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Good Guidance Practices, GGP's. It does not create or confer rights for or on any person
and does not operate to bind FDA or the public. An alternative approach may be used if
such approach satisfies the requirements of the applicable statute, regulations, or both.
This guidance will be up dated in the next revision to include the standard elemnt s of GGP 's .
FRIDAY, JUNE 23, 1978
PART V
DEPARTMENT
OF HEALTH,
EDUCATION, AND
WELFARE
Food and Drug
Administration
ETHYLENE OXIDE,
ETHYLENE
CHLOROHYDRIN, AND
ETHYLENE GLYCOL
Proposed Maximum Residue
Limits and Maximum Levels
of Exposure
PROPOSED RULES
F. Mutagenicity controls. In animals exposed to the tions of ethylene oxide ranged from 2
Evidence from a variety of prokaryo- action of high concentrations of ethyl- percent for the conjunctiva to greater
tic (bacterial) and eukaryotic (animals ene oxide, chromosome abrerrations than 40 percent for the lens after a 6-
and higher plants) systems indicate were detected in 9.4f 0.9 percent; in hour acute topical ocular instillation.
that ethylene oxide causes mutations. animals exposed to the action of low After a single anterior chamber instil-
The test organisms include Drosophi- concentrations. 7.6f 0.1 percent; in the lation, 0.5 percent and 5 percent were
lia melanogaster (Rapoport. Ref. I?; control, 2.6f 0.3, (p<0.001). --- the maximum nondamaging concen-
Bird. Ref. 18; Nakao and Auerbach. trations of ethylene chlorohydrin for
Ref. 19). Neurospora c m s a (Kolmark the iris and conjunctiva, respectively.
and Kilbey, Ref. 20). barley (Ehren- C. Animal Subchronic Toxicity (Re-
berg and Gustafsson. Ref. 21; Sulowka A. Human Acute Tostcfty
et al.. Ref. 22). AsperpiUru (Morpurgo, peated doses for a period not ex-
Serious systemic toxic effects have ceeding 1year)
Ref. 23). and Salmonella typhimurium been reported from exposure to ethyl-
(Rannug. Ref. 79). The studies by ene chlorohydrin. Inhalation of ethyl- Ethylene chlorohydrin has been ad-
Embree and Hine (Ref. 24) and ene chlorohydrin vapor may result in ministered subchronically by the oral
Rannug et al. (Ref. 79) indicate that nausea, dizziness. vomiting. circulatory route. both by gavage and in the diet.
ethylene oxide can induce basepair failure. Btupification, and death. Poi- to the ra$. dog, and monkey. parenter-
substitutions (a type of gene muta- soning occurs from inhalation of 18 ally to the dog and rat; and by inhala-
tion). This is consistent with the DDm. Ethylene chlorohydrin irritates tion to rats (Refs. 4. 32. 41-44). Effects
action of monof unctional W l a t i n g mucous membranes and causes kidney include depressed weight gain and in-
agents. In addition, ethylene oxide has and liver degeneration The effects creased mortality. subacute myocardi-
been shown to induce chromosome ab- may be cumulative (Ref. 1). tis. and changes in organ weights.
errations in maize (Faberge. Ref. 25). Data from the 30-day subcutaneous
barley (Moutschen-Dahmen et al.. B. Animal Acute To+icfty dosing (27 mg/kg) of ethylene chloro-
Ref. 26). Vicia faba (loveless. Ref. 27). hydrin to dogs indicated hepatocellu-
1. Lethal dose from oral and paten- lar degenerative changes and in-
Tmfescantia (Smith and Lotfy. Ref. t d adminfstnrCLorr-The acute tax- creased sexm alkaline phosphatase
28). Drosophila (Nakslo and Auerbach. icity (ID,) values have been deter- and bilirubin levala One dog died. No
Ref. 19). and rats (Strekalova, Ref. 29, mined for ethylene chlorohydrin in hepatic effects were seen with signifi-
Efnbree and Hine, Ref. 24). mice, rats, rabbits, and dogs (Refs. 4. cantly lower .doses (9 mg or 3 mg/kg).
Embree (Ph.D. dissertation. Ref. 30) 43. 82-84). The results of these studies ~emi;lLferous tubular - degeneetion
employed three different assays for point to IDUvalues in a range of 56 was detected at the 27 and 9 mg/kg
mutagenicity in the rat. In a direct cy- mg/kg by the parenteral route in rats dose levels.
togenetic assay of bone marrow sam- to 178 -/kg by the oral route in mice In another study (Feuer. G. et al..
ples from rats 'exposed to 250 pprn of (Ref. 3). Ethylene chlorohydrin was Ref. 39). subcutaneous dally dosing of
ethylene oxide in air for 7 &/day for shown to be somewhat more toxic rats (20 -/kg of ethylene chlorohy-
3 days. the frequency of chromosome acutely than ethylene oxide. The drin for 7 days) caused a reduction in
aberrations increased from .05 (con- route of admfnlstration appeared to the activities of hepatic drug-metabo-
trols) to .84 (treated). In a rat domi- have little influence on the acute tox- llzing enzymes and of glucose 6-phos-
nant lethal assay conducted with icity values. The animals showed signs phatase. A trend of reduction was seen
males exposed to 1.000 pprn ethylene of central nervous system effects such also at 3 or 10 mg/kg in male rats.
oxide in air for 4 hours. increases in as depression and labored respiration A 21-day ocular irritation study has
post-implantation loss were found in and usually died within 24 hours with- been performed in rabbits with solu-
weeks 1. 2. 3. and 5 after exposure in- out specific organ pathology. tions of ethylene chlorohydrin. ethyl-
dicating genetic damage in post-meio- In another study (Friedman et al.. ene glycol, and combinations of ethyl-
tic and meiotic sperm cells. In the Ref. 38). a single oral dose of ethylene ene chlorohydrin and ethylene glycol
third test, a micronucleus test which chlorohydrin (10 to 50 m g / k g ) caused (Ref. 7). The concentrations of the
measures the appearance of micronu- a dose-related decrease of liver protein ethylene chlorohydrin solutions
clei in 'wbchromatic erYthrocutes. synthesis and glutathione level in rats. raqged from 0.1 to 40 percent; of the
rats in groups of five were e x b e d far 2. Imitation to eye and tissue&-The ethylene glycol solutions. from 0.5 to
4 hours to doses of 10. 25. 50. 250. and results of studies to determine the 80 perceneand of the combination so-
1.000 pprn of ethylene oxide in air. A acute effect of ethylene chlorohydrin lution of ethylene chlorohydrlrr and
linear increase in micronuclel was seen on eye and other tlssues have been ethylene glycol, from 0.1 percent/0.5
with doses up to 50 pprn (only 50 ppm summnarized by Bruch (Ref. 3). Maxi- percent to 30 percent/?O percent.
and above were statistically higher mal noeffect concentrations ranged Maxhial conjunctival congestion and
than controls). The effect of 250 pprn from 0.5 percent (0.25 mg total dose) discharge, moderate swellins, increas-
was only slightly greater than a t 50 ing corneal cloudiness, damage as ed-
administered subcutaneously in guinea denced by fluorescein statning, and
ppm. but the effect of 1.000 pprn was pigs to 20 percent (40 mg total dose) pannus were obsemed with solutions
more than three times greater than at by dermal application in the rabbit. In of 40 percent ethylene chlorohydrln;
250 ppm. Although. the micronucleus the eye and tissue studies by Woodard moderate conjunctival congestion.
test is an indirect test for chromoso- and Woodard (Ref. 4). ethylene chlor- minimal discharge and mfnlmal swell-
mal damage. studies (Refs. 76 and 77) ohydrin solution produced induration ing with solutions of 80 percent ethyl-
have shown that it correlates with and ecchymoses (small hemorrhages) ene glycol; and moderate conjunctival
some direct methods. f in one of -five anlmals tested following congestion, moderate discharge, mini-
In another study by Strekalova; E. subcutaneous injection (0.5 percent) in mal swelling, flare. hitis. corneal
E., et al.. tRef.,31) of the mutagenic the guinea pig. mlnirnal irritation cloudiness, damage as evidenced by
effect in rats of ethylene oxide on after dermal administration in the fluorescein staining, and moderate
mammalian somatic and reproductive rabbit, and lacrimation and conjuncti- pannus wlth solutions of 30 percent/TO
cells. cytogenic analysis of the: bone val erythema, corenal opacity, Lri* percent ethylene chlorohydrin/ethyl-
marrow and analysis of the male re- and conjunctival irritation following ene glycol.
productive cells were carried out by ocular adminlstratlon in the rabbit.
the method of dominant lethal muta- The acute eye irritant properties of D.Animal Chronic Toxicity (Repeated
tlons. Cytogenic analysis of the bone ethylene chlorohydrin (In a balanced doses for period exceeding 1 Year)
marrow showed an increased incidence salt solution) were investigated in the
of chromosome reorganizations in ex- rabblt by McDonald et al.. (Ref. 6). The results of oral and parenteral
perimental male animals compared to The maximal nondamaging concentra- administration of ethylene chlorohy-
in chronic toxicity studies are 2. ~miiationto we and thua-The C. Animal Chronic Toricit~ (Repeated
summarized In references 40 h d 44- results.of studies (Ref. 4) to determine do- for perlods exceeding 1year)
47. No chronic systemic toxic dfecb the acute eye and tissue irritant prop- A number of oral chronic studies
or carcinogenic effects were detected ertiea of ethylene glycol (In aqueous have been performed with ethylene
In mice and rats. aolution and in undiluted form) have glycol, but a no-effect level has not
E. Mulagenicitg been ~urmgarizedby Bmch (Ref. 3). been clearly established. In two rat
The highest no-effect concentration of studies (Refs. 52 and 53). dietary levels
Two studies have been reported in ethylene glycol ranged from 1 percent of 0.5 percent and higher depressed .
which increaseg in chromosome aber- (0.5 mg total dose) by subcutaneous
rations in rat bone marrow cells were administration to 10 percent by ocular growth and produced oxalate calculi
induced after exposure to ethylene (10 mg total dose) and intramuscufar and deposition of crystals in the kid-
chlorohydrin (Isakova. O. K., et al., (50 mg total dose) admhMration. neys. In one of these studies, the no-
Ref. 32 and Semenova, V. N., et 8I., Both ethylene glycol solutions and un- effect level appeared to be approxi-
Ref. 33). Rosenkranz and W'lodlro~~btdiluted compound produced aome mild mately 0.2 percent. In another study
(Ref. 341 found a dose-related increase Lnitati~nby the intandermal route. (Ref. 511, three monkeys were fed eth-
in mutation rate in strains TA1530 and transient lacrimation and erythema ylene glycol for 3 Years, one monkey
TA1535 of Sulmonella,but na fncnase from at a level of 0.2 percent and 2 monkeys
ocular sdministration, and mini-
in strain TA1538, which fndic8tes that mal irritatiu at a level of 0.5 percent. No effects
ethylene chlorohydrh Induces baSe- cation following dermal appli- were seen. In still another study (Ref.
pair substitutions, but not frameshift 47). ethylene glycol showed no car-
mutations. Data from studies by ethylene The acute eye lrrltant properties of cinogenic effect when administered
Rannug et al. (Ref. 79) show ethylene lution) were glycol tin a balanced salt 80- subcutaneously at a dose of 1.000 mg/
chlorohydrfn to be a weaker mutagen et al. (Ref. 6). investigated by McDonald kg twice a week to rats for 1year fol-
than ethylene oxide in causing mu& m The maximum nonda- lowed by an additional 6 months with
tions in SdmoneUa TA1535. a- concentrations of ethylene no treatment.
glycol 6 hours after topical ocular in-
F. Te?u&venicfty and FetotaeZcftu stillation ranged from 4 percent for D. Mutagenicfly
Verrett (Ref. 80) tested ethylene the conjunctiva to greater than 80 per- The Food and Drug Admlnlatration
chlorohydrin for teratogenic and feto- cent for the lens. After a single anter- is aware of one report (Rapoport, Ref.
toxic effects in the developing chick ior chamber infection of ethylene 17) which suggests that ethylene
embryo by injecting 5. 12.5, 25, and 50 glycol, the nondnmaging concentm- glycol at high concentrations may
mg/@ in the alr sac of 4-day old em- tions ranged from 2 percent for the cause mutations in DmophUfa. To
bryos. This resulted in a dose-related iris to from 20 percent to 80 percent FDA's knowledge, this has not been
increase in defective embryos. A later for the cornea. lens, and retina confirmed. Using a bacterial plate
study (Courtney and Andrews. Ref. B. Animal Subchronic Totteity (Re- assay. Embree (Ref. 30) tested ethyl-
81) in CD-1 mice failed to produce peated doses for a period not ex- ene glycol on S. typhimurfum strains
malformations when ethylene chloro- ceedlng 1Year) TA1535. TA1537. and TA1538 wlthout
hydrln was administered orally or by microsoma1 activation and found no
inhalation. 1. Oral, parentem& and inlrcrlcrtion revertents.
administmtiolr-In a subchmnic oral
EmYLENE GLYCOL stud$ in the monkey (Ref. 48). ethyl-
A Human Acute Toxicity ene glycol was sdminlstered in the The commissioner believes that
drinking water from 13 to 157 dam. there.b need for the continued use of
The shgle oral.lethal dose of ethyl- The no-effect level was 1milliliter per ethylene oxide as a steNant for cer-
ene glycol for a human has been esti- kilogram tml/kg) total dose. From 1
mated at 1.4 me/@ or about 100 milll- ml/ke to 15 ml/kg, mild glomerular tain drug products and medical devices
liters for an average adult (Rowe. Ref. damage with azotemh was not& for human use because of a lack of ac-
37). Thia estimaQ indicates that the Total doses of 15 -/kg and above pro- ceptable alternatives. Although steam
compound is more acutely toxic for duced deposition of calcium oxalate sterilization under pressure is usudXy
humans than for the animal spedes considered the most economical and
for which LDu ranges have been deter- crystals in the proximal renal tubules
and associated tubular degeneration.
the most efficient sterilant. maw
mined. heat-labile biochemical substances
In other suhchronic studies (Ref. 49). such as vitamins, amino addf and
B. Animal Acute Tartcity monkeys were exposed to ethylene antibiotics, as well as many plastics.
1. Lethal dose from oral and paren- glycol by inhalation a t a concentration cannot tolerate moist or dry heat. Fur-
ted adminfrtmtiolr-The most of 600 mllligmms per cubic meter (me/ ther. most articles that must be sterile
recent study of the acute and paren- ma), contlnuous~for 5 to 7 months. cannot be sterilized by ionidng radi-
teral toxicity of ethylene glycol by At 5 months. liver mitochonria showed ation because of physical damage due
four routes of administration-in mke, resplration and uncoupled oxidative to radiation As previously stated, for-
rats. and rabbits is summarized by phosphowlation Mitochondria from maldehyde and glutaraldehyde were
Bruch (Ref. 31. The LDuls ranged monkeys exposed for 6 and 7 months cited. (Ref. 1) as possible substitutes
from 2.4 gram/@ by the intraperiton- had nonnal phosphate/oxygen (P/O) for ethylene oxide; but no literature
eal route of administration in female ratios and resplration that was return- on tests for long-term toxidty is avaU-
mice to 17 gram/kg by the oral rou Lng to normal. Rats and mice exposed able for glutaraldehyde, and formalde-
In rats. Although there is some df by the inhalation route to 300 mg/m:
ation from earlier findings (Browning, 8 hrs/day, for 16 weeks. showed no ef-
hyde has been shown to be mutagenic
Nonetheless. when ethylene oxide is
Ref. 35; Lang et al. Ref. 36). the vari- fects (Ref. 50). In rats and dogs treat- used as a s erilant during the manu-
ation does not appear to be due to ed by the subcutaneous route for 30 facture of drug products and medical
dose concentrations or sex. Unlike em- days, 50 mg/kg was a noeffect dose devices for human use, its residue and
ylene oxide and ethylene chlorohy- for the rat; a noeffect dose was not es- that of its two major reaction products
drin. which gene* produced death tablished for the dog (Ref.4). Bqth may produce toxic reactions in pa-
within 24 hours. ethylene glycol pro- species showed an increased number of tients. Consequently. the Commission-
duced a number of delayed deaths white cella er is proposing herein to establish
which were associated with kidney le- 2. Ocular.--See discussion of ocular maximum residue limits and exposure
sions accompanied by the deposition irritation study in paragraph C. under levels for ethylene oxide. ethylene
of oxalate crystals in the kidney. "Ethylene Chlorohydrin" above. chlorohydrin, and ehtylene glycol.
Residue limits would be set for certaln of ethylene oxide, ethylene chlorohy- proposal, a drug product intended to
drug products for human and,veteri- drin. and ethylene glycoi can be reli- be reconstituted or diluted prior to dis-
nary use; for medical devices for ably determined: Gas and thin-layer pensing or use would be required to
human use, and for certain other arti- chromatogra~hlc. polarographic, co- conform to the established residus
cles. The proposed limits are intended lorimetric, mass spectrographic, radio limits as reconstituted or diluted. This
to take into consideration the lowest tracer and other methods have been requirement is consistent with the
possible llmits achievable under cur- published which can identify and purpose of the proposed current good
rent good manufacturing practices. measure minute residues of ethylene manufacturing practice regulations.
Maximum daily exposure levels oxide and its reaction products. None- regarding the maintenance of a prod-
would also be set, but for drug prod- theless, the Commissioner recognizes uct's identity. strength. quality, and
ucts only. These proposed exposure that there are technical problems as- purity until its time of use.
levels are based on the toxicity data sociated with identifying and deter- B. Medical Devices for Human Use
previously discussed. The Commission- mining the minute amounts of ethyl-
er is proposing to include the residue ene oxide and ethylene oxide reaction The Commissioner also proposes to
limits and exposure levels for drug products. For example. any of the fol- establish maximum residue limib for
products for human and veterinary lowing factors may affect the amount ethylene oxide. ethylene chlorohydrin.
use in the current good manufacturing of residue of ethylene oxide and its re- and ethylene glycol in certain devices
practice regulations in 21 CFR Part action products or how readily that intended for human use: small im-
211. The residue limits for medical de- residue can be detected: the applied plants (less than 10 grams). which in-
vices would be included in a new 21 dosage, the type and cycle of the ster- clude sutures and contact lenses.
CF'R Part 821. The Commissioner in- ilizer'and conditions of aeration. the medium implants (10 to 100 grams).
tends that these requirements will, for physical state. catalytic nature. and large implants (greater than 100
those patients using drugs and medical reaction Ishietics of the product, the grams), intrauterine devices, intraocu-
devices for human use for which eth- diffusion rate of ethylene oxide into lar lenses, devices contacting human
ylene oxide has been used as a steri- and out of the product, the m~isture mucosa (mouth, nose. trachea. urinary
lant. limit exposure to ethylene oxide. and lrlr content in the product, and tract), devices contacting blood but
ehtylene chlorohydrin, and ethylene any synergfstic effects. The Commis- used outside the body (hernodialysis
glycol to levels below those that are sioner advises that he will view as cur- units, blood oxygenators, blood bags).
presently known to be harmful. rent good manufacturing practice any devices contacting normal skin (surgi-
generally accepted scientific method cal drapes. bandages). and surgical
M A l u M u x RESIDUE LIMITS for laboratory control of residues of scrub sponges.
ethylene oxide and its two major reae As wlth drug products, the residue
A. Drug Products and O k Articles tion products if it includes (1) batch limits proposed are the maximum ac-
for Human and Veterinary Use sampling. (2 3 appropriate sample sizes. ceptable limits for medical devices in
The notice proposes maximum resi- (3) sample handling techniques which their market containers at the time of
due limits for ethylene oxide, ethylene assure no residue loss from the point release for marketing. The residue
chloroh~drir.and ethylene glpcol in of sample collection to that of assay limits were derived from values devel-
ophthalmic prepamti& fo; -topical completion, and (4) adequate methods oped from a Toxicity Working Group
use. injectable ~ r e ~ a r a t i o ntlncluding
s to measure product residue changes of the AAMI Ethylene Oxide (279)
veterinary ink-ry infusion from the time of sample collection Subcommittee, from industrial data
products), intrauterlne devices con- during the quarantine period to the submitted to FDA in response to the
taining a drug component. surgical time of release of the product for ship- September 12. 1973 FEDERALREGISTER
scrub sponges containing a com- ment and sale. notice, and from residue limits already
ponent. and hard gelatin capsule The Commissioner further purposes established by current good manufac-
shells. The residue limits would be the that. for each drug product in which turing practice for similar products
maximum acceptable W t s for any of ethylene oxide ls used as a sterilank abject to approved new drug applica-
these drug products or other article the manufacturer prepare a residue tions. For example, the proposed resi-
for which ethylene oxide is used as 8 dissipation curve for residues of ethyl- due Wts for intrauterine devices and
sterilant during any part of the manu- ene oxide. ethylene chlorohydrin. and surgical scrub sponges are the same as
facturing process. including the manu- ethylene glycol for each manufactur- those being propbed by thfs notice for
facturing proceSs for any component ing procedure in which ethylene oxide similar articles which are classified as
of the product or for the product's is used as a sterilant. This will provide drugs.
container. The limits would apply to a full dissipation profile for each ster- As in the case of drug products. resi-
the product as it appears in its market ilized article and will enable a manu- due Urnits established for certain
container at the time it is releasd for facturer to determine the point in medical devices would apply if ethyl-
marketing. and throughout the period time at which the product will be ene oxide was used at a sterilant
of its shelf life. The llmits proposed within the established limits for pur- during any part of the manufacturing
are based on data that have been pre- poses of release for marketing. process of the device. including the
viously submitted to FDA in new drug As noted, the Commissioner has also manufacturing process for any compo-
applications. which data consist of proposed that the residue limits would nents of the device. or the device's
values that are currently being net by apply during the shelf life of the prod- market contaher. Each device manu-
some manufacturers. uct. Proposed current good manufac- facturer would be required to assure.
Under the proposed regulatioh. turing pkctice regulations published by appropriate laboratory testing, that
each manufacturer of a drug product in the FEDFXAL REGISTER of F t ? b ~ - the device as it appears in its market
or other article to which the residue 13. 1976 (41 F'R 6878) wo rld require contaher does not exceed the residue
limits apply would be required to expiration dating for all drug products limit when released for marketing.
assure by appropriate laboratory test- so the application of the residue re- Some analytical methods that will pro-
Lng that such product or other article quirement throughout a productpa duce reliable determinations of resi-
in its market container does not shelf life is consistent with the pur- dues in drugs of ethylene oxide. ethyl-
exceed the residue l M t s when re- pose of the proposed current good ene chlorohydrin. and ethylene glycol
leased for marketing. The Commis- manufacturing practice regulations have been discussed under parsgraph
sioner advises that a number of an& that products maintain their identity, A above. The Association for the Ad-
lytical methods (Refs 54 through 75) strength. quality, and purity until the vancement of Medical I n s t ~ e n t a -
are available through which residues time of use. In addition, under this tion Ethylene Oxide (279) Subcorn-
mittee has validated (Ref. 57) three Current calculations reading to esti- sioner, to adequately protect users of
analytical methods for the detection mates of human genetic risk are based products sterilized with ethylene
of residues in medical devices (Refs. on various assumptions and tests that oxide, proposes to add an additional
54. 55. and 56). In addltion. some man- are in a relatively early stage of evalu- safety factor of 10 in proposing an ac-
ufacturers and equipment producers. ation and Widation. Levels of ethyl- ceptable exposure level. A level of 30
and certain others persons have devel- ene oxide and ethylene chlorohydrin micrograms per kilogram per day (pg/
oped methods or have sponsored the considered safe by traditional toxicolo- kg/day) for 30 days is therefore pm-
publication of methodology for deter- gical tests (for example. measurements posed as an acceptable level of expo-
mining residues on treated plastics. of physiological, biochemical. or sure to ethylene oxide residue.
fabrics. and pharmaceuticals (Refs. 58 pathological changes in the body func- Ethylene chlorohydrjn-In the Woo-
through 75). tion) may not be safe when the poten- dard and Woodard study (Ref. 4)'dogs
The proposed mle would further re- tial for mutagenicity is considered. and rats also received subcutaneous in-
quire. as in the case of drug products. Nonetheless, the Commtssioner's judg- jections of ethylene chlorohydrin for
for each medical device for human ment is, given the potential risk of MU- 30 days. At the lowest ethylene chloro-
use, including its component parts and tageniclty from exposwe to ethylene hydrin level tested 13 rng/kg/day). and
market container. that the manufac- oxide and its reaction product ethyl- as with ethylene oxide, some of the
turer prepare a residue dissipation ene chlorohydrin, that he must at- animals showed slight hematological
curve for residues of ethylene oxide. tempt now to restrict that exposure in- changes. and 1/4 dogs had ectopic he-
ethylene chlorohydrin, and ethylene sofar as products within his jurisdic- rnatopoiesis of the spleen (see the dis-
glycol for each manufacturing proce- tion are involved. He therefore pro- cussion of h i n d Subchronic Toxic-
dure in which ethylene oxide is used poses to establish maximum daily ity. Paragraph C, under Ethylene
as a sterilant. This would provide a levels of exposure based on available Chlorohydrin). Amin, the dose-re-
dissipation profile for. each sterilized toxicity data. certain assumption^, and sponse data by Woodard and Woodard
article and would enable a manufac- the application of an additional "best do not show a clear "no effect" level.
turer to determine the point in time at judgment" safety factor. The C o w Based on the trends shown by the
which the medical device would be sfoner advises that as the scientific dose-response data. Bruch again esti-
within the established residue limits basis for making risk judgments rela- mated that if the lowest dose tested
so that it might be released for mar- tive to mutagenic it^ imsroves. the were cut by 50 percent (te., 1.5 mg/
keting. agency will reconsider - established kg/day), a "no effect" level had a high
The Commission is not. at this time. maximum daily levels of exposure. probability of being achieved. As with
proposing that the residue limits es- This reconsidedon may involve a ethylene oxide. Bruch then applied a .
tablished for medical devices be maln- further lowering of these exposure 10-fold safety factor which yields an
tained throughout the shelf life of the levels. The Commissioner proposes to assumed safe level of 0.15 mg/kg/day
device. Diffusion of ethylene oxide establish maximum daily levels of ex- for 30 days for man.
and its reaction products from a device posure to ethylene glycol based on Because of mutagenic potential of
is influenced by several factors, such available toxic it^ data ethylene chlorohydrin and because of
as the type of material in the device The ~ommis&oner therefore pro- its similarities with ethylene oxide.
(ex.. type of plastic). physical dimen- ~ o s e s to establish maximum daily the Commissioner believes that the
sions. exposed surface areas. and pack- ievels of exposure to ethylene oxid& same additional safety factor is s m -
aging. Further. residues of ethylene ethylene chlorohydrin, and ethylene larly appropriate for produds contatn-
oxide are more likely to be converted glycol based on the following calcula- ing ethylene chlorohydrin Therefore,
to ethylene.glyco1 (the less toxic of tions: he proposes that an additional safety
the reaction products) than to ethyl- Ethylene oxi&-In the toxicity factor of 10 be applied, yielding an ex-
ene chlorohydrin. The Commissioner studies reported by Woodard and posure level of 15 pg/kg/day of ethyl-
believes that even though a theoreti- Woodard (Ref. 4). dogs and rats re- ene chlorohydrin residue.
cal calculation could be made that the ceived subcutaneous infections of eth- Ethylene glycol.-The Woodard and
residues of either ethylene chlorohy- ylene oxide for 30 days. At the lowest Woodard study also contained data on
drin or ethylene glycol could increase level of ethylene oxide administered (6 a 30-day toxicity study in dogs and
from the time of shipment of the mg/kg/day) (see paragraph C.1. under rats based on daily subcutaneous infee
device. there should also be a corre- "Ethylene oxide" above). some hema- tions of ethylene glycol. At the lowest
sponding loss of these residues based tological changes were noted in both ethylene glycol level tested (50 m g /
on diffusion. The Commissioner con- animal species and 2/4 dogs had ecto- kg/day 1. there were some slight hema-
cludes that. until more data are availa- pic hematopoiesis of the spleen. Thus, tological changes in the anlmnln. As
ble regarding the diffusion of residues the dose-response data by Woodard with ethylene oxide and ethylene
from device materials. he cannot rea- and Woodard do not show a clear "no chlorohydrin, the dose-response data
sonably expect a manufacturer to effect" lever for ethylene oxide. Based from the study do not .show a clear
assure that devices comply with these on the trends shown by the dose-re- "no effect" level. Based on trends
residue limits throughout the shelf sponse data. Bruch (Ref. 3) estimated shown by the dose-response data,
life of the device. that if the lowest dose tested had been Bmch estimated by cutting the lowest
MAXIMVEd DAXLY LEVELS OF EXPOSDRE cut by 50 percent (1.e.. 3 mg/kg/day). a dose tested by 50 percent (25 mg/&/
"no effect" level had a high probabil- day). a "no effect" level had a high
A. Drug Prpducts and Other Artices ity of being achieved. A 10-fold safety probability of being achieved. As with
for Human and Veterinaty Use , factor (a factor frequently used in ex- ethylene oxide. Bmch applied a 101
The Commissioqx also proposes to trapolating systemic "no effect" doses fold safety factor, which yields an esti-
establish maximum daily levels of ex- to m: n) was then applied by Bruch to mated safe dose of 2.5 mg/kg/day for
posure to ethylene oxide and ethylene yield an assumed safe level of 0.3 mg/ 30 days. Because the Commissioner is
chlorohydrin. because of the p'otential kg/day for 30 days. Using that safety not aware of evidence showing ethyl-
risk of mutagenicity from exposure to factor for a 70-kg man, the safe (In ene glycol to have mutagenic poten-
drug products containing these resi- terms of toxicity) daily dose would be tial. he concludes that an additional
dues. He also proposes to establish a 21 mg. safety factor is unnecessary.
maximum daily level of exposure to However. because ethylene oxide has B. Medical Devices for Human Use
ethylene glycol because of known tox- irreversible toxic effects. e.g.. muta-
icity from exposure to drug products genicity, for which sufficient dosage The Commissioner has determined
containing this residue. data are not available, the Commis- that the maximum levels of exposure
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