      UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                          		OFFICE OF CHEMICAL SAFETY
                                                                                            	AND POLLUTION PREVENTION

MEMORANDUM

DATE:	September 29, 2016

SUBJECT:	Aliphatic Solvents.  Human Health Assessment Scoping Document in Support of Registration Review.  

PC Codes:  063502, 063503
DP Barcode:  D432571
Decision No.:  515563
Registration No.:  57582-1
Petition No.:  NA
Regulatory Action:  Registration Review 
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  3004-01
TXR No.:  NA
CAS Nos.:  8042-47-5, 64742-46-7, 64742-52-5, 
64742-54-7, 72623-84-8, 72623-85-9, 72623-86-0, 72623-87-1, 178603-64-0, 178603-65-1, 178603-66-2, 445411-73-4
MRID No.:  NA
40 CFR:  NA


FROM:	Myron S. Ottley, Toxicologist
Risk Assessment Branch 3 (RAB3)
Health Effects Division (7509P)
            
            THROUGH:	Christine Olinger, Chief
Risk Assessment Branch 3 (RAB3)
Health Effects Division (7509P)
            
            TO:	Veronica Dutch/Jill Bloom, Chemical Review Manager
Risk Management and Implementation Branch 5
Pesticide Reevaluation Division (7508P)

Executive Summary

To evaluate the scope of work necessary to support Registration Review, HED considers previous risk assessments; any new toxicity, exposure and usage data; and current Agency policy and methodologies. The most recent risk assessment for Aliphatic Solvents was conducted in 2007 for the Registration Eligibility Decision Document (EPA 2007).  Aliphatic solvents are the products of petroleum distillations processes, and thus, they are complex mixtures of long-chain aliphatic (paraffinic) compounds.  They are formulated as liquid concentrates for use as insecticides and/or larvicides on crops, animal premises, commercial/industrial premises, medical premises, aquatic areas, and residential premises, as well as occupational and residential uses as acaricides, fungicides, herbicides, and virucides (for plant pathogens).  Currently, the aliphatic solvents are registered for mosquito control in aquatic and agricultural settings, and are exempt from the requirement of a tolerance (40 CFR § 180.905).  Non-pesticidal uses include ingredients in baby lotions, cold cream, ointments and cosmetics, and as an intestinal lubricant laxative.  They are also approved by FDA for use as various food/feed additives in chewing gum base, cheese and raw fruit, and for use in animal feeds.

The last risk assessment (EPA 2007) concluded that the existing database (including literature studies) showed low absorption rates and low toxicity for the Aliphatic Solvents, and that a quantitative risk assessment is not required.  Therefore, toxicity endpoints and points of departure (PODs) were not selected.  

No additional data are required to update the dietary, residential, and occupational exposure assessment.  Previously no hazard was identified, so quantitative exposure assessments have not been conducted.  During Registration Review the exposure and risk assessments will be updated in accordance with the re-evaluation of the toxicity database.  Furthermore, the Agency will examine the need for a volatilization assessment, as well as evaluate the potential for exposure from spray drift during Registration Review.  

Introduction

As part of Registration Review, the Pesticide Reevaluation Division (PRD) has requested that the Health Effects Division (HED) provide a human health risk assessment scoping document for the Aliphatic Solvents to support Registration Review.  To evaluate the scope of work necessary to support Registration Review, HED has considered previous risk assessments, updates to its toxicity, exposure, and usage databases, and the latest Agency science policy and risk assessment methodologies.  The most recent risk assessment for Aliphatic Solvents was conducted in 2007 for the Registration Eligibility Decision Document (EPA 2007).

The aliphatic solvents are the product of petroleum distillations processes, and thus, they are complex mixtures of long-chain aliphatic (paraffinic) compounds. They are formulated as liquid concentrates for use as insecticides and/or larvicides on crops, animal premises, commercial/industrial premises, medical premises, aquatic areas, and residential premises, as well as occupational and residential uses as acaricides, fungicides, herbicides, and virucides (for plant pathogens). The aquatic area applications are for usage as a mosquito larvicide/pupacide. Application equipment includes the following: for agricultural crops, by airplane, groundboom sprayer, airblast sprayer, handgun sprayer, low-pressure handwand sprayer, and/or high-pressure handwand sprayer; for use at commercial/industrial sites, by low-pressure handwand sprayer, handgun sprayer, airplane, truck-mounted ULV sprayer, airblast sprayer, rights-of-way sprayer, and/or high pressure handwand sprayer; and for residential settings, by hose-end sprayer, low pressure handwand sprayer, and/or trigger-pump sprayer. For the aliphatic petroleum hydrocarbons, several end-use products allow for application to agricultural crops via chemigation, and some products can be applied via dip to ornamental nursery stock, pineapples, and citrus.  Crops with the highest usage are a variety of tree fruit and nuts, probably because these crops often require dormant season treatments with oils to reduce in-season pest problems.  Use in non-agricultural sites such as nursery and floriculture has remained relatively constant, at about 300,000 lb annually (based on limited data for 2006 and 2009).

Mineral oil has numerous non-pesticidal uses.  It is a common ingredient in baby lotions, cold creams, ointments and cosmetics.  It can also be used as an intestinal lubricant and laxative.  Mineral oil, petrolatum, and petroleum wax are approved by FDA as food/feed additives for a variety of applications, including the following examples: chewing gum bases, defoamers in food, and protective coatings for cheese and raw fruit (21CFR573.680; 1 CFR 172.878; 21 CFR 172.880; 21CFR172.884; 21CFR.886, and 21CFR178.3620, and 21CFR178.3650).  Mineral oil may be safely used in animal feed, subject to the provisions of this section.   

Hazard Identification/Toxicology

With oral dosing, mineral oils and aliphatic petroleum hydrocarbons are poorly absorbed across the gastrointestinal tract lining, and most are rapidly eliminated unchanged in the feces (75 to 98% of the administered dose). In addition, these materials also show very poor permeability across the dermal barrier (very little is absorbed through the skin). Similarly, any of these materials which enter the lungs is also generally not absorbed, but there may be phagocytosis by the surrounding lung cells, with some materials then being transported to the spleen and liver, with eventual elimination occurring, mostly un-metabolized, within the feces. The extraordinarily low absorption by oral and inhalation routes is consistent with essentially no adverse toxicity seen in any of the oral and inhalation toxicity studies.

Acute toxicity studies show the aliphatic solvents to be in Toxicity Category IV for oral (> 5,000 to 15,000 mg/kg), dermal (> 2,000 mg/kg), and dermal irritation studies, and Toxicity Category III for inhalation (> 3.5 mg/L) and eye irritation studies. They are not skin sensitizers.

Oral subchronic and chronic toxicity:  Subchronic oral toxicity studies from the literature are available and indicate that minimal to no systemic toxicity was observed. In a recently published article, dearomatized solvents were administered for 90-days by oral gavage up to 5,000 mg/kg/day (highest dose). Adaptive liver changes were observed in all treatment groups and kidney changes were observed at the high dose. The BMDL was calculated at 1857 mg/kg/day based on increased serum ALT (Andenuga et al 2014). 

Reproduction/Developmental toxicity:  The only information regarding developmental and reproductive toxicity is from the 2007 RED.  Dermal exposure of laboratory animals to mineral oil produced no adverse effects on reproductive or developmental toxicity parameters, either in parents or offspring. The literature may also provide information for risk assessment during Registration Review.

Subchronic dermal and inhalation toxicity:  A short-term dermal exposure  NOAEL of 2000 mg/kg/day was observed in a 28-day dermal study, in which no adverse systemic effects were observed at the highest test concentration of 2000 mg/kg/day, which is above the limit dose. In addition, these materials show very poor permeability across the dermal barrier.

In inhalation studies, limited systemic toxicity was seen, but rather effects were observed likely due to their physical properties (i.e., the observed effects are not due to chemical toxicity, but due to irritating effects, such as interstitial inflammation and alveolar histiocytosis, related to the body's defense mechanism against the exposure to a foreign material, when the aliphatic oils enter the lungs).  Since these irritating effects seen in laboratory animals are considered inherently self-limiting in human exposure situations, they were not considered appropriate for endpoint selection in human health risk assessments in the 2007 RED document.  However, the inhalation studies will be re-evaluated during Registration Review. 


Carcinogenicity: Guideline oral chronic/carcinogenicity studies are not available for the aliphatic solvents since the studies were not previously required due to low oral toxicity (EPA 2007).  However, dermal carcinogenicity studies exist for the aliphatic solvents and these studies should be submitted and reviewed by the Agency.  Mutagenicity studies are available for these chemicals and have been previously reviewed by the Agency.  The mutagenicity of various test materials were all characterized as being non-mutagenic, in general, but with issues due to the presence of suspended oil droplets, likely from the poor water solubility of the test materials.  During Registration Review, the dermal carcinogenicity studies should be reviewed by the Agency to determine whether the studies are applicable to the aliphatic solvents included in this risk assessment and whether there is concern for carcinogenicity after dermal exposure.

Conclusion: The toxicity database is considered adequate to support existing registrations (TXR 0057504). The need for oral, dermal, and inhalation endpoints will be re- evaluated during Registration Review.

Dietary Exposure

Applications may be made to food crops, but the uses have been exempt from the requirement of a tolerance due to lack of hazard identified via the oral route (40 CFR 180.905, 40 CFR 180.910, 40 CFR 180.930)

Conclusion:  The need for a quantitative dietary assessment is not anticipated but will also be determined based on the re-evaluation of the toxicity database during the Registration Review.  risk assessment.  Changes to the tolerance exemption are also not anticipated. 

Residential Exposure and Occupational Exposure

Currently, there is a potential for dermal and inhalation exposure to aliphatic solvents (both mineral oils and aliphatic petroleum hydrocarbons) in residential and occupational settings from application and post-application.  However, the Agency has previously determined only a qualitative exposure assessment is required for these scenarios because no dermal or inhalation endpoints have been identified, and because the application rates, anticipated use patterns, and current labels for the aliphatic solvents products are not of concern to the Agency. This qualitative exposure/risk assessment also suggests there are no concerns for handlers, reentry workers, or for those in residential settings or from mosquito uses. 
  
Conclusions:  Should there be any changes to the hazard and dose-response assessments when the toxicity data are re-evaluated, or changes to exposure methods, the Agency will update the occupational and residential exposure assessments as needed.


Non-Occupational Spray Drift 

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom) employed for Aliphatic Solvents.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.  This document outlines the quantification of indirect non-occupational exposure to drift.  

Conclusions: The Agency will evaluate the potential for exposure from spray drift during Registration Review.  However, for Aliphatic Solvents, since there are currently no endpoints selected for risk assessment, no concerns are anticipated.  Residential bystander exposures resulting from off-site transport (i.e., volatilization) may occur as a result of occupational applications of Aliphatic Solvents.  The need for a bystander risk assessment for Aliphatic Solvents will be considered during Registration Review, but since this is a qualitative risk assessment, no concerns are anticipated.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), HED considers and aggregates chemical exposures and risks from three major sources:  food, drinking water, and residential exposures.  In an aggregate assessment, exposures from dietary and residential sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL), or the risks themselves can be aggregated.  Since no hazard has been identified for the registered uses of the aliphatic solvents, there are no concerns for the aggregate exposure to the aliphatic solvents. 

Conclusion:  The need for an updated aggregate assessment will be determined once the toxicity database has been re-evaluated.

Public Health and Pesticide Epidemiology Data 

There were few incident cases reported for aliphatic solvents in IDS.  SENSOR-Pesticides had a total of 583 cases, all involving multiple active ingredients including an aliphatic solvent.  Most of these incidents were low severity. Since aliphatic solvents are co-formulated with many different active ingredients in many products, the incident reports do not provide information specific to exposure to aliphatic solvents. 

Conclusions: Based on the low frequency and severity of incident cases reported for Aliphatic Solvents in both IDS and SENSOR-Pesticides there does not appear to be a concern at this time that would warrant further investigation.  The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Cumulative
Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to Aliphatic Solvents and any other substances, and Aliphatic Solvents does not appear to produce a toxic metabolite produced by other substances. Therefore, EPA has not assumed that Aliphatic Solvents has 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 chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

Studies in which adult human subjects were intentionally exposed to aliphatic solvents to determine their dermal and inhalation exposure have not been used to address human health risk assessments on these chemicals.  

References

Table 1. Memoranda Relevant to Registration Review of Aliphatic Solvents 
Author
Barcode
Date
Title
S. Bradbury
None
11/29/2007
"Revised Reregistration Eligibility Decision (RED) Document for the Aliphatic Solvents Case (Mineral Oil and Aliphatic Petroleum Hydrocarbons."
R. Locke 
D217192
08/29/1996
Petroleum Oils, Review of Toxicology Data
S. Dobreniecki
TXR 0057504
09/30/2016
Aliphatic Solvents:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 1, 2016:  Recommendations on the Need for a Quantitative Risk Assessment
S. Recore
D435587
09/07/2016
Aliphatic Solvents: Tier I (Scoping) Review of Human Incidents and Epidemiology
D. Adenuga et al. 
None
2014
The sub-chronic oral toxicity of dearomatized hydrocarbon solvents in Sprague-Dawley rats. Regulatory Toxicology and Pharmacology 70 (2014) 659 - 672.





        Table A1. Description of Chemicals included in the Aliphatic Solvents Case
    Chemical Name
 CAS number
                                  Description
  Mineral oil; Oil mist       (mineral) 
 
  8012-95-1 

  Liquid hydrocarbons from petroleum. 

 Mineral oil; Hydrocarbon oils; paraffin liquid

 8020-83-5

 A mixture of liquid hydrocarbons obtained from petroleum.

 White mineral oil, petroleum

 8042-47-5
 A highly refined petroleum mineral oil consisting of a complex combination of hydrocarbons obtained from the intensive treatment of a petroleum fraction with sulphuric acid and oleum, or by hydrogenation, or by a combination of hydrogenation and acid treatment. Additional washing and treating steps may be included in the processing operation. It consists of saturated hydrocarbons having carbon numbers predominantly in the range of C15 through C50.

 Lubricating oils, petroleum C15-30, hydrotreated neutral oil based, containing. solvent deasphalted residual oil

 72623-84-8
 A complex combination of hydrocarbons obtained by treating light vacuum gas oil, heavy vacuum gas oil, and solvent deasphalted residual oil with hydrogen in the presence of a catalyst in a two stage process with dewaxing being carried out between the two stages. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C15 through C30 and produces a finished oil having a viscosity of approximately 10cSt at 40.degree.C (104.degree.F). It contains a relatively large proportion of saturated hydrocarbons.

 Lubricating oils, petroleum, C15-30, hydrotreated neutral oil- based

 72623-86-0
 A complex combination of hydrocarbons obtained by treating light vacuum gas oil and heavy vacuum gas oil with hydrogen in the presence of a catalyst in a two stage process and dewaxing being carried out between the two stages. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C15 through C30 and produces a finished oil having a viscosity of approximately 15cSt at 40°C. It contains a relatively large proportion of saturated hydrocarbons.

 Lubricating oils, petroleum, C20-50, hydrotreated neutral oil- based

 72623-87-1
 A complex combination of hydrocarbons obtained by treating light vacuum gas oil, heavy vacuum gas oil and solvent deasphalted residual oil with hydrogen in the presence of a catalyst in a two stage process with dewaxing being carried out between the two stages. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C20 through C50 and produces a finished oil with a viscosity of approximately 32cSt at 40°C. It contains a relatively large proportion of saturated hydrocarbons.
 Distillates, petroleum, solvent-refined heavy paraffinic

 64741-88-4
 A complex combination of hydrocarbons obtained as the raffinate from a solvent extraction process. It consists predominantly of saturated hydrocarbons having carbon numbers predominantly in the range of C20 through C50 and produces a finished oil with a viscosity of at least 100 SUS at 100°F (19cSt at 40°C).
 Distillates, petroleum, solvent-refined light paraffinic

 64741-89-5
 A complex combination of hydrocarbons obtained as the raffinate from a solvent extraction process. It consists predominantly of saturated hydrocarbons having carbon numbers predominantly in the range of C15 through C30 and produces a finished oil with a viscosity of less than 100 SUS at 100°F (19cSt at 40°C).

 Distillates, petroleum, hydrotreated heavy paraffinic

 64742-54-7
 A complex combination of hydrocarbons obtained by treating a petroleum fraction with hydrogen in the presence of a catalyst. It consists of hydrocarbons having carbon numbers predominantly in the range of C20 through C50 and produces a finished oil of at least 100 SUS at 100°F (19cSt at 40°C). It contains a relatively large proportion of saturated hydrocarbons.

 Distillates, petroleum, hydrotreated light paraffinic

 64742-55-8
 A complex combination of hydrocarbons obtained by treating a petroleum fraction with hydrogen in the presence of a catalyst. It consists of hydrocarbons having carbon numbers predominantly in the range of C15 through C30 and produces a finished oil with a viscosity of less than 100 SUS at 100°F (19cSt at 40°C). It contains a relatively large proportion of saturated hydrocarbons.

 Distillates, petroleum, solvent-dewaxed light paraffinic

 64742-56-9
 A complex combination of hydrocarbons obtained by removal of normal paraffins from a petroleum fraction by solvent crystallization. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C15 through C30 and produces a finished oil with a viscosity of less than 100 SUS at 100°F (19cSt at 40°C).

 Distillates, petroleum, solvent-dewaxed heavy paraffinic

 64742-65-0
 A complex combination of hydrocarbons obtained by removal of normal paraffins from a petroleum fraction by solvent crystallization. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C20 through C50 and produces a finished oil with a viscosity not less than 100 SUS at 100.degree.F (19cSt at 40.degree.C).




Appendix 2:  Toxicological Profile Table for the Aliphatic Solvents 

             Table A.2.1. Summary of Acute Toxicity for the Aliphatic Solvents (Mineral Oil and Petroleum Hydrocarbons)
 Study Type
                             Test species: Result
                                       
                                   Reference
                                PC Code: 063502
 Test Material: Mineral Oil
          CAS#: 8012-95-1
 Gowan Spray Oil (EPA Reg. 10163-RLU)
  MRD-87-984; mineral oil
        90 Neutral Oil ; mineral oil (100% purity)

  Acute oral
   Mouse: LD50 = 22 g/kg (NIOSH, 2003 [document cited is in
German; translation indicates that mineral oil was not tested alone, only in combination with other chemicals])

 Rat: LD50 = > 25 mL/kg (> 28 g/kg) no deaths observed (Hine and Zuidema (1970) also cited in INCHEM (WHO), 1982)

     Rat: LD50 >5 g/kg (EPA, 1992)

            Rat: LD50 > 5 g/kg for males and females (EPA, 1994c)

                                      NFa

 Acute dermal
                                      NFa
     Rabbit:  LD50 > 2 g/kg (EPA, 1992)
                  Rat:  LD50 >2 g/kg for males and females
                                 (EPA, 1994c)
                   Rat:  LD50 >2 g/kg for males and females
                                 (EPA, 1994b)
  Acute inhalation
                                      NFa
     Rat: LC50 > 4.6 mg/L (EPA, 1992)
      Rat: LC50 > 4.7 mg/L (EPA, 1994c)
        Rat: LC50 > 3.5 mg/L (EPA, 1994b)

   Acute eye irritation

           Rabbit:  Moderate effect at 500 mg (NIOSH, 2003)

                                      NFa
Rat: Slight eye irritation; did not clear at day 14 (last day of observation) (EPA, 1994c)

                                      NFa

[a]: NF: not found


             Table A.2.2. Summary of Acute Toxicity for the Aliphatic Solvents (Mineral Oil and Petroleum Hydrocarbons)
 Study Type

           Test species: Result

                                PC Code: 063502
 Test Material: Mineral Oil
          CAS#: 8012-95-1
 Gowan Spray Oil (EPA Reg. 10163-RLU)
  MRD-87-984; mineral oil
        90 Neutral Oil ; mineral oil (100% purity)

   Acute dermal irritation
                    Guinea pig: Mild effect at 100 mg/24 hour
                                 (NIOSH, 2003)

                                      NFa

                                      NFa

                                      NFa
                                       




 Skin sensitization

                                      NFa
                                      NFa
                                      NFa
[a]: NF: not found

