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EC number: 603-436-5
CAS number: 13076-17-0
Lactide (18:1 mixture of L-lactide and
m-lactide) was tested in dogs in a 2-week dose range finding study and a
subsequent 90d full study (similar to OECD 409). The primary toxic
effect was irritation of the gastrointestinal tract at 100 mg/kg bw/day
in the 90d study.
In addition, in an oral subchronic
repeated dose toxicity study conducted with a suitable read-across
partner, calcium lactate was used to assess the specific target organ
toxicity of the target substance. Based on the results, no
classification for specific target organ toxicity is warranted for
Table 1: Overview of effects
In a subacute oral toxicity (dose
range finding) study, lactide (18:1 mixture of L-lactide and
m-lactide) was administered to 2 beagle dogs/sex/dose by capsule at dose
levels of 10, 100, 400, 1000 and 2500 mg/kg bw/day for 2 weeks. The
primary toxic effect of lactide in dogs was irritation of the alimentary
tract. As irritating effects occurred down to a daily dose of 400 mg/kg
bw/day a (local) LOAEL can be determined with 400 mg/kg bw/day. At a
daily dose of 100 mg/kg bw/day no lesions were noted by gross and
histopathology. Thus, the (local) NOAEL can be determined with 100 mg/kg
At 1000 and 2500 mg/kg/d effects on
body weight, and absolute and relative organ weights were reported in
thymus and spleen. These effects were considered to be related to the
irritation of the alimentary tract. In contrast, a mild to moderate
renal tubular regeneration was reported in all animals of the 2,500
mg/kg/d dose. Regeneration of the renal tububar epithelium is frequently
seen as a reparative or adaptive change following tubular epithelial
necrosis, and is suggestive of prior damage to this tissue. Although the
mechanism of this effect is unknown, it cannot be excluded it is based
on lactide toxicity. Based on the possible renal toxicity the (systemic)
LOAEL is 2500 mg/kg bw/day. The (systemic) NOAEL for orally administered
lactide to dogs under the conditions of this study is 1000 mg/kg/day.
L-lactide is the enantiomer of D-lactide and therefore suitable as
information is used in a read-across approach in the assessment of the
target substance. For details and justification of read-across please
refer to the read-across report attached to IUCLID section 13.
Incidence= number of dogs in a given dose
group with a given lesion. n=4 for all dose groups
In a subchronic toxicity study lactide
(18:1 mixture of l-lactide and m-lactide) was administered to 4 beagle
dogs/sex/dose by capsule at dose levels of 4, 20, 100 mg/kg bw/day for
The only apparent toxic effect at 100
mg/kg bw/day was gastrointestinal irritation. Therefore, the local LOAEL
is 100 mg/kg bw/day. No systemic effects were reported at 100 mg/kg
bw/day. Thus, the systemic NOAEL for orally administered lactide under
the conditions of this study was considered to be 100 mg/kg bw/day.
This subchronic study in dog is
acceptable and satisfies the principle requirement for a subchronic oral
study similar to OECD 409 in dog.
Lactate is a normal metabolic species in all
vertebrates; tolerance for lactate is high. Adverse effects observed
were due to calcium overload.
a subchronic toxicity study (similar to OECD 408), Calcium lactate was
administered to Fischer 344/DuCrj rats.
In Experiment I, Calcium lactate was mixed
at 5, 2.5, 1.25, 0.6, and 0.3% in the drinking water and the rats were
given this solution ad libitum for 13 weeks. As a result, the inhibition
of body weight gain in the 5% group fell within 10% of that in the
control group. Some examination values showed variations in the
hematological and hematobiochemical studies, but no controversial
findings were obtained in the pathohistological search. Since the
highest solubility of Calcium lactate is 5%, experiments II and III were
carried out by giving blended diet in order to study the toxicity at
higher doses. In experiment II, Calcium lactate was mixed at
concentrations of 30, 20, 10, and 5% in the B-blend powder diet and then
the rats were given this diet ad libitum for 20 weeks. In experiment
III, the rats were given the CRF-1 or the B-blend powder diet ad libitum
for 8 weeks. As a result, in experiment II, nephrocalcinosis was
observed in all the groups including the control group. The degree of
the lesion was in reverse correlation with the administered
concentrations of calcium and the lesion was seen more intensely in
female rats. In experiment III, nephrocalcinosis resulting from the
administration of the B-blend diet was already observed in the 4th week.
Nephrocalcinosis as observed in experiments II and III was attributable
to the small Ca/P value in the B-blend diet.
From the above results, the optimal dose for
a long-term toxicity/carcinogenicity study has been determined to be 5
and 2.5% based on the values obtained from experiment I.
Lactide is rapidly hydrolysed to
lactic acid in water and in-vivo (gastric acid). Lactic acid is a
ubiquitous and essential molecule of life. Lactate is non-toxic, any
(local) effects are due to pH effects only.
In addition, in an oral toxicity (dose
range finding) study, lactide was administered to beagle dogs by capsule
at dose levels of 10, 100, 400, 1000 and 2500 mg/kg bw/day for 2 weeks,
and 0, 4, 20 and 100 mg/kg bw/day for 13 weeks. The primary toxic effect
of lactide in dogs was irritation of the alimentary tract. As irritating
effects occurred down to a daily dose of 400 mg/kg bw (for 2 wks), the
sub-chronic study was run with a maximum dose of 100 mg/kg bw/day.
At 1000 and 2500 mg/kg bw/day effects
on body weight, and absolute and relative organ weights were reported in
the 14-day dose range finding study for thymus and spleen. These effects
were considered secondary to the irritation of the alimentary tract. In
addition, a mild to moderate renal tubular regeneration was reported in
all animals of the 2500 mg/kg bw/day dose. Regeneration of the renal
tubular epithelium is frequently seen as a reparative or adaptive change
following tubular epithelial necrosis, and is suggestive of prior damage
to this tissue. Although the mechanism of this effect is unknown,
lactide toxicity cannot be excluded. Based on the possible renal
toxicity the (systemic) LOAEL is 2500 mg/kg bw/day. That's well above
the limit dose of 1000 mg/kg bw/day for a sub-acute toxicity study.
No systemic adverse effects were
reported at the highest dose tested in the 90d study (100 mg/kg bw/day).
Therefore, the (systemic) NOAEL for orally administered lactide in a 90
d study in dog is considered to be 100 mg/kg bw/day. The primary toxic
effect after oral dosing was irritation of the gastrointestinal tract at
100 mg/kg bw/day.
addition, in an oral subchronic repeated dose toxicity study conducted
with a suitable read-across partner, calcium lactate was used to assess
the specific target organ toxicity of the target substance. High
levels of exposure to calcium lactate in the diet (up to 30% in feed)
did not lead to any lactate-associated effects after sub-chronic
exposure; all effects observed were due to the excessive intake of
calcium. It could be concluded that any deleterious effects of lactic
acid are caused by the effect of lactic acid on local pH, not on any
biological effect of lactate. High dermal exposure to lactate, in
cosmetic creams, did not lead to any effects, with the exception of
slight irritation at the highest doses.
In addition, lactic acid is a natural
metabolite found in humans and animals as it is endogenously produced
from metabolic pathways such as glycogen breakdown, glycolysis and amino
acid metabolism. Normal human blood contains 8-17 mg lactic acid/100 mL
plasma, and the concentration of lactate in normal human skin is three
times or more of that in the blood due to glycolytic enzymes, which
actively convert glucose to lactic acid in the epidermis. Lactic acid
has been detected in blood but also in several other body fluids and
tissues. Concentrations of lactic acid increase significantly during
intense exercise. At rest, blood concentrations have been reported of
1-1.5 mMol/L (90.1-135.12 mg/L), which can increase up to 10 mMol/L
(900.8 mg/L) during exercise. External human exposure to lactic acid can
occur via its natural presence in food, for example in fruit,
vegetables, sour milk products, and fermented products such as
sauerkraut, yogurt and beer. Based on the available information on
concentrations of lactic acid in some of these products, an estimate of
the daily consumption of lactic acid due to its natural presence in food
was made using the ‘FAO/WHO standard European diet’. A (minimum) daily
intake of 1.175 g/person/day was calculated using the available
information. Another source of external exposure is its use as food
additive; as such it is authorized in Europe (E270) and the United
States (generally recognized as safe = GRAS). A daily intake of
1.65-2.76 g/person/day was estimated using the “Per Capita times 10”
method, based on the amount of lactic acid placed on the market (EU and
USA) as a food additive by Purac. Due to its role as a common and
natural food ingredient, and ubiquitous metabolic product/substrate in
mammals with proven low toxicity, it can safely be concluded that lactic
acid does not contribute to any systemic effects. Lactic acid is a major
and essential species in mammalian primary metabolism, and a ubiquitous
ingredient in all kinds of food. There is no way of lowering exposure
below minimum required levels or normal (or even abnormal) internal
levels. Furthermore, lactic acid bacteria, which produce lactic acid as
their major fermented product, are abundantly found in humans, including
breast milk and vaginal cavity, and are considered as probiotic
bacteria. Infants can be exposed to lactic acid bacteria during
breastfeeding. Lactic acid bacteria are known to be beneficial in
preserving healthy vaginal functions such as maintenance of acidic
vaginal pH and the prevention of infections.
The results obtained from sub-chronic
toxicity studies (IUCLID section 7.5.1) and from a chronic toxicity
study (IUCLID section 7.7) showed that there is no lactic acid specific
adverse systemic effect after repeated exposure.
Altogether, given the existing data and
taking a weight-of-evidence approach, there is no systemic toxicity
concern of lactic acid/lactide and no classification is warranted.
D-lactide is to be considered non-toxic; the
only effect are due to local irritation in the gastrointestinal tract as
a consequence of the formation of lacate derivates including lactoyl
lactic acid and monomeric lactic acid. Therefore, based on the available
data from suitable read across partners and in accordance with the CLP
Regulation 1272/2008, D-lactide does not warrant classification for
repeated dose toxicity.
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