From: Monona Rossol <0000030664c37427-dmarc-request**At_Symbol_Here**LISTS.PRINCETON.EDU>
Subject: Re: [DCHAS-L] Limonene article in CEN
Date: Mon, 18 Mar 2019 16:20:55 +0000
Reply-To: ACS Division of Chemical Health and Safety <DCHAS-L**At_Symbol_Here**PRINCETON.EDU>
Message-ID: 48505608.6189415.1552926055528**At_Symbol_Here**

Yes, Tiliak, I have all that U.S. data, which is why I cite the E.U. regulations. Our regulations do not make any sense from a consumer's perspective.  In 1958 when the Food & Drug Act was passed, FDA listed EVERY CHEMICAL being used that that time as GRAS.  No testing required.  That's why FDA regularly bans chemicals they approved blindly for decades.  Good examples are phenolphthalein and herbal dantron laxatives, both of which seriously funked cancer tests in the 80s and 90s.  

And since dantron is 1,8-dihydroxyanthraquinone, that reminds me:  whole aloe juice made the 2016 IARC 2B list.  Shouldn't the idiots who drink this stuff at least know that it it is a listed carcinogen and contains anthraquinones and anthrone-glucosides which have analogs that cause cancer?  

That same year, an FDA-approved medicine I've taken for 30 years, hydrochlorothiazide, was listed as 2A with both animal and human data showing it causes skin cancer by ingestion.  I should have had that cancer data when I first started taking it, but our U.S. FDA rules only "recommend" that drug companies do chronic testing. Our regulations suck.

However, I may decide, based on my own risk assessment, to continue taking hydrochorothiazide since I probably have a greater need to lower my blood pressure at times like this. 

D-Limonene is a Category 1 skin sensitizer and it has NO BUSINESS in cosmetics. I predict in a few more years there will be sufficient human data to associate it with asthma.   The reason it is in all our products is that we drink a lot of orange juice which means there are tons of this smelly stuff that need a market.

Let's hope d-limonene finds it's true market as just a pesticide/repellant/biocide under EPA rules.


from: ACS Division of Chemical Health and Safety <DCHAS-L**At_Symbol_Here**PRINCETON.EDU> on behalf of TILAK CHANDRA <0000058f112ac338-dmarc-request**At_Symbol_Here**LISTS.PRINCETON.EDU>
Sent: Monday, March 18, 2019 8:30 AM
Subject: Re: [DCHAS-L] Limonene article in CEN
FYI. Tilak
From literature:

R-(+)-limonene (D-limonene) is a commonly used flavor additive in food, beverages and fragrances for its pleasant lemon-like odor.  Considering its increasing applications, it's necessary to understand toxicol. effects and risk assocd. with its use.  R-(+)-limonene is rapidly absorbed in exptl. animals and human beings following oral administration.  In humans, it gets distributed to liver, kidney, and blood resulting in the formation of metabolites like perillic acid, dihydroperillic acid, limonene-1,8-diol and limonene-1,2 diol.  Important toxic effects primarily reported in rodents are severe hyaline droplet nephrotoxicity (only in male rats due to specific protein =CE=B12u-globulin; however, this effect isn't valid for humans), hepatotoxicity and neurotoxicity.  R-(+)-limonene does not show genotoxic, immunotoxic and carcinogenic effects.  Substantial data is available about limonene's stability after treatment with thermal and non-thermal food processing techniques; however!
 , information about toxicity of metabolites formed and their safe scientific limits is not available.  In addn., toxicity of limonene degrdn. products formed during storage of citrus juices isn't known.  Based on all available toxicol. considerations,

R-(+)-limonene can be categorized as low toxic additive.  More detailed studies are required to better understand interaction of limonene with modern food processing techniques as well as degrdn. products generated and toxicity arising from such products.
A review.  Limonene was one of the main ingredients in citrus essential oils.  It had been widely used in food and pharmaceutical industries due to its antibacterial and anticancer bioactivities.  This paper reviewed recent progress in understanding the safety of limonene from the perspectives of toxicol. assessment, genotoxicity, cytotoxicity and its influence on human, animals and environment.  We hoped that this review could provide refs. for the effective and safe application of limonene.
By: Kim, Young Woo; Kim, Min Ji; Chung, Bu Young; Bang, Du Yeon; Lim, Seong Kwang; Choi, Seul Min; Lim, Duck Soo; Cho, Myung Chan; Yoon, Kyungsil; Kim, Hyung Sik; Kim, Kyu Bong; Kim, You Sun; Kwack, Seung Jun; Lee, Byung-Mu
A review.  D-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor.  D-Limonene has been designated as a chem. with low toxicity based upon LD (LD50) and repeated-dose toxicity studies when administered orally to animals.  However, skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products.  In exptl. animals and humans, oxidn. products or metabolites of D-limonene were shown to act as skin irritants.  Carcinogenic effects have also been obsd. in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein =CE=B12u-globulin responsible for this effect in rodents is absent in humans.  Thus, the liver was identified as a crit. target organ following oral administration of D-limonene.  Other than the adverse dermal effects noted in humans, other notable!
  toxic effects of D-limonene have not been reported.  The ref. dose (RfD), the no-obsd.-adverse-effect level (NOAEL), and the systemic exposure dose (SED) were detd. and found to be 2.5 mg/kg/d, 250 mg/kg//d, and 1..48 mg/kg/d, resp.  Consequently, the margin of exposure (MOE = NOAEL/SED) of 169 was derived based upon the data, and the hazard index (HI = SED/RfD) for D-limonene is 0.592.  Taking into consideration conservative estn., D-limonene appears to exert no serious risk for human exposure.  Based on adverse effects and risk assessments, D-limonene may be regarded as a safe ingredient.  However, the potential occurrence of skin irritation necessitates regulation of this chem. as an ingredient in cosmetics.  In conclusion, the use of D-limonene in cosmetics is safe under the current regulatory guidelines for cosmetics.

D-limonene is one of the most common terpenes in nature.  It is a major constituent in several citrus oils (orange, lemon, mandarin, lime, and grapefruit).  D-limonene is listed in the Code of Federal Regulations as generally recognized as safe (GRAS) for a flavoring agent and can be found in common food items such as fruit juices, soft drinks, baked goods, ice cream, and pudding.  D-limonene is considered to have fairly low toxicity.  It has been tested for carcinogenicity in mice and rats.  Although initial results showed d-limonene increased the incidence of renal tubular tumors in male rats, female rats and mice in both genders showed no evidence of any tumor.  Subsequent studies have determined how these tumors occur and established that d-limonene does not pose a mutagenic, carcinogenic, or nephrotoxic risk to humans.  In humans, d-limonene has demonstrated low toxicity after single and repeated dosing for up to one year.  Being a solvent of cholesterol, d-limonene has!
  been used clinically to dissolve cholesterol-containing gallstones.  Because of its gastric acid neutralizing effect and its support of normal peristalsis, it has also been used for relief of heartburn and gastroesophageal reflux (GERD).  D-limonene has well-established chemopreventive activity against many types of cancer.  Evidence from a phase I clinical trial demonstrated a partial response in a patient with breast cancer and stable disease for more than six months in three patients with colorectal cancer.

-----Original Message-----
From: ACS Division of Chemical Health and Safety <DCHAS-L**At_Symbol_Here**PRINCETON.EDU> On Behalf Of DCHAS Membership Chair
Sent: Monday, March 18, 2019 7:13 AM
Subject: [DCHAS-L] Limonene article in CEN

From: Monona Rossol <actsnyc**At_Symbol_Here**>
Re: limonene in CEN

A very misleading article on (+)-limonene from marigolds appeared on page 15 of the Chemical & Engineering News, March 11, 2019.  The writer notes this chemical was found in the fragrance of marigolds which explains why these flowers keep certain insect pests away from greenhouse tomatoes. The writer doesn't tell us that (+)-limonene has been an EPA-registered pesticide ingredient for decades and it has been long-known that it is not just a repellent, it is a fly killer.  I became aware of this fact after a college lab course in which we bred fruit flies was terminated by bending a wee bit of orange peel (full of limonene) above our little containers of critters.. Stone cold dead was the almost instant result.

So the most important issue in this experiment was missed, namely that (+)-limonene did not need to be sprayed onto the plants to be effective.  Researchers found that only using a vapor dispenser similar to a room deodorizer was enough. This means: 1) huge savings can be realized on the amount of pesticide needed; 2) its well-known adverse (Category 1) aquatic toxicity issue can be easily avoided; and 3) it is possible to target only species that are smart enough to get away from the pesticide before it is lethal to them. 

And then there are all the occupational exposure issues this use raises.  Any accurate GHS SDS on (+)-limonene will list it as a Category 2 skin irritant and a Category 1 skin-sensitizer.  And the DFG-TWA workplace air quality standard is only 5 ppm, above which d-limonene may also be a threat to the fetus. There also is significant anecdotal evidence that it is an asthmagen.  That presents some interesting worker protection issues in an enclosed greenhouse environment.

I also would suggest that the chemical should not only be identified as "(+)-limonene."  Make sure readers know this is orange peel oil, citrus oil, d-limonene, dipentene, and so on.  This chemical is banned in the E.U. from cosmetics, fragrances, and children's products as any other Category 1 skin-sensitizer would be. Here in the U.S.., we have trouble finding products without citrus as a fragrance or ingredient.   Which also makes me wonder whether or not U.S. consumers can be included among those those species smart enough to get away from d-limonene before it is harmful to them.

Monona Rossol

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