This guidance was written prior to the February 27, 1997 implementation of FDA's

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

[4110-031
DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE
Food and Drug Administration
[21 CFR Parts 21 1 and 8211
[Docket No. 77N-04241
ETHYLENE OXIDE, ETHYLENE CHLOROHYDRIN,
AND ETHYLENE GLYCOL
Proposed Maximum Residw Units and
Maximum Levels of Exposure
AGENCY: Food and Drug Admtnistm
tion.
ACTION: Proposed rule.
SUMMARY: This proposal would
impose restrictions on the continued
use of ethylene oxide as a sterilant for
certain drug products and medical-de-
.vices for human use,by: (1)Establish-
lng maximum residue limits for ethyl-
ene oxide and its two major reaction
Droducts. ethylene chloroh~drln (2-
chloroethanolj and ethyleneglycol, in
drug ~roductsfor human and veterf-
nary use. including biological products
for human use. and in medical devices
for human use and (2) establishing
maximum,daily levels of exposure for
drug products for ethylene oxide and
its two major reaction produck Thia
action is being taken because residues
of ethylene oxide and its two major re-
action products in drug products and
devices for which ethylene oxide is
used as a sterilant may produce toxic
reactions in patients, and because of
the potential risk of mutagenicity
from exposure to these residues.
DATES: Comments by August 22,
1978. The Commissioner proposes that
the final regulation based on this pro-
posal be effective 60 days after pub&
cation of the final regulation in the
FeDnuLREGISTER.
ADDRESS: Writen comments (four
copies. indentifled with Docket No.
77N-0424) to the Hearing Clerk (HFC-
20). Food and Drug Administration,
Rm. 4-65. 5600 Mshers Lane. Rock-
ville. MD 20857.
FOR FUR- INFORMATION
CONTAC'E
Marilyn L. Watson. Bureau of Drugs
(HFD-SO), Food and Drug Admlnln-
tration, Department of Health, Edu-
cation. and Welfare. 5600 Mshers
Lane. Rockville. MD 20857. (301-443-
3640). Z
SUPPLEMENTARY INFORMATION:
Ethylene oxide %hasbeen used for a
number of years M a sterilant for
human drugs (ex.. certain ophth+Udc
and parenteral drug products), veterl-
nary drugs te.g.. ophthalmic ointments
for small animals and certain i n t m
mammary lnfusion products). biologi-
cal products for human use (ex.. tu-
berculin test preparations and inacti-
FEDERAL REGISTER, VOL 43, NO. 122-FRIDAY. JUNE 23, 1978
PROPOSED RULES
vation of some vaccines), medical de- (HEW) Committee to Coordinate
vices for human use containing heat Toxicology and Related Programs
sensitive plastic components (e.g.. chartered a subcommittee to provide
hsart pacemakers, kidney dialysis ma- the Assistant Secretary for Health
chines. and heart lung machines) as with a comprehensive analysis of the
well as for other devices such as surgi- benefits and risks of ethylene oxide.
cal sutures, intraocular lemks. and The HEW subcommittee concluded in
surgical scrub sponges. Ethylene oxide a report of April 1. 1977 .(Ref. 1) that
also has been used as a sterilant for "ethylene oxide is an extremely useful
the individual ingredients of drug chemical which. unformnately. pos-
products and for containers, container sesses mutagenic properties." The
closures, and delivery systems of drugs report further stated that "there is
and medical devices for human use. little evidence that it is also carcino-
Because some drugs. medical devices genic to experimental animals, al-
for human use, and other articles though adequate testing has yet to be
cannot be sterilized by heat, filtration. conducted."
radiation, or liquid chemical agents The Environmental Protection
without degradation or other damage, Agency (EPA) reviewed the report of
gaseous sterilization must be used. the HEW subcommittee and other lib
Possible substitutes for ethylene o#de erature available on the toxicity of
are formaldehyde or glutaraldehyde. ethylene oxide and its two major reac-
Of these. there is no literature on tests tion products and fssued in the FEDER-
for the long-term toxicity of gluteral- AL REGISTERof January 27. 1978 (43
dehyda. Formaldehyde has. however. FR 3801) a "Notice of Rebuttable Pre-
been shown to be mutagenic (Ref. 1).
Ethylene oxide is an allrylating sum~tion Aeainst Registration and
continued E&gistratlon of Pesticide
agent which reacts primarlly with nu- Products
cleophtllc groups-amfnes. alcbhols. based en Containine Ethylene Oxide,"
reports of mutagenicity and
phenols, organic and inorganic adds, reproductive effects. This is the f i r s t
and water. Its biochemical reactions
include those with the ring nitrogens step in EPA's regulatory procedures
that could result in cancellation of the
of purine and pyrimidine bases and registration
the amino and carboxy groups of as a pesticide of ethylene
amino acids and proteins. Ethylene oxide. The EPA action and this proposal
oxide reacts with the chlorlde ion to should be viewed as compatible efforts
form ethylene chlorohydrfn or with to reduce the risks presented by ethyl-
water to form ethylene glycol.
In re~ponseto questions raised re- ene oxide to levels which are consid-
garding the safety and effectiveness of ered safe. At present. there are several
ethylene oxide as a sterilant for druRs memoranda of understanding between
and medical devices for human use FDA and EPA under which the two
agencies have agreed to share regula-
and because of reports of serious ad- tory
responsibility for actions which
verse reactions associated with the use under the varlous statutes they
of products sterilized with ethylene arise The existing memoranda
oxide. a notice was published in the administer.
FeDnu~REGISTEX of September 12, do not discuss the particular regula-
1973 (38 FR 25213) inviting the sub- tory ene
problems associated with ethyl-
oxide, however. and the precise de-
mission of published and unpublished regarding the relationship be-
data concerning the use. performsnce,
and toxicity of ethylene oxide and its tween this action and the notice of re-
reaction products, or any other date tion buttable presumption agsfnst reglstra-
having a bearing on the safety and ef- Issued b y EPA must await -each
fectiveness of ethylene oxide. agency's final action.
-An internal Food and Drug Adminis- In addition to its use as a sterilant in
tration (FDA) Ethylene oxide Review the manufacture of drugs and devices.
Committee evaluated the data subtnlb uses with which this proposal is con-
ted in response to this notice, other cerned, ethylene oxide Is also lisw ln
data contained in new drug appllcb FDA's food additive regulations as a
tions and petitions, data submitted by fumigant for the control of m l m r -
the Association for the Advancement ganisms and insect infestation Jn
of Medical Instrumentation (AAMI) ground spices and other natural sea-
Ethylene oxide (2-79) Subcommittee, soning materlsls. A separate Proposal
and data from other sources. The FDA concerning the food additive uses of
committee submitted recornmencia- ethylene oxide will be published in the
tions to the Commissioner of Food and FEDERALREGISTER in the future.
Drugs on May 30.1975 (Ref. 2). One of The Commissioner has no informa-
the actions recommended by the FDA tion showing that ethylene oxide is an
committee and approved by the Com- essential sterilant for cosmetics; t&ere-
missioner was'the eventual ~ublication fore no requirements that permit its
of maximum residue llmiti for ethyl- continued use as such are proposed
ene oxide and for it8 two major reac- herein. Nonetheless. the Commission-
tion products, ethylene chlorohydrfn er Invites the submission of data or
h d ethylene glycol. other information regarding the use of
In January 1977, the Department of ethylene oxide as a skil8nt for COS-
Health. Education, and Welfare's metics. The FDA is partic~larlyinter-
 PROPOSED RULES 27475
ested in information on the types and mum nondamaging concentration of four dogs at all dosage levels. Other
frequency of use of ethylene oxide. on ethylene oxide ranged from 0.1 per- pharmacologic effects observed were
methods of determining residual cent for the anterior chamber. iris, muscular hypertonidty. lawered body
amounts of ethylene oxide. ethylene and lens to 1 percent for the cornea temperature, prostration (at the 54-
chlorohydrin, and ethylene glycol in and conjunctiva m / k g dosaee) and ataxla, duglcfsh be-
cosmetics, and on procedures that 3. Inhcrlcrtion-Hhe and Rowe (Ref. havior, tremors. loss of skin elastidty,
might be followed to reduce residual 8) compiled data on inhalation expo- lacrimation. and conjunctival conges-
levels to the lowest concentrations ob- sure from studies of Jacobson et al. tion (at the 36-mg/kg dosage).
tainable under current technological (Ref. 9). Hollingsworth et al. (Ref. 10). 2. I ~ a 2 a t i o n . - H o ~ o r t het al.
constraints. Waite et al. (Ref. 111, and Flury and (Ref. 10) and Jacobson et rd. (Ref. 9)
Zernik (Ref. 12). The data illustrate canduded studies in which a vulety
the variable lethal response by SpedeS, of animal species (rats. rabbits. mon-
The following information summa- concentration, and duration of expo- keys, mice, gulnea pfgs) were repeated-
rizes the toxicity data on ethylene sure for guinea plgs, cats. dogs, and b exposed to ethylene oxide vapors at
oxide. ethylene chlorohydrin, and eth- rabbits. In gene* no deaths were re- concentrations that ranged from 100
ylene glycol as contained in the HEW ported at ethylene oxide exposure to 841 ppm. The result8 of these stud-
subcommittee report as well as addi- levels of 250 to 280 parts per dllion ies are sumrmrrlred by aine and Rowe
tional toxicity data received by the (ppm) for these anlmaln. (Ref. 8). Pathological fiAdings.includ-
agency since the HEW subcommittee C. A n f d Subchmnfc Tosidty (re- ed growth depression, anemia, imp&-
report. peated doses for a period not ex- ment of nervous system function in-
ceeding 1year) cluding posterior paresis and transient
LTRYLMt OXIDE parrr~legla,severe lung Wurp and, in
1. O d and parentcml administra- guinea pig& degeneration of the tu-
A. Human Acute Toxfcitv tfon-Ethylene oxide was adminis- bules of the testes.
Ethylene oxide is an eye and respira- tered to rats orally by gavage five
,
tory tract irritant and a skin vesicant times a week (Ref. 10). At the high D. Hemolytic Wects.
(blistering agent). Nausea, dizziness. dosage level (100 mgflrg. 15 doses were Hemolysh has been nported wfth
and signs'of mental disturbance have administered in 21 days) a marked loss ethylene oxide sterilized devices used
been observed in humans accidentally of body weight, gastric irritation, and for blood perfusion, and with devices
exposed to high concentrations of the slight liver damage were found. Re- used for intravenous admlalstrstion In
compound (Ref. 1).
b. Animal Acute Tozicity
peated oral d- of 30 me/& given
daily, 5 days a week, for a period of 30 -
~atients(Refs. 85-87). Anemia of dos&
- ~ - - - - ~

related severity was reported (Ref.4)

days produced no toxic effect fn rats. to have develoDed in dogs injectedsub-
1. Lethal dose from oral and paren- In another study (Ref. 4). ethylene cutaneeus4 (6 to 36 ethylene
terd adminfstmtfon-The LDU of oxide was Bdministered to rats and oxide in saline solution for 30 -1.
ethylene oxide (administered in aque- dogs by daily subcutaneous Injection However, a later study by FDA waS
ous solution to rats. mice. and rabbits) for 30 days at 3 dosage levels (6. 18, unable to confirm the findine of
from oral and parenteral exposure and 54 -/kg). In the dog study, the anemia In this FDA s h r d ~ , three
(studies by Woodard and Woodard. high dosage level was reduced to 36 beagle dogs were dosed intravenously
Ref. 4) has been summarized by Bruch mg/kg on day 7 due to severe pharma- with ethylene oxide glucose solution
(Ref. 3). The doses ranged from 127 cologic and toxicilogic effeds and con- daily for 3 weeks. Doses were in-
milligrams per kilogram (mg/kg) by tinued at that dosage for the remain- creased from 3 to 60 m/kg at ixitefi
the subcutaneous route in the rat to der of the study. The noeffect level vah. Three controls received the vehi-
631 mg/kg by the oral route in rabbits. for the rat was 18 mgflrg. A no-effect cle. No evidence of anemia was detect
In most &es. deaths occurred within level was not established for do& how- ed (Bal-. Ref, 13).
24 hours. Signs of ~harmacolo~ica~ ever. the lowes do- admtnistered
action included ataxic prostration, la- was 6 mg/kg. All rats survived the du-
bored respiration. and an occasional ration of the study but experienced in- E. Allcwenic Response
tonic convulsion flammation and OCC8S10nal hemor- Sensftizataon-allergic-type reacttons
2. Irritation to eye and tfssueb- rhage and necrosis at the injection have been reported in workers
Woodard and Woodard (Ref. 4) in a sites. 'Male rats at the high dosage drenched with ethylene oxide ~0luti0n
study designed to determine the acute level showed a mean body weight of 92 (Sexton and Henson. Ref. 14) and ps-
eye and tissue irritant properties of percent of that achieved by control tients exposed to improperly degassed
ethylene oxide tin aqueous solution) rats. dressings (Hanifln, Ref. 15). Ethylene
reported no effect at solution concen- Dogs on the high level dosage 54(36) oxide (1 percent solution) was mot a
trations ranging from 0.1 percent (5 -/kg showed extensive and some contact sensitizer in the occlusive
mg total dose) by subcutaneous admin- times necrotic idlammatory changes. patch test in guinea pigs nor did a Q.1
istration to guinea plgs to 2.1 percent whereas dogs at a lower level dosage percent ethylene oxide solution pro-
(2 me total dose) by ocular instillation (18 m g / k and 6 -/kg) showed duce sensitization by the intracutan-
in rabbits. marked local inflammatory changes. eous injection method In this spedes
In a study by McDonald et al. (Ref. The study also showed increased mor- t Woodard and Woodard, Ref. 4).
6). the acute eye irritant properties of tality at the high level dosage (54(36) In a report (Ref. 78) of recent skin
ethylene oxide tin a balances salt solu- -/kg). and reduced hemoglobin and irritation studies by Shupak, spon-
tion) were investigated in rabblts. 'I? hernatocrit
$? values at all dosage levels. sored by AAMI. Ethylene Oxide (Z-79)
study showed that the maximum non- Hemstological changes of dose-related Subcommittee. delayed sensitization in
damaging concentrations (highest con- severity attributed to sever local tlssue human subjeds was observed in re-
centration that produced no treat- injury at the injection sites were re- sponse to ethylene oxide contained in
ment-related damage to the eye) of ported. Hepatic ohanges such as in- polyvinylckloride blocks and films and
ethylene oxide for ocular tissues after creased liver weights a t each dose. and in petrolatum. This finding supports
a 6-hour acute topical ocular instill& cholestasfs at the high dose (54(36) an earller report of anaphyla~bfrom
lion varied from 0.1 percent in the mg/kg) in each dog and at the mid reaction products of ethylene oxide
conjunctiva.to greater than 20 percent dose (18 -/kg) in one of four dogs. gas used in the sterilization of renal
for the lens and retina After a single were observed. Increased ectopic he- dialysis equipment (Poothullfl et al..
anterior chamber injection. the maxi- matopoiesis was observed in two of Ref. 16).

FEDERAL REGISTER, VOL 43, NO. 122--FRIDAY, JUNE 23, 1978


F. Mutagenicity
Evidence from a variety of prokaryo-
tic (bacterial) and eukaryotic (animals
and higher plants) systems indicate
that ethylene oxide causes mutations.
The test organisms include Drosophi-
lia melanogaster (Rapoport. Ref. I?;
Bird. Ref. 18; Nakao and Auerbach.
Ref. 19). Neurospora c m s a (Kolmark
and Kilbey, Ref. 20). barley (Ehren-
berg and Gustafsson. Ref. 21; Sulowka
et al.. Ref. 22). AsperpiUru (Morpurgo,
Ref. 23). and Salmonella typhimurium
(Rannug. Ref. 79). The studies by
Embree and Hine (Ref. 24) and
Rannug et al. (Ref. 79) indicate that
ethylene oxide can induce basepair
substitutions (a type of gene muta-
tion). This is consistent with the
action of monof unctional W l a t i n g
agents. In addition, ethylene oxide has
been shown to induce chromosome ab-
errations in maize (Faberge. Ref. 25).
barley (Moutschen-Dahmen et al..
Ref. 26). Vicia faba (loveless. Ref. 27).
Tmfescantia (Smith and Lotfy. Ref.
28). Drosophila (Nakslo and Auerbach.
Ref. 19). and rats (Strekalova, Ref. 29,
Efnbree and Hine, Ref. 24).
Embree (Ph.D. dissertation. Ref. 30)
employed three different assays for
mutagenicity in the rat. In a direct cy-
togenetic assay of bone marrow sam-
ples from rats 'exposed to 250 pprn of
ethylene oxide in air for 7 &/day for
3 days. the frequency of chromosome
aberrations increased from .05 (con-
trols) to .84 (treated). In a rat domi-
nant lethal assay conducted with
males exposed to 1.000 pprn ethylene
oxide in air for 4 hours. increases in
post-implantation loss were found in
weeks 1. 2. 3. and 5 after exposure in-
dicating genetic damage in post-meio-
tic and meiotic sperm cells. In the
third test, a micronucleus test which
measures the appearance of micronu-
clei in 'wbchromatic erYthrocutes.
rats in groups of five were e x b e d far
4 hours to doses of 10. 25. 50. 250. and
1.000 pprn of ethylene oxide in air. A
linear increase in micronuclel was seen
with doses up to 50 pprn (only 50 ppm
and above were statistically higher
than controls). The effect of 250 pprn
was only slightly greater than a t 50
ppm. but the effect of 1.000 pprn was
more than three times greater than at
250 ppm. Although. the micronucleus
test is an indirect test for chromoso-
mal damage. studies (Refs. 76 and 77)
have shown that it correlates with
some direct methods. f in one of -five anlmals tested following
In another study by Strekalova; E.
E., et al.. tRef.,31) of the mutagenic
effect in rats of ethylene oxide on
mammalian somatic and reproductive
cells. cytogenic analysis of the: bone
marrow and analysis of the male re-
productive cells were carried out by
the method of dominant lethal muta-
tlons. Cytogenic analysis of the bone
marrow showed an increased incidence
of chromosome reorganizations in ex-
perimental male animals compared to
FEDERAL REGISTER, VOL 43. NO. 127.--FRIDAY, JUNE 23, 1978
PROPOSED RULES
controls. In animals exposed to the
action of high concentrations of ethyl-
ene oxide, chromosome abrerrations
were detected in 9.4f 0.9 percent; in
animals exposed to the action of low
concentrations. 7.6f 0.1 percent; in the
control, 2.6f 0.3, (p<0.001). ---
A. Human Acute Tostcfty
Serious systemic toxic effects have
been reported from exposure to ethyl-
ene chlorohydrin. Inhalation of ethyl-
ene chlorohydrin vapor may result in
nausea, dizziness. vomiting. circulatory
failure. Btupification, and death. Poi-
soning occurs from inhalation of 18
DDm. Ethylene chlorohydrin irritates
mucous membranes and causes kidney
and liver degeneration The effects
may be cumulative (Ref. 1).
B. Animal Acute To+icfty
1. Lethal dose from oral and paten-
t d adminfstnrCLorr-The acute tax-
icity (ID,) values have been deter-
mined for ethylene chlorohydrin in
mice, rats, rabbits, and dogs (Refs. 4.
43. 82-84). The results of these studies
point to IDUvalues in a range of 56
mg/kg by the parenteral route in rats
to 178 -/kg by the oral route in mice
(Ref. 3). Ethylene chlorohydrin was
shown to be somewhat more toxic
acutely than ethylene oxide. The
route of admfnlstration appeared to
have little influence on the acute tox-
icity values. The animals showed signs
of central nervous system effects such
as depression and labored respiration
and usually died within 24 hours with-
out specific organ pathology.
In another study (Friedman et al..
Ref. 38). a single oral dose of ethylene
chlorohydrin (10 to 50 m g / k g ) caused (Ref. 7). The concentrations of the
a dose-related decrease of liver protein
synthesis and glutathione level in rats.
2. Imitation to eye and tissue&-The
results of studies to determine the
acute effect of ethylene chlorohydrin
on eye and other tlssues have been
summnarized by Bruch (Ref. 3). Maxi-
mal noeffect concentrations ranged
from 0.5 percent (0.25 mg total dose)
administered subcutaneously in guinea
pigs to 20 percent (40 mg total dose)
by dermal application in the rabbit. In
the eye and tissue studies by Woodard
and Woodard (Ref. 4). ethylene chlor-
ohydrin solution produced induration
and ecchymoses (small hemorrhages)
subcutaneous injection (0.5 percent) in
the guinea pig. mlnirnal irritation
after dermal administration in the
rabbit, and lacrimation and conjuncti-
val erythema, corenal opacity, Lri*
and conjunctival irritation following
ocular adminlstratlon in the rabbit.
The acute eye irritant properties of D.Animal Chronic Toxicity (Repeated
ethylene chlorohydrin (In a balanced
salt solution) were investigated in the
rabblt by McDonald et al.. (Ref. 6).
The maximal nondamaging concentra- administration of ethylene chlorohy-
tions of ethylene oxide ranged from 2
percent for the conjunctiva to greater
than 40 percent for the lens after a 6-
hour acute topical ocular instillation.
After a single anterior chamber instil-
lation, 0.5 percent and 5 percent were
the maximum nondamaging concen-
trations of ethylene chlorohydrin for
the iris and conjunctiva, respectively.
C. Animal Subchronic Toxicity (Re-
peated doses for a period not ex-
ceeding 1year)
Ethylene chlorohydrin has been ad-
ministered subchronically by the oral
route. both by gavage and in the diet.
to the ra$. dog, and monkey. parenter-
ally to the dog and rat; and by inhala-
tion to rats (Refs. 4. 32. 41-44). Effects
include depressed weight gain and in-
creased mortality. subacute myocardi-
tis. and changes in organ weights.
Data from the 30-day subcutaneous
dosing (27 mg/kg) of ethylene chloro-
hydrin to dogs indicated hepatocellu-
lar degenerative changes and in-
creased sexm alkaline phosphatase
and bilirubin levala One dog died. No
hepatic effects were seen with signifi-
cantly lower .doses (9 mg or 3 mg/kg).
~emi;lLferous tubular - degeneetion
was detected at the 27 and 9 mg/kg
dose levels.
In another study (Feuer. G. et al..
Ref. 39). subcutaneous dally dosing of
rats (20 -/kg of ethylene chlorohy-
drin for 7 days) caused a reduction in
the activities of hepatic drug-metabo-
llzing enzymes and of glucose 6-phos-
phatase. A trend of reduction was seen
also at 3 or 10 mg/kg in male rats.
A 21-day ocular irritation study has
been performed in rabbits with solu-
tions of ethylene chlorohydrin. ethyl-
ene glycol, and combinations of ethyl-
ene chlorohydrin and ethylene glycol
ethylene chlorohydrin solutions
raqged from 0.1 to 40 percent; of the
ethylene glycol solutions. from 0.5 to
80 perceneand of the combination so-
lution of ethylene chlorohydrlrr and
ethylene glycol, from 0.1 percent/0.5
percent to 30 percent/?O percent.
Maxhial conjunctival congestion and
discharge, moderate swellins, increas-
ing corneal cloudiness, damage as ed-
denced by fluorescein statning, and
pannus were obsemed with solutions
of 40 percent ethylene chlorohydrln;
moderate conjunctival congestion.
minimal discharge and mfnlmal swell-
ing with solutions of 80 percent ethyl-
ene glycol; and moderate conjunctival
congestion, moderate discharge, mini-
mal swelling, flare. hitis. corneal
cloudiness, damage as evidenced by
fluorescein staining, and moderate
pannus wlth solutions of 30 percent/TO
percent ethylene chlorohydrin/ethyl-
ene glycol.
doses for period exceeding 1 Year)
The results of oral and parenteral
 PROPOSED RULES

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.

FEDERAL REGISTER, VOL 43, NO. 122--FRIDAY, JUNE 23, 1978


Residue limits would be set for certaln
drug products for human and,veteri-
nary use; for medical devices for
human use, and for certain other arti-
cles. The proposed limits are intended
to take into consideration the lowest
possible llmits achievable under cur-
rent good manufacturing practices.
Maximum daily exposure levels
would also be set, but for drug prod-
ucts only. These proposed exposure
levels are based on the toxicity data
previously discussed. The Commission-
er is proposing to include the residue
limits and exposure levels for drug
products for human and veterinary
use in the current good manufacturing
practice regulations in 21 CFR Part
211. The residue limits for medical de-
vices would be included in a new 21
CF'R Part 821. The Commissioner in-
tends that these requirements will, for
those patients using drugs and medical
devices for human use for which eth-
ylene oxide has been used as a steri-
lant. limit exposure to ethylene oxide.
ehtylene chlorohydrin, and ethylene
glycol to levels below those that are
presently known to be harmful.
M A l u M u x RESIDUE LIMITS
A. Drug Products and O k Articles
for Human and Veterinary Use
The notice proposes maximum resi-
due limits for ethylene oxide, ethylene
chloroh~drir.and ethylene glpcol in
ophthalmic prepamti& fo; -topical
use. injectable ~ r e ~ a r a t i o ntlncluding
s to measure product residue changes
veterinary ink-ry infusion
products), intrauterlne devices con-
taining a drug component. surgical
scrub sponges containing a com-
ponent. and hard gelatin capsule
shells. The residue limits would be the
maximum acceptable W t s for any of
these drug products or other article
for which ethylene oxide is used as 8
sterilant during any part of the manu-
facturing process. including the manu-
facturing proceSs for any component
of the product or for the product's
container. The limits would apply to
the product as it appears in its market
container at the time it is releasd for
marketing. and throughout the period
of its shelf life. The llmits proposed
are based on data that have been pre-
viously submitted to FDA in new drug
applications. which data consist of
values that are currently being net by
some manufacturers.
Under the proposed regulatioh.
each manufacturer of a drug product
or other article to which the residue
limits apply would be required to
assure by appropriate laboratory test-
Lng that such product or other article
in its market container does not
exceed the residue l M t s when re-
leased for marketing. The Commis-
sioner advises that a number of an&
lytical methods (Refs 54 through 75)
are available through which residues
FEDERAL REGISTER, VOL 43, NO. 122-FRIDAY,
PROPOSED RULES
of ethylene oxide, ethylene chlorohy-
drin. and ethylene glycoi can be reli-
ably determined: Gas and thin-layer
chromatogra~hlc. polarographic, co-
lorimetric, mass spectrographic, radio
tracer and other methods have been
published which can identify and
measure minute residues of ethylene
oxide and its reaction products. None-
theless, the Commissioner recognizes
that there are technical problems as-
sociated with identifying and deter-
mining the minute amounts of ethyl-
ene oxide and ethylene oxide reaction
products. For example. any of the fol-
lowing factors may affect the amount
of residue of ethylene oxide and its re-
action products or how readily that
residue can be detected: the applied
dosage, the type and cycle of the ster-
ilizer'and conditions of aeration. the
physical state. catalytic nature. and
reaction Ishietics of the product, the
diffusion rate of ethylene oxide into
and out of the product, the m~isture
and lrlr content in the product, and
any synergfstic effects. The Commis-
sioner advises that he will view as cur-
rent good manufacturing practice any
generally accepted scientific method
for laboratory control of residues of
ethylene oxide and its two major reae
tion products if it includes (1) batch
sampling. (2 3 appropriate sample sizes.
(3) sample handling techniques which
assure no residue loss from the point
of sample collection to that of assay
completion, and (4) adequate methods
from the time of sample collection
during the quarantine period to the
time of release of the product for ship-
ment and sale.
The Commissioner further purposes
that. for each drug product in which
ethylene oxide ls used as a sterilank
the manufacturer prepare a residue
dissipation curve for residues of ethyl-
ene oxide. ethylene chlorohydrin. and
ethylene glycol for each manufactur-
ing procedure in which ethylene oxide
is used as a sterilant. This will provide
a full dissipation profile for each ster-
ilized article and will enable a manu-
facturer to determine the point in
time at which the product will be
within the established limits for pur-
poses of release for marketing.
As noted, the Commissioner has also
proposed that the residue limits would
apply during the shelf life of the prod-
uct. Proposed current good manufac-
turing pkctice regulations published
in the FEDFXAL REGISTER of F t ? b ~ -
13. 1976 (41 F'R 6878) wo rld require
expiration dating for all drug products
so the application of the residue re-
quirement throughout a productpa
shelf life is consistent with the pur-
pose of the proposed current good
manufacturing practice regulations
that products maintain their identity,
strength. quality, and purity until the
time of use. In addition, under this
JUNE 23, 1978
proposal, a drug product intended to
be reconstituted or diluted prior to dis-
pensing or use would be required to
conform to the established residus
limits as reconstituted or diluted. This
requirement is consistent with the
purpose of the proposed current good
manufacturing practice regulations.
regarding the maintenance of a prod-
uct's identity. strength. quality, and
purity until its time of use.
B. Medical Devices for Human Use
The Commissioner also proposes to
establish maximum residue limib for
ethylene oxide. ethylene chlorohydrin.
and ethylene glycol in certain devices
intended for human use: small im-
plants (less than 10 grams). which in-
clude sutures and contact lenses.
medium implants (10 to 100 grams).
large implants (greater than 100
grams), intrauterine devices, intraocu-
lar lenses, devices contacting human
mucosa (mouth, nose. trachea. urinary
tract), devices contacting blood but
used outside the body (hernodialysis
units, blood oxygenators, blood bags).
devices contacting normal skin (surgi-
cal drapes. bandages). and surgical
scrub sponges.
As wlth drug products, the residue
limits proposed are the maximum ac-
ceptable limits for medical devices in
their market containers at the time of
release for marketing. The residue
limits were derived from values devel-
oped from a Toxicity Working Group
of the AAMI Ethylene Oxide (279)
Subcommittee, from industrial data
submitted to FDA in response to the
September 12. 1973 FEDERALREGISTER
notice, and from residue limits already
established by current good manufac-
turing practice for similar products
abject to approved new drug applica-
tions. For example, the proposed resi-
due Wts for intrauterine devices and
surgical scrub sponges are the same as
those being propbed by thfs notice for
similar articles which are classified as
drugs.
As in the case of drug products. resi-
due Urnits established for certain
medical devices would apply if ethyl-
ene oxide was used at a sterilant
during any part of the manufacturing
process of the device. including the
manufacturing process for any compo-
nents of the device. or the device's
market contaher. Each device manu-
facturer would be required to assure.
by appropriate laboratory testing, that
the device as it appears in its market
contaher does not exceed the residue
limit when released for marketing.
Some analytical methods that will pro-
duce reliable determinations of resi-
dues in drugs of ethylene oxide. ethyl-
ene chlorohydrin. and ethylene glycol
have been discussed under parsgraph
A above. The Association for the Ad-
vancement of Medical I n s t ~ e n t a -
tion Ethylene Oxide (279) Subcorn-

mittee has validated (Ref. 57) three
analytical methods for the detection
of residues in medical devices (Refs.
54. 55. and 56). In addltion. some man-
ufacturers and equipment producers.
and certain others persons have devel-
oped methods or have sponsored the
publication of methodology for deter-
mining residues on treated plastics.
fabrics. and pharmaceuticals (Refs. 58
through 75).
The proposed mle would further re-
quire. as in the case of drug products.
for each medical device for human
use, including its component parts and
market container. that the manufac-
turer prepare a residue dissipation
curve for residues of ethylene oxide.
ethylene chlorohydrin, and ethylene
glycol for each manufacturing proce-
dure in which ethylene oxide is used
as a sterilant. This would provide a
dissipation profile for. each sterilized
article and would enable a manufac-
turer to determine the point in time at
which the medical device would be
within the established residue limits
so that it might be released for mar-
keting.
The Commission is not. at this time.
proposing that the residue limits es-
tablished for medical devices be maln-
tained throughout the shelf life of the
device. Diffusion of ethylene oxide
and its reaction products from a device
is influenced by several factors, such
as the type of material in the device
(ex.. type of plastic). physical dimen-
sions. exposed surface areas. and pack-
aging. Further. residues of ethylene
oxide are more likely to be converted
to ethylene.glyco1 (the less toxic of
the reaction products) than to ethyl-
ene chlorohydrin. The Commissioner
believes that even though a theoreti-
cal calculation could be made that the
residues of either ethylene chlorohy-
drin or ethylene glycol could increase
from the time of shipment of the
device. there should also be a corre-
sponding loss of these residues based
on diffusion. The Commissioner con-
cludes that. until more data are availa-
ble regarding the diffusion of residues
from device materials. he cannot rea-
sonably expect a manufacturer to
assure that devices comply with these
residue limits throughout the shelf
life of the device.
MAXIMVEd DAXLY LEVELS OF EXPOSDRE
A. Drug Prpducts and Other Artices
for Human and Veterinaty Use ,
The Commissioqx also proposes to
establish maximum daily levels of ex-
posure to ethylene oxide and ethylene
chlorohydrin. because of the p'otential
risk of mutagenicity from exposure to
drug products containing these resi-
dues. He also proposes to establish a
maximum daily level of exposure to
ethylene glycol because of known tox-
icity from exposure to drug products
containing this residue.
FEDERAL REGISTER, VOL 43, NO. 122-FRIDAY,
PROPOSED RULES
Current calculations reading to esti-
mates of human genetic risk are based
on various assumptions and tests that
are in a relatively early stage of evalu-
ation and Widation. Levels of ethyl-
ene oxide and ethylene chlorohydrin
considered safe by traditional toxicolo-
gical tests (for example. measurements
of physiological, biochemical. or
pathological changes in the body func-
tion) may not be safe when the poten-
tial for mutagenicity is considered.
Nonetheless, the Commtssioner's judg-
ment is, given the potential risk of MU-
tageniclty from exposwe to ethylene
oxide and its reaction product ethyl-
ene chlorohydrin, that he must at-
tempt now to restrict that exposure in-
sofar as products within his jurisdic-
tion are involved. He therefore pro-
poses to establish maximum daily
levels of exposure based on available
toxicity data. certain assumption^, and
the application of an additional "best
judgment" safety factor. The C o w
sfoner advises that as the scientific
basis for making risk judgments rela-
tive to mutagenic it^ imsroves. the
agency will reconsider - established
maximum daily levels of exposure.
This reconsidedon may involve a
further lowering of these exposure
levels. The Commissioner proposes to
establish maximum daily levels of ex-
posure to ethylene glycol based on
available toxic it^ data
The ~ommis&oner therefore pro-
~ o s e s to establish maximum daily
ievels of exposure to ethylene oxid&
ethylene chlorohydrin, and ethylene
glycol based on the following calcula-
tions:
Ethylene oxi&-In the toxicity
studies reported by Woodard and
Woodard (Ref. 4). dogs and rats re-
ceived subcutaneous infections of eth-
ylene oxide for 30 days. At the lowest
level of ethylene oxide administered (6
mg/kg/day) (see paragraph C.1. under
"Ethylene oxide" above). some hema-
tological changes were noted in both
animal species and 2/4 dogs had ecto-
pic hematopoiesis of the spleen. Thus,
the dose-response data by Woodard
and Woodard do not show a clear "no
effect" lever for ethylene oxide. Based
on the trends shown by the dose-re-
sponse data. Bruch (Ref. 3) estimated
that if the lowest dose tested had been
cut by 50 percent (1.e.. 3 mg/kg/day). a
"no effect" level had a high probabil-
ity of being achieved. A 10-fold safety
factor (a factor frequently used in ex-
trapolating systemic "no effect" doses
to m: n) was then applied by Bruch to
yield an assumed safe level of 0.3 mg/
kg/day for 30 days. Using that safety
factor for a 70-kg man, the safe (In
terms of toxicity) daily dose would be
21 mg.
However. because ethylene oxide has
irreversible toxic effects. e.g.. muta-
genicity, for which sufficient dosage
data are not available, the Commis-
JUNE 23, 1978
sioner, to adequately protect users of
products sterilized with ethylene
oxide, proposes to add an additional
safety factor of 10 in proposing an ac-
ceptable exposure level. A level of 30
micrograms per kilogram per day (pg/
kg/day) for 30 days is therefore pm-
posed as an acceptable level of expo-
sure to ethylene oxide residue.
Ethylene chlorohydrjn-In the Woo-
dard and Woodard study (Ref. 4)'dogs
and rats also received subcutaneous in-
jections of ethylene chlorohydrin for
30 days. At the lowest ethylene chloro-
hydrin level tested 13 rng/kg/day). and
as with ethylene oxide, some of the
animals showed slight hematological
changes. and 1/4 dogs had ectopic he-
rnatopoiesis of the spleen (see the dis-
cussion of h i n d Subchronic Toxic-
ity. Paragraph C, under Ethylene
Chlorohydrin). Amin, the dose-re-
sponse data by Woodard and Woodard
do not show a clear "no effect" level.
Based on the trends shown by the
dose-response data. Bruch again esti-
mated that if the lowest dose tested
were cut by 50 percent (te., 1.5 mg/
kg/day), a "no effect" level had a high
probability of being achieved. As with
ethylene oxide. Bruch then applied a .
10-fold safety factor which yields an
assumed safe level of 0.15 mg/kg/day
for 30 days for man.
Because of mutagenic potential of
ethylene chlorohydrin and because of
its similarities with ethylene oxide.
the Commissioner believes that the
same additional safety factor is s m -
larly appropriate for produds contatn-
ing ethylene chlorohydrin Therefore,
he proposes that an additional safety
factor of 10 be applied, yielding an ex-
posure level of 15 pg/kg/day of ethyl-
ene chlorohydrin residue.
Ethylene glycol.-The Woodard and
Woodard study also contained data on
a 30-day toxicity study in dogs and
rats based on daily subcutaneous infee
tions of ethylene glycol. At the lowest
ethylene glycol level tested (50 m g /
kg/day 1. there were some slight hema-
tological changes in the anlmnln. As
with ethylene oxide and ethylene
chlorohydrin, the dose-response data
from the study do not .show a clear
"no effect" level. Based on trends
shown by the dose-response data,
Bmch estimated by cutting the lowest
dose tested by 50 percent (25 mg/&/
day). a "no effect" level had a high
probability of being achieved. As with
ethylene oxide. Bmch applied a 101
fold safety factor, which yields an esti-
mated safe dose of 2.5 mg/kg/day for
30 days. Because the Commissioner is
not aware of evidence showing ethyl-
ene glycol to have mutagenic poten-
tial. he concludes that an additional
safety factor is unnecessary.
B. Medical Devices for Human Use
The Commissioner has determined
that the maximum levels of exposure
 PROPOSED RULES
(30 pg/kg/day for ethylene oxide, 15 due limits the manufacturer would and Related Programs on the "Benefits and
pg/kg/day for ethylene chlorohydrin still be required to reduce the amount Risks from the Use-of Ethylene Oxide for
and 2.5 mg/kg/day for ethylene of residue for the product so that. on Sterilization." April 1.1977.
glycol) proposed for drug products the basis of the recommended dosage. 2. FDA Ethylene Oxide Review commit-
cannot reasonably be applied to medi- the total daily exposure level would tee memorandum. "Safety and Efficacy of
Ethylene Oxide as a Sterilant and Fumi-
cal devices for human use at this time. not be exceeded In additioll. for a gant." May 30.1975.
The application of such exposure -drug product that is labeled to be re- 3. Bruch. C. W. "Sterilization of Plastics:
levels would necessitate the develop constihted or. dilutdd before dispens- Toxicity of Ethyelene Oxide Residues." in
ment of a significant number of ex- ing, or use. the stated residue limits "Industrial Sterilization." edited by G.
emptions. as many medical devices as would be required to be met at the Briggs Phillips and W. S. Miller. Duke Uni-
presently manufactured would be time the drug is reconstituted or dilut- versity Press. Durham. NC. PP. 49-77. 1973.
unable to meet these daily exposure ed. A medical device for human use 4. Woodard, 0. and M. Woodard, "Toxic-
levels. and with existing technology would be deemed to be in compliance ity of Residuals From Ethylene Oxide Gas
may not be readily modified to do so. if the residues of ethylene oxide. eth- Sterilization." pp. 140-161 In the Proceed-
ings of the 1971 HIA Technical Symposium.
Other factors that have dissuaded ylene chlorohydrin, and ethylene Health Indutrles Association. Washington.
the Commissioner from applying glycol do not exceed those set forth in DC.
levels of exposure to medical devices the regulation at the time of release of 5. Drsize, J. H .. "Dermal Toxicity." in
for human use at this time deal with the device for marketing. Dally expo- "Appraisal of the Safety of Chemicals in
the nature, manner. and frequency of sure levels for devices would not be es- Fboda. Drugs, and Cosmetics," Association
use of many medical devices. For ex- tablished. of Food and Drug Officials of the US, pp.
ample, devices used topically. such as Even though the Commissioner con- 4839,1965.
sponges and pads. are used only once siders the proposed residue limits ac- 6. McDonald. T. 0.. et al.. "Acute Ocular
and would not be expected to deliver ceptable, manufacturers should at- Toxicity of Ethylene Oxide, Ethylene
Glycol, and Ethylene Chlorohydrin." BuUe-
tempt to achieve even lower levels pre-
their total residue to the patient. De- sumlng current good manufacturing tin of Uw Pamtcml D w Association,
vices that are implwted, however. practices 27(4):153-164,1973.
would be expected to deliver a greater used will are followed and the level 7. Alcon Laboratories. Inc,letter regard-
percentage of their residue immediate- tiveness of not
the
compromise the effec-
sterilant or the sterility ing "Ethylene Oxlde Safety and Efficacy
ly following insertion, with a slowing of the product. Review." submission to FDA. December 20.
of the rate of delivery thereafter. 1973.
There is. at the same time, a lack of more The Commissioner recognizes that 8. IIine. C. H. and V. It Rowe. "Ethylene
data on the rate of residue diffusion tentialdata are needed before the po- Oxide." in "Industrial Hydene and Toxicol-
and inovement from various ~lastic tion products of ethylene oxide and its reac- ogy." M Rev. ,Ed., VoL IL 'Toxicology.''
materials; and it would be bpr&tical be fully assessed. to act as mutagens can edited by D. W. Fansett and D. D. Irish, In-
tersdence Publisher. New York pp. 1626-
to expect medical device rnanufactur- submisdon of any He encourages the
published &d un- 1634,1963.
ers to be able to work in concert d t h published data concerning the use. 9. Jacobson, K. H, E. B. Hackley. and L
physicians' and other health profes- performance. and toxicity of ethylene FeinsUver. "The Toxicity of Inhaled Ethyl-
sionals to restrict the amount of pa- oxide and its two major reaction prod- ene Oxide and Propylene Oxide Vapors."
tient contact from different devices ucts, and any other data having a Reprlnt. w i t h additions. A m Archives Qfln-
use on the same day. Based on these bearing on the safety and effective- dwtrlQl HccrlLh. 13237-244.1956.
factors. the Commissioner has con- ness of these compounds. The Com- 10. Holllagsworth, R. L., V. K. Rowe. F.
Oyen. D. D. McCollister, and H.C. Spencer.
cluded that he cannot effectively set missioner also invites the submission "Toxidty of Ethylene Oxide Determined on
proposed maximum levels of exposure of similar data for any drug products Experimental Anbalk" AbfA Archim Qf
for medical devices for human use. or medical devices for human use not Industrial Heal4 13(3):217-227.1956.
However. he invites the submission of subject to this notice so that residue 11. Waite. C. P.. F. 'A Patty. and W. P.
published and unpublished data on limits may' also be established for Yant,."Acute Response of Guinea Pigs to
rates of diffusion of various residues these products. Vapors of Some New Commercid Organic
from plastic materials. The Commis- Compounds." US. Public Health Reports,
Final residue llmits will be deter- 453832-1843.193Q.
sioner advises, however. that the pro- mined by the agency from comments 12. Flqry. F. and R Zernilr, "Sch8dliche
posed residue limits for medical de- and data submitted by interested per- Gase." Springer. Berlln. pp. 291-295.1931.
vices for human use have been calcu- sons in response to this proposal. The la. B a l m TA Toxicity of Ethylene
lated to reduce as much as possible Commhioner notes that there are Oxide and Chloroethanol." FDA By-Ues
maximum daily levels of residue expo- presently ongoing animal toxicity No. 3. 1976.
sure. studies involving ethylene oxide and 14. Sexton. R J. and E
. V. Henson. "Der-
Its reaction products. There are 29ear matologlcal Injuries by Ethylene Oxide."
ethylene oxide studies on rats under Journcrl of IndurWal Hygiene and ltuicol-
Under these proposed requirements. way at Camegie-Mellon Institute of om,31(5):297300.1949.
15. Hanlfin. J. M, "Ethylene Oxlde Der-
a drug product would be deemed to be Research. Th'ese will include teratol- matitls" (Letter), 3outna.l Qf Ute Amcrlcczn
in compliance if the residues of ethyl- o m mutagenicity, and a one genera- Medical Assodation, 211(2):213.1971.
ene oxide. ethylene chlorohydrin. and tion reproductive study. The National 16. Poothullil, J, A. Shlmfiu. R P. Day.
ethylene glycol do not exceed those Cancer Institute has also begun 2-year and J. Dolovich, "AnaphyLaxfs From the
set forth in the regulation. at the time carcinogenicity studies on ethylene ProducUs) of Ethylene Oxide Gfs." Anrrcrlr
of release of the product for market- chlorohydrin and has scheduled %-year of Intmral Medicine 8258-60.1975.
ing and throughout the shelf life. and, ethylene oxide carcinogenicity tests. 17. Rapoport. L A, "The Effect of Ethyl-
ene Oxide. Glydde. and Glycol on Oenlc
the maximum daily level of exposure' Results of these tests may provide the Mutations," Doklady Akcrdtmii Nauk SSSR,
does not exceed 3(r. pg/kg/day for 30 bases for revision of established values 60(3):467-472. 1948.
days for ethylene oxide. 15 p~!/kg/day for exposure levels or residues. 18. Btrd, M. J, "Chemical Production of
for 30 days for ethylene chlorohydrin Mutatiom in Drwophila.' Cornparkon of
and 2.5 mg/kg/day for 30 days for eth- Techniques," QcncHu. S0:480-485.1952
ylene glycol. Thus. if the dosage of a Copies of all references cited below 19. Nakao. Y. and C Auerboch. 'Test of a
drug product in its recommended or are on public display in the office of Possible CorrelaUon Between Cmss-LMdng
approved labeling were such that the the Hearing Clerk. Faod and Drug Ad- and ChromoM,rne Breaklng AbUties of
Chemical Nutagena." ZdtschtW fucr Vcrcrc
exposure levels established for the midstration. bungslehrr. 92457-461.1961.
product would dill be exceeded, not- 1. Report of the Subcommittee to the 20. Kolmark H. 0. and B. J. gllbey. "IU-
withstanding compliance with the resi- HEW Committee to Coordinate Toxicology hetic Studies of Mutation Induction by

FEDERAL REGISTER VOL 43, NO. 112--FRIDAY, JUNE 23, 1978


Epoxides In Neurospona cmssa," Mokcular
and Genenal Genetic& 101:89-98. fser,.
21. Ehrenberg, L and A. Gustafgion. "On
the Mutagenic Action of Ethylene Oxlde
and Diepoxybutsne In Barley," Hmd-
43:595-802. 1957.
22. Sulovska. K., D. LLndgren. G. MLsson.
and L Ehrenberg. "The Mutagenic Effect of
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39. Feuer. G.. T. Balats R. Farkus. M. S.
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PROPOSED RULES
of TarfcoZopv and Environmental Health, Pharmaceutical Sctencu. 64(8):1412-1417.
3569-576. 1977. 1975.
40. Ambmse. A. M. "Toxicoloeical Studlea 58. Brown, D. J.. "Determination of Ethyl-
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41. Carson. S.'and B. L Oser. "Oral Todo- 59. Adler. N. "Residual Ethylene Oxide
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42. Uwience. W. H .. K. Itoh. J. E. Turner. P h c r w i c a l SdenceS. 54(5):735-742.
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43. Taylor. J. M, "Ethylene Chlorohy- Ucq" J o u d af Phannacu and Phannaco&
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1969. 61. WeInberger. J, "GIG Determlnatlon
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Several.Compounds," US. Government F b of O f ' Analytical Chemirts. 64(5X1093-
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-----
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oethanol In the Rat," Biochemical P h a w Pmducta In Wheat Flour and Other Com-
COW, 163185-199,1967. modlties Residues from F'umlgation of Ster-
47. Mason. M.M, C. C. Cate. and J. Baker, illsatton. and Effects of Proce3sing;" P a t i -
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Chemicals Used in the Preparation of Vso- 64. Ragella, E. P, B. S. Flsber. B. A. Kll-
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48. Roberts. J. A. and H. R Selbold. "Eth- gated with Ethylene Oxide or Propylene
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49. Bachmann. E. and L Goldberg, *TZef&p 65. Zagar, L k. "Determiaation of Rerrid-
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51. Blood E R. G. A. Elliott, and M. 6. 67. White. J. D. and T. J. Bradley. Resldu-
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plied Phannaco&v, C489-491.1962 c d Scknnq 62(10):1634-1637.1973.
52. Blood, E R, "Chronic Toxicity Of Eth- 68. Kul@rnl R K., D. Bartak D. K. 011s-
ylene Glycol In the Rat," Food and CamrcL terhout, and F. Leonard. "Determination of
ics T a t f c ~ l o.3:229-234.1965.
~. Residual Ethylene Oxide In Catheters by
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Calvery, "Observations of the Chmnlc Toxi- Biomedical M a h i a h &?aearch, 2165-171.
cities of Propylene Glycol. Ethylene Glycol. 1968
Diethylene GlycoL Ethylene Glycol Mono- 69. Crltchfleld. F. E and J. B. Johnson.
Ethyl-Ether. and Diethylene Glycol Mono- "Colorimetric Determlns.Uon of Ethylene
Ethyl-Ether." Journal of Pharmacolomr and Oxide by Conversion to Formaldehyde."
E + p c r l ~ W- T h ~ p e u t i c r . 7C266-213; Analytical Chemfrt~Y,29<SM97-800.195?.
70. Mc Guaalgle, R 0, J, A. Renner. 8. J.
54. Spitz. 11.D. and J. Weinberger. "Deter- Romano. and R A. Abodeelp. Jr, "Residual
mJnation of Ethylene Oxide. Ethylene
' Ethylene Oxide: Levels In Medlcal Grade
Chlorohydrin. and Ethylene Glycol by Oas Tublng and Effects on an In Vltro Bi&@c
Chromatography." Journal of Phanncrceuti- System." J o u d of Biomedical Mate-
cal Scfencc~. 60(2):271-274.1971. Research, 9:273-283.1975.
55. Mogenhan. J. A. J. E. Whitbourne. 71. Landen. W. 0, D. W. Thompson. shd
and R. R. Emt, "Determination of Ethyl- It M. Floyd. "Detennlnation of Ethylene
ene Oxlde In Surgical Materials by Vacuum Oxide and Ethylene Glycol In Wet S u r g t d
Extraction and Gas Chromatography." Dressings," FDA By-Lines. NO. 2.1971.
l o u d of Pharm4~eutical sclenoer, 72. Wesley, F; B. Rourke. and 0. Darbl-
60(2):222-224.1971. shire. "The Formation of Petalstent Toxk
56. Romano. S.J, J. A. Remer. and P. M. chlorohydrins In Foodstuffs by Fwdgatloa
Leitner. "Gss Chromatography DetermLna- with Ethylene Oxlde and With Propylem
tlon of Residual Ethylene Oxlde by Head Oxide." Journal of Food Sc(mn, 361037-
Space Analysk" Analytical chcmirtry. 1042.1965.
4% 14):2327-2330,1973. 73. Slag& C, J. M. H. Daemen. W. Dankel-
56. Romano. S. J., and J. A. Renner. man.and W. A. Sipman. "AnaImh of Poly-
"Comparison of Analytical Methods for Re- ethylene Oxide Adducts by Cleavage wlth
sidual Ethylene Oxlde Analysts." Journal af Hydrobromlc Acid In AceUc Add and Subse-
 PROPOSED RULES
quent Gas-Chromatographic Determination 506. 507. 512. 513-521. 701. 52 Stat. dues of ethylene oxide and its reaction
of the React~on Products." Z. Analytical 1049-1050 as amended, 1052-1053 as products from any drug product sub-
Chemistry. 264(5):401-406. 1973. . amended. 1055-1056 as amended. 55 ject to paragraph (a) of this section.
74. "Polyethylene Glycols." pp. 626-629. Stat. 851. 59 Stat. 463 as amended; 82 under the conditions for use in the
In Food Chemicals Codex. 2d Ed.. National
Academy of Sciences, Washlngton. DC. Stat. 347-351. 90 Stat. 540-574 (21 drug product's recommended or ap-
1972. U.S.C. 321. 351, 355. 356. 357. 360~- proved labeling. shall not exceed the
75. Whitbourne. J. E.. H. A. Mogenhan. 36pk. 371)). the Public Health Service following limits set:
and R. R. Ernst. "Determination of 2-Chlor- Act (sec. 351.58 Stat. 702. as amended; Ethylene oxide. 30 pg/kg/day/3~days
oethanol in Surgical Materials by Extrac- 42 U.S.C. 262). and under authority Ethylene chlomhydrin. 15 pg/kg/day/30
tion and Gas Chromatography." Journal of delegated to the Commissioner (21 days
Pharmaceutical Scaences, 58(8):1024-1025, CFR 5.11, it is proposed that Chapter I Ethylene glycol. 2.5 mg/kg/day/30 days
1969. of Title 21 of the Code of Federal Reg-
76. Mgier. P. and W. Schmid. "Ten Model ulations be amended as follows: A product which complies with para-
Mutagens Evaluated by the Micronucleus graph (a) of this section shall also
Test." Afutation Research. 40:325-337. 1976. PART 221--CURRENT GOOD MANUFACTUR- comply with the limits set forth in
77. Friedman. M. A.. and J. Staub. "Induc- ING MACME FOR FlNlSHED PHARMACEU- this paragraph.
tion of Micronuclei in Mouse and Hamster TICALS
Bone Marrow by Chemical Carcinogens." PART 821-CURRENT GOOD MANUFACTUR-
Mutation R e s e a m 43:255-261.1977. 1. BY adding a new Q 211.70 to Sub- ING PRACTICE FOR MEDICAL DEVICES: STER-
78. Andersen. S. R.. "Ethylene Oxide Tox- part C to read as follows: ILE DEVICES
icity." Presentation a t the Association for
the Advancement of Medlcal Instrumenta- 9211.70 Maximum residue limits and 2. By adding a new Part 821 consist-
tion meeting, San Francisco. California. maximum daily lereir of exposure for ing of one section to read as follows:
March 16.1977.
79. Rannug. U.. R. Gothe. and C. A. ethylene oxide, ethylene chlorohydrin.
Wachtmeister. "The Mutagenicity of Chlor- and ethylene glycol. sec.
oethylene Oxide. Chloroacetaldehyde. 2- (a) Residue_ limits: Each drug prod- 821.100 Maximum residue limits for ethyl-
Chlomethanol. and Chloroacetic Acid. Con- uct of a type listed in this paragraph ene oxide. ethylene chlorohydrin. and
ceivable Metabolites of Vinyl Chloride." for which ethylene oxide is used as a ethylene glycol.
Chemico-Biological InLercrctions, 12:251- sterilant in the .manufacture of the A r m r o ~ ~ nSecs.
: 513-521. 701. 52 Stat.
263. 1976 1055-1056 as amended. 90 Stat. 540-574 (21
80. Verrett. M. J.. "Investigation of the finished product. its components. or
its market container shall not. when US.C. 360~-36Ok371).
Toxic and Teratogenic Effects of 2-Chlor-
oethanol to the Developing Chick Embryo." tested as packaged in its market con- Q 821.100 Maximum residue limits for eth-
Internal FDA memorandum to T. Balau. tainer. exceed the following residue ylene oxide, ethylene ehlorohydrin, and
March 21. 1974. levels: ethylene glycol.
81. Courtney, K. D.. and J. E. Andrews.
"Teratogenlc Evaluation of 2-Chloroethanol (a) Each medical device for human
in the CD-1 Mouse," Unpublished. 12 pp. use of a type listed in this paragraph
82. Lawrence. W. H.. J. E. Turner. and J. E-I- Ethyl- Ethyl- for which ethylene oxide is used as a
Autlan. "Toxicity of Ethylene Chlorohydrin Drug product ene me ene sterilant in the manufacture of the
I: Acute Toxicity Studies." Journal o/ Phar- oxide ChlorO- OlYCOI finished device. its cbmponent parts.
maceutical Sciences, 60 (4): 568-571.1971. hydrin
83. Goldblatt. M. W.. "Toxic Effects of or its market container s h a l l not,
Ethylene Chlorohydrii." Part 11. Experi- Ophth8Imlcd (for b p l a l
when tested as packaged in its market
mental. British Journal of Industrial Medi- . 10 20 60 container, exceed the following resi-
cine. 1:213-223. 1944. InJectabla(Including due levels:
84. Johnson. hf. K.. "Detoxification of veterinuy
In- [Parts per mUllonl
Ethylene Chlorohydrin, "Food and Cosmet-
ics Tozicology, 5:449. 1967. Ln(ur10nr), 10 10 20
Intrauterinede*lce
85. Hirose. T.. R Goldsteln. and C. Balley.
"Hemolysb of Blood Due to Exposure to
tcontahhc a &us)
surrlal scrub .pollma
,. 5 10 10 Medical device
Ethyl- Ethyl- Ethyl-
ene ene ene
Different Types of Plastic Tubing and the twntrlnlngadrug),, 25 250 500 oxide chloro- glycol
Influence of Ethylend Oxide Sterilization," Hard lehtln a m u l e hydrin -
Journal of Thoracac and Cardiovascular she-, 35 10 35
Surgery, 45(2):245-251.1963. Implant:
86. Clarke. C. P., W. L Davidson. and J. B. Small (<lo-).,.. 250
(b) Each drug product shall c o n f o p Medlum (10-100
Johnston. "Haemolysis of Blood Following
Exposure to an Australian Manufactured to the limits set forth in peragraph (a) IvUns) .................."- 100
brset>100 grams)- 25
of this section during the shelf life of
Plastic Tubing Sterilized by Means of Ethyl- Intrauterine device--., 5
ene Oxide Gas," The Awtralion and New the product. Idraocular lerises....-, 25
Zealand Journal o/Surwry, 3653-56.1966. tc) Any &ug product failing to Devices wntactlng
87. O'Leary. R. K. and W. L Guess. "Toxi-
comply with the requirements of para- mucosa -..-.....,,......-...- 250
cological Studies on C e M n Medical Grade Devices contsctlng blood
Plastics Sterilized by Ethylene Oxide."
graphs (a) and (b)of this section shall texvivo) ......................... 25
not be released for marketing. Devlces contrcthg skln, 250
Journal of Pharmaceutical Sciences. 57(1):
12-17. 1968. (d) Each manufacturer of a drug Surgical scrub sponges .... 25
product subject to this section shall -- - -

The Commissioner has carefully prepare a residue dissipation curve for

considered the environmental effect&. each manufacturing procedure in (b) Any medical device for human
of the proposed regulation and. be- which ethylene oxide is used as a steri- use failing to comply with the require-
cause the proposed action will not sig- lant for the drug product, its compo- ments of paragraph (a) of this section
nlficantly affect the quality of the nents. or its market container. shall not be released for marketing.
human environment, has concluded (el Each drug product intended to be (c) Each manufacturer of a medical
that an environmental impact state- reconstituted or diluted prior to dis- device for human use subject to this
ment is not required. A copy of the en- pensing. or use. shall conform to the section shall prepare a residue-dissipa-
vironmental impact assessment is on limits set forth in paragraph (a) of tion curve for each manufacturing
file with the Hearing Clerk, Food and this section as reconstituted or dilut- procedure in which ethylene oxide is
Drug Administration. ed. used as a sterilant for the device. its
Therefore. under the Federal Food. ( f ) Daily exposure levels: the maxi- component parts. or its market con-
Drug, and Cosmetic Act (secs. 501, 505. mum daily level of exposure to resi- tainer.

Interested persons may. on or before
August 22, 1978. submit to the Hearing
Clerk (HFC-20). Food and Drug Ad-
ministration, Rm. 4-65, 5600 Fishcrs
Lane. Rockville. Md. 20857, written
comments regarding this proposal.
Four copies of all comments shall be
submitted, except that individuals
may submit single copies of comments.
a n d shall be identified with t.he Hear-
ing Clerk docket number found in
* U.S. GOvE!UW.YT PBISTISG OFFICE:
PROPOSED RULES 27483
brackets in the heading of t.his docu- amended by Exccutive Order 11949) and
ment. Received comments may be seen OMB Circular A-107. A copy of the econom-
in the above office between the hours ic impact asscsment is on file with the
of 9 am. &7d 4 p.m.. Monday through Hearing Clerk Food and Drug Administra-
tion.
miday.
Dated: June 16.1978.
Nore.-The Food and Drug Administra- SHERWIN GARDNER.
tion has determined that this document
Acting Commissioner
does not contain a major proposal requidng
preparation of an economk impact state- of Food and Drugs.
ment under Executive Order 11821 (a3 [FR Doc 78-17384 Filed 6-22-78; 8:45 am1
FEDERAL REGISTER, VOL 43, NO. 122-FRIDAY, JUNE 23, 1978
1 9 8 4 - 4 2 1-177: 10002