg/m3 air statistically significantly increased activities/concentrations of lactate dehydrogenase (LDH), N‐acetylglucosaminidase (NAG), alkaline phosphatase (ALP), intracellular acid phosphatase (ACPH) and intra‐/extracellular phospholipids, including foamy cells, were observed. Mild, however, statistically significant effects on ACPH and mildly increased cellular volumes were

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already observed in rats exposed to 2.1 mg/m3 air. Staining of BALF using the polychrome tannic acid revealed a concentration‐dependent increase of phospholipids in all isocyanate exposure groups. In neither group there was any evidence of increased lung weights or influx of inflammatory or phagocytotically active cells. There was no evidence of concentration‐dependent hematological effects considered to be pathodiagnostically relevant. Also the clinical‐chemistry did not reveal any evidence of concentration‐dependent effects considered to be pathodiagnostically relevant up to and including 10.4 mg/m3. In summary, this study demonstrates that the test substance was well tolerated locally and systemically. The histopathological examination of the entire respiratory tract, demonstrated statistically significantly increased incidences of laryngeal epithelial hyper‐/metaplasias at exposure levels equal or exceeding 2.1 mg/m3 and conspicuous alveolar duct fibrosis in the high level exposure group. The squamous metaplasia/hyperplasia at 2.1 mg/m3 is a common finding for irritating substances and thus it was not considered to be adverse. A NOAEC of 2.1 mg/m3 was identified based on alveolar fibrosis and increased LDH, ALP, and NAG in the BALF.

2.3.2 Analogue/MetaboliteData

2.3.2.1

o Analogue of the hydrolysis product

o OECD SIDS, 1994 (Excerpted):

“Upon repeated administration to rats or mice in drinking water or in the

diet, the NOAEL was approximately 500 mg/kg‐bw/day following 15 days or

13 weeks of administration. When rats or mice were exposed by inhalation

to , the lowest NOAEL for nasal irritation and

histological alterations following 12 and 90 days of exposure was 31 mg/m3

(10 mg/m3 or ca. 2.1 ppm ) and 5 mg/m3 (1.6 mg/m3 or ca. 0.3 ppm

), respectively. Experimental evidence indicates that is not

genotoxic. No adverse reproductive effects were observed in a one

generation reproduction study (NOAEL > 160 mg/m3 )

when rats and mice were exposed by inhalation. Developmental studies

indicate that fetal toxicity was present only at concentrations which were

maternally toxic, and no malformations were detected.”

2.3.3 SDSDataThe SDS is relevant to the new chemical substance because it is based on a mixture containing >99% of new chemical substance.

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2.3.4 OtherInformation EPA used the data submitted with (same‐as) for identifying points of departure

and quantitative risk assessment because EPA received and evaluated full study reports

for the summarized studies under Section 2.3.1. The data provided with P‐18‐0320 were

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not used in this assessment because they were only provided as summaries, which lacked

sufficient detail for EPA to determine the quality, reliability, and relevance of the

underlying data.

2.3.5 ExposureRoutesofInterest

2.4 PointofDepartureSelectedandBasis

2.4.1 PODforInhalationExposuresType: NOAEC

Value: 2.1mg/m3

Chemical: (same‐as)

Route: Inhalation (aerosol)

Study Type: Subacute 4‐week nose‐only inhalation study (OECD 412)

Hazard Endpoint: Lung effects

Selection Rationale: Based on a well‐conducted inhalation study on the new chemical

substance, alveolar fibrosis was observed at 10 mg/m3 and was accompanied by changes in the

BALF as indicated by increased LDH, ALP, NAG, and ACPH. Effects were observed at lower

concentrations such as squamous metaplasia which are consistent with reversible irritation.

This POD only covers the lung effects endpoint. Respiratory irritation and sensitization were

qualitatively evaluated.

Benchmark MOE: 100 (10x for intraspecies, 10x for interspecies).

Reference: Submitted with

Route of Interest

X Inhalation:

X Dermal:

Ingestion: No hazards identified for the expected hydrolysis product

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3 HUMANHEALTHRISK

3.1 USESandEXPOSURES

3.1.1 UsesHardener

3.1.2 WorkerExposurePer Engineering Report dated 11/05/2018

3.1.2.1 Inhalation Processing:

Negligible,VP < 0.001 torr and generation of respirable PMN not expected.

Use: PDR (mist) = mg/day over 250 days/yr (“What if”) (Basis: )

3.1.2.2 DermalProcessing:

PDR = mg/day over 250 days/yr ( (Basis: Unloading Raw Material from Containers)

Use: PDR = mg/day over 250 days/yr (

(Basis: Unloading Raw Material from Drums)

3.1.3 GeneralPopulationExposure:Per Exposure Report dated 05/12/2020

Exposure Scenario1 Water Landfill

Release activity(ies)2; exposure calculation(s)3

Drinking Water Fish Ingestion 7Q10

4

CC = NES

PDM Days

ExceededLADD

ADR LADD ADR LADD

mg/kg/day mg/kg/day mg/kg/day mg/kg/day μg/l # Days mg/kg/day

PROC:Max ADR 1.88e‐2 ‐‐ 6.10e‐4 ‐‐ ‐‐ ‐‐ ‐‐

PROC:Max LADD ‐‐ 5.01e‐5 ‐‐ 3.61e‐7 ‐‐ ‐‐ ‐‐

USE:Max ADR 5.22e‐3 ‐‐ 3.00e‐4 ‐‐ ‐‐ ‐‐ ‐‐

USE:Max LADD ‐‐ 3.25e‐4 ‐‐ 2.34e‐6 ‐‐ ‐‐ 1.21e‐3

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Exposure Scenario

Stack Incinerator 1 Incinerator 2 Fugitive Air

Release activity

ADR (24-hr conc.)

LADD (Annual conc.)

ADR (24-hr conc.)

LADD (Annual conc.)

ADR (24-hr conc.)

LADD (Annual conc.)

ADR (24-hr conc.)

LADD (Annual conc.)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

mg/kg/day (µg/m3)

USE n/a n/a n/a n/a n/a n/a 2.14e-4

(9.55e-1) 5.77e-5

(6.54e-1)

3.1.3.1 DrinkingWaterADR as high as 1.88E‐02 mg/kg‐bw/day

3.1.3.2 FishADR as high as 6.10E‐04 mg/kg‐bw/day

3.1.3.3 LandfillLADD as high as 1.21 E‐03 mg/kg‐bw/day

3.1.3.4 Air/InhalationADR as high as 2.14E‐4 mg/kg‐bw/day (9.55E‐01 µg/m3). LADD as high as 5.77E‐05 mg/kg‐bw/day (fugitive)

3.1.4 ConsumerExposureNo identified consumer exposures

3.2 RISKCALCULATIONS

3.2.1 WorkerCalculations

Benchmark

MOE

Endpoint

TypeExposure

Route

POD Conc.

mg/m3

POD

Period

hrs/day

POD

Duration

days/wk

Exposure

mg/day

Potential

Dose Rate

(PDR)

Total Worker

Breathing

Volume for

PDR

Exposure

Period m3

Worker

Exposure

Duration

Hours/Da

y

Exposure

Duration

Days/Wk

Default

Worker

Structural

Alert as %

of PMN

POD Conc ‐

Duration &

Breathing

Rate

Correction

ScenarioHEC

mg/m3

Exposure

TWA

mg/m3

Margin of

Exposure

MOE

100 NOAEL

Inhalation 2.1E+00 6.00 5 10.0 8.00 5 4.90 10.00 100% 7.7E‐01 3.7E‐01 2 Fold Factor = 48

Worker Margin of Exposure (MOE) Calculations using Animal Oral POD and Engineering Report PDR

Animal or Human POD Worker Exposure

Human

Breathing

Rates

Risks were identified for workers for lung effects via inhalation exposure based on quantitative hazard data for the new chemical substance (MOE = 2; Benchmark MOE = 100; Fold factor= 48). Irritation and sensitization hazards to workers via inhalation and dermal contact were identified based on data on the new chemical substance. Risks for these endpoints were not quantified due to a lack of dose‐response for these hazards. However, exposures can be mitigated by the

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use of appropriate PPE, including impervious gloves, eye protection, and respiratory protection. EPA expects that employers will require and that workers will use appropriate PPE consistent with the SDS prepared by the submitter, in a manner adequate to protect them.

3.2.2 GeneralPopulationCalculations

Benchmark

MOE

Endpoint

TypeInhalation

Exposure

Scenario

POD

Conc.

mg/m3

POD

Period

hrs/day

POD

Frequency

days/wk

Exposure

(24‐hr

conc.)

(ug/m3)

Population

Exposure

Duration

Hours/Day

Exposure

Frequency

Days/Wk

Structural

Alert as %

of PMN

POD Conc ‐

Duration

Correction ‐

ScenarioHEC

mg/m3

Margin of

Exposure

MOE

100 NOAEC

Fugitive Air 2.10 6.00 5 9.6E‐01 24.00 7 100% 3.8E‐01 393

Population/Consumer Margin of Exposure (MOE) Calculations using Animal Inhalation POD and Exposure Report 24‐hr conc.

Animal or Human POD Population Exposure

Risks were not identified for the general population for lung effects via inhalation exposure based on quantitative hazard data for the new chemical substance (MOE = 393; Benchmark MOE = 100). No hazards were identified for a hydrolysis product of the new chemical substance; therefore, risks were not calculated. Based on no identified hazards, risks are not expected via drinking water, groundwater ingestion impacted by landfill leaching, and fish ingestion.

Irritation and sensitization hazards to the general population are not expected via drinking water ingestion or fugitive air releases due to dilution of the chemical substance in the media.

3.2.3 ConsumerCalculationsRisks to consumers were not evaluated because consumer uses were not identified as conditions of use.

p-18-0320 hlth risk assessment final 05-13-20

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