Safety Assessment of Etidronic Acid and Salts of Etidronic Acid as Used in Cosmetics

49 Pages·2017·2.6 MB·English

by  Lillian Becker

Safety Assessment of
Etidronic Acid and Salts of Etidronic Acid
as Used in Cosmetics

Status: Draft Final Report for Panel Review
Release Date: March 17, 2017
Panel Meeting Date: April 10-11, 2017

The 2017 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V.
Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald
C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A.
This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review
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[email protected]
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MEMORANDUM
To: CIR Expert Panel and Liaisons

From: Lillian C. Becker, M.S.
Scientific Analyst and Writer

Date: March 17, 2017

Subject: Safety Assessment of Etidronic Acid and Its Simple Salts as Used in
Cosmetics

Attached is the Draft Final Report of Etidronic Acid and Salts of Etidronic Acid as used in
cosmetics. [etidro042017Rep] These crystalline diphosphonate ingredients function in
cosmetics as chelating agents. These ingredients are also used to treat bone diseases
characterized by osteoclastic bone resorption. “Etidronate” is a general term used for this
group of compounds and is sometimes used in the literature instead of the specific acid or
salt.
In September 2016, the Panel issued a Tentative Report with the conclusion that these
ingredients are safe in cosmetics in the present practices of use and concentration described
in this safety assessment. The data presented no concern for use of these ingredients in
cosmetics.
2017 VCRP data have been incorporated into the report. The number of uses for each
ingredient increased by 19 or fewer with no new types of uses.
No other new data have been submitted. Council comments have been addressed.
[etidro042017PCPC_1,2] Papers describing additional side effects of long-term oral use of
etidronate as a drug, including osteonecrosis of the jaw (ONJ) were discovered; the
information was inserted into the report and the paragraphs marked with lines on either side
to indicate insertion of the new data.
The Panel should carefully review the Abstract, Discussion, and Conclusion of this report and
issue a final report.

__________________________________________________________________________________________
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SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY ____Etidronic Acid and Its Simple Salts_______________________________
MEETING _____April 2017______________________________________________________________

Public Comment CIR Expert Panel Report Status
Priority List
INGREDIENT
PRIORITY LIST

SLR
July 5, 2016

DRAFT REPORT
Sept 2016
Draft Report
60 day public comment period

Table

Table IDA TR
IDA Notice IDA
DRAFT TENTATIVE
Draft TR REPORT

Table

Table
Tentative Report
Issue TR
October 11, 2016
Draft FR DRAFT FINAL REPORT
Apr 2017
60 day Public comment period
Table
Table Different Conclusion

Issue
PUBLISH Final Report
FR

___
Distributed for comment only -- do not cite or quote

History – Etidronic Acid and Its Simple Salts
2015 – 2016 Priority List
July, 2016 – SLR posted with a request for additional information.
September, 2016 – The Panel issued a tentative report with the conclusion that these
ingredients are safe as used. The Panel was satisfied that there was sufficient data for
each data point and that read-across for these data were appropriate.
The Panel acknowledged the moderately widespread clinical use of these ingredients to treat
bone diseases and determined that there were no systemic concerns about their use in
cosmetics based on the data presented. Although there were no phototoxicity or
photosensitization data, the Panel agreed that these ingredients are not expected to
absorb UV light. Inhalation data on sodium etidronate and genotoxicity data on sodium
etidronate and trisodium etidronate were used to address concerns about the lack of
inhalation toxicity data and the minimal genotoxicity data available for the ingredients in
this safety assessment.
April, 2017 – The Panel is to review the Abstract, Discussion, and Conclusion. A final report
should be issued.
Distributed for comment only -- do not cite or quote

Etidronic Acid and its Simple Salts Data Profile for April, 2017. Writer – Lillian Becker
Acute Repeated

ADME toxicity dose toxicity Irritation Sensitization
Penetration Dermal owLog K Use Oral Dermal Inhale Oral Dermal Inhale Ocular Animal Ocular In Vitro Dermal Animal Dermal Human Dermal In Vitro Animal Human In Vitro Repro/Devel Genotoxicity Carcinogenicity Phototoxicity
Etidronic Acid X X X X X X X X
Disodium Etidronate X X X X X X X X X
Tetrapotassium Etidronate X
Tetrasodium Etidronate X X X X X

Supporting Data:
sodium etidronate X X
trisodium etidronate X
etidronate X
Distributed for comment only -- do not cite or quote

Search Strategy – Etidronic Acid and Salts
SciFinder
Names and CAS Nos.
Etidronic Acid
2809-21-4
Disodium Etidronate
7414-83-7
Tetrapotassium Etidronate
14860-53-8
Tetrasodium Etidronate
3794-83-0

Tetrapotassium Etidronate - 40 hits, 0 useful
Disodium Etidronate – 560 Hits. Culled by “adverse effects, including toxicity”; “biological study”;
“preparation”; “properties”; “uses”; “additional related references”, 521 hits. Removed patents, 259 hits,
29 ordered.
Tetrasodium Etidronate - 363 Hits. Culled by “adverse effects, including toxicity”; “biological study”;
“preparation”; “properties”; “uses”; “additional related references”, 329 hits. Removed patents, 27 hits, o
useful.
Etidronic Acid – 8298 hits. Culled by “adverse effects, including toxicity”; “biological study”;
“preparation”; “properties”; “uses”; “additional related references”, 9436 hits. Removed patents, 4430 hits.
“Toxicity” – 244 hits.

Substance Search
3707 hits. Removed patents, 3707 hits. Refine by toxicity, 0 hits.
Refine by dermal, 7 hits, 1 useful.
Refine by skin, 48 hits, 5 useful.
Refine by carcinogen, 382 hits, English 382 (Culled by Concept Headings: human, drug toxicity, human
groups, carcinoma, allergy, animal cell line, animal tissue, rat, skin neoplasm, teratogenesis, teratogens,
toxicity, toxins) 56 hits
Refine by genotox – 1 hit, not useful
Refine by reproduction – 57 hits, 2 useful
Refine by teratogen – 4 hits, useful
Refine by manufacture – 18 hits, 0 useful
Refine by ocular – 13 hits, 1 useful
Refine by inhalation – 10 hits, 0 useful
Refine by irritation – 19 hits, 1 useful
Refine by sensitization – 135 hits, 1 useful

Additional Substance Search
Structure-based search of Ca, Mg, K, and Na salts of Etidronic Acid, minus those results found by
searching the actual ingredients. Removed patents and non-English results. 303 hits. 1 useful.
Duplicate info from another reference. Not useful.
Distributed for comment only -- do not cite or quote

PubMed
“etidronic acid” AND tox* 138 hits, 6 useful; ; AND derm*, 6 hits, none useful; AND carc*, 7 hits, 0 useful;
AND repro*, 1 hit, 1 useful; AND teratogen*, 0 hits; AND genotox*, 1 hit, not useful; AND ocular*, 4 hits, o
useful; AND inhal*, 8 hits, 0 useful.

“Disodium Etidronate” AND tox*, 6 hits, 2 useful; AND derm*, 0 hits; AND carc*, 0 hits; AND repro*, 39
hits, 0 useful; AND teratogen*, 2 hits, 0 useful;; AND genotox*, 0 hits; AND ocular*, 0 hits; AND inhal*, 1
hit, 0 useful.

“Tetrapotassium Etidronate” AND tox*, 0 hits; AND derm*, 0 hits; AND carc*, 0 hits; AND repro*, 0 hits;
AND teratogen*, 0 hits; AND genotox*, 0 hits; AND ocular*, 0 hits; AND inhal*, 0 hits.

“Tetrasodium Etidronate” AND tox*, 1 hit, not useful; AND derm*, no hits; AND carc*, no hits; and repro*,
no hits; AND teratogen*, no hits; AND genotox* no hits; AND ocular*, no hits; AND inhal*, no hits.

ECHA
CAS Nos. Data for etidronic acid and tetrasodium etidronate. No data for disodium etidronate and
tetrapotassium etidronate.

HPVIS – no hits

NTP – no hits

SCCP – HEDP and salts

NICNAS - HUMAN HEALTH TIER II ASSESSMENT FOR Etidronic acids
ToxNet – 4 sets of data.
Google – SIDS Dossier; NTIS summary
Distributed for comment only -- do not cite or quote

Transcripts - Etidronic Acid and Salts
September 2016
Dr. Marks’ Team
DR. MARKS: Okay. Any other comments about these group of ingredients? If not, then let's move on to
etidronic acids. This is the first review of these ingredients. The acid and its simple salts.
Tom, Ron and Ron, are you okay with the ingredients in this report?
DR. SHANK: Yes, we have all the information we need, it's safe as used.
DR. MARKS: That's the second part. Any (inaudible)?
DR. SLAGA: Yeah, we have all the information we need to.
DR. MARKS: Okay. Let me see, we have no sensitization for the disodium salt but it should be fine. We
can, okay to read across from the asset to the tetrasodium, disodium? Yeah?
DR. SLACK: Yes.
DR. MARKS: So we will second that, I will second a motion tomorrow, presumably with a safe
conclusion.
DR. HILL: From, from a chemistry perspective, I just wanted to say though, I wanted to make sure that
the toxicology information was searched, so as to include, because I didn't see this in the
search algorithm for sure, all of the simple salts of this, as opposed to a etidronic acid
itself, that, that we have captured all the pertinent toxicology information that might arise
from the simple sales, by which I mean sodium, potassium, maybe ammonium, the
simple salts, because I couldn't tell from the search algorithm that we would in fact
capture all of that. It might just be as simple as rerunning the -- simple as -- as rerunning
the search and including those, the CAS numbers for those salts, if nothing else, and just
search in chemical abstracts database which would also pick up PubMed at least,
because I, I wasn't clear from the algorithm that was given that we would capture tox that
was coming from testing those salts.
DR. HELDRETH: So, by, by that do you mean something beyond the, the names of the ingredients?
DR. HILL: Okay. Yeah, okay, so here, yeah, right, because for example, monosodium etidronate, sodium
etidronate, trisodium etidronate, monopotassium or dipotassium or tripotassium
etidronate, or an acetate or a citrate salt. So if you just stuck to the names of the
ingredients, you would miss some of those salts. And I guess the easiest way to search
that really would be by structure in the chemicals abstracts database and then you could,
if you had the search set that you had before, you could see if any, you know, merge this
and see if anything new pops up that you need to have a quick look at.
DR. DELDRETH: That can be done.
DR. MARKS: Any more comments? If not, then tomorrow, I'll second a motion presumably with a safe
conclusion.
DR. HILL: Just one, I have a general comment. I did not get, I did not get a chance, I couldn't get the
Journal of Chemical Education reference that's there for reference seven from home, and
I did not get a chance to go back to work where I could get it before I left for here. But I
wanted to make sure that that is talking about an industrial -- this is a general issue. That
it is talking about commercial production method rather than something that's done in a
research lab. So whenever we talk about method of manufacture, it's okay to talk about
laboratory synthesis. But what we really need to know is how are these things produced
commercially for the ingredients that enter into the cosmetics stream. In other words,
what cosmetic formulators are using, how are those produced commercially. Because
what that's about is what potential impurities are in there that we might have concern
Distributed for comment only -- do not cite or quote

about. That's really the main thing. What other substances, what impurities might we
have concern about that arise from the method of manufacture. So if we just have one
paper and it happens to be something that I did in my chemistry lab to synthesize this,
that might or might not reflect what's done commercially. There may be six or eight
different processes. We really need that information, but without violating intellectual
property rights, that's the caveat and the catch. But I think still sketchy enough
information can be provided without industry giving away trade secrets, that we still can
make an assessment there. That's what we're being asked to do, I believe.
DR. MARKS: Okay. Next ingredient is hops.
DR. SLAGA: I'll drink to that.

Dr. Belsito’s Team

DR. BELSITO: … Etidronic acid and its simple salts. So this is the first time we're looking at this
molecule or family. The majority of the data is going to be summaries from ECCA
[ECHA] website. It's reported in 341 formulations, 12 leave-on, use concentration up to
0.9 percent in other hair coloring preparations.
So with that as background, first of all these are bisphosphonates and so they're used
as -- bisphosphonates or other, I'm sorry. Thank you. And so they're used for treatment
of osteoporosis, osteopenia.
So I thought the systemic endpoints were okay but it was insufficient for UV absorption or phototox and
photosensitization and also we had very limited sensitization data. We should ask for
more.
DR. LIEBLER: Okay. I had no concern about absorption. These aren't going to they're not going to
absorb, or phototox because they don't absorb. There's no chromophore in these.
DR. BELSITO: All right.
DR. LIEBLER: Yeah. So these will not absorb UV light or visible light for that matter, so that's not an
issue as far as I'm concerned. And if you think we're short on sensitization data, then
we --
DR. BELSITO: No, I mean, I said we had limited, so since I was going insufficient for photo -- for photo
absorption, so then we need to look at exactly what we have for sensitization. So we
have guinea pig maximization with disodium Etidronic, 5 percent at induction, 25 percent
challenge, with 20 animals, and that was it for disodium Etidronic. That's the only
sensitization data we have.
DR. LIEBLER: Yeah. So this is something that I would ask you, if the fact that these moderately
widespread clinical use in trying to retain and promote bone density, and would you be
less worried about sensitization? I mean, these are taken orally, but are there other
expected correlates of something that might be a skin sensitizer that, you know, an
orally-taken drug that you would look out for and if you don't see it, then that reduces
your concern?
DR. BELSITO: I haven't seen much in the way of drug hypersensitivity to these. I mean, the big issue
with the bisphosphonates is if you try and get a dental implant while you're on them it's
going to fail. I mean that's been the thing that's been the big news in the medical
literature would be is you don't go doing dental implants on women with
bisphosphonates. But --
DR. KLAASSEN: Why is that?
Distributed for comment only -- do not cite or quote

DR. BELSITO: I don't, you know, I mean, I don't really follow that literature, but if you just google
bisphosphonates and apparently it results in bone necrosis and implant failure and huge
problems. But I don't know what the mechanism is.
DR. KLAASSEN: It didn't seem like it would help at first glance.
MR. DEWAN: Just the other way around. It should help.
DR. KLAASSEN: Yeah, theoretically but that's why in science you do experiments, because what you
think will happen doesn't always happen.
DR. LIEBLER: So these drugs inhibit bone absorption?
DR. BELSITO: Mm-hm. Yeah, I know.
DR. LIEBLER: So unless you feel we need more sensitization data, I was happy with what we had. I was
safe as used when formulated with nonirritating.
DR. BELSITO: Okay. So they cause osteonecrosis, oral bisphosphonates and experienced
osteonecrosis associated with dental implants. It's been huge lawsuits and I don't know
that they (inaudible).
DR. LIEBLER: Interesting.
DR. BELSITO: You know, I mean, I haven't seen it as a problem. You know, but I don't know how many
products on the market. I mean, quite honestly, I read labels all the time and I haven't
seen a lot of products that have contained these, so what kind of products are they used
in again? They're used 0.9. I mean, they're really low percentages. And the highest
percentages is.9. And in a rinse-off.
MS. BECKER: Hair coloring.
DR. LIEBLER: As (inaudible) agents in hair products.
DR. BELSITO: 0.12 in a leave-on. You know, I mean, they're such low concentrations.
DR. LIEBLER: Right.
DR. BELSITO: I mean, let's see what Jim says, but I mean, I'm okay. I'm just pointing out that --
MS. BECKER: Just pointing out detected sodium [Tetrasodium] is 254 uses in bath soaps and
detergents.
DR. BELSITO: Mm-hmm.
MS. BECKER: Otherwise, it seems to be mostly in hair products and nail products.
DR. SNYDER: So in several of the tox studies you talk about doses and active acid. So what does that
mean?
MS. BECKER: Do you want to go ahead?
DR. LIEBLER: It probably means the acid form, not the salt. Or the amount of the molecule that is not in
salt form.
DR. SNYDER: The NOEL was greater than or equal to -- I don't know if you can have a NOEL greater
than or equal to, but anyway, active acid kilogram per day Etidronic acid. Well, we
already know it's the acid because it's Etidronic acid; it's not a salt. So I don't understand
why that was specifically done in some of those and not all of them.
MS. BECKER: It was as provided by the source.
DR. SNYDER: And then in the developmental reproductive tox studies, you need to specify the NOELs,
N- O-E-Ls, whether they're material, fetal, or what. None of them are designated whether
it was maternal or fetal N-O-E- L.
MS. BECKER: A lot of studies, that's pretty much what they tell you without saying which way it goes.
But I will double-check.
DR. SNYDER: Down below you say, the last sentence of that section you say that the maternal and
fetal -- that was a N-O-E-L, but all the rest of them before you don't specify. It just says --
MS. BECKER: The source didn't say which way they considered it.
DR. SNYDER: Okay.