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EC number: 203-710-0
CAS number: 109-83-1
BASF, 2009. Methylaminoethanol. Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats Oral Administration (Gavage). According to the GLP and OECD guideline 422.
Table 8: Absolute organ weights
Test group (mg/kg bw/day)
Terminal body weight
* : p ≤ 0.05; **: p ≤ 0.01
Table 9: Relative organ weights
Table 10: Histopathology
Multifocal tubular degeneration
Multifocal tubular degeneration; increase of the kidney weight
increase of the kidney weight
diffuse tubular degeneration
Ovarian cysts incidental
Fatty change of hepatocytes
Fore- and glandular stomach
Erosions or ulcers
Mesenteric lymph node
reduced cellularity of cortex
Methylaminoethanol was administered orally via gavage to groups of 10
male and 10 female Wistar rats (F0 animals) at dose levels of 50, 150
and 450 mg/kg bw/d.
The objective of the study was to detect possible effects of the test
substance on the integrity and performance of the reproductive system of
both sexes. Furthermore, it was intended to obtain information about the
general toxicological profile including target organs and the no
observed adverse effect level (NOAEL) after repeated oral
administration. Control animals were dosed daily with the vehicle
(highly deionized water). The duration of treatment covered a 2-week
pre-mating and mating period in both sexes, approximately 1 week
post-mating in males, and the entire gestation period as well as 4 days
of lactation in females.
Regarding clinical examinations, signs of general systemic toxicity were
only observed at a dose level of 450 mg/kg bw/d as there were
significantly lower body weights in male and female parental animals
accompanied with reduced food consumption and reduced general condition
in single animals in several phases of the study. Reduced food
consumption and body weights during gestation in females of test group 2
(150 mg/kg bw/d) were most likely related to implantation losses.
Detailed clinical examinations in an open field, detailed observations
in a functional observational battery (FOB) and measurements of motor
activity did not reveal indications of test substance-induced effects in
low, mid and high-dose rats. Therefore, the clonic convulsions were
assessed as being incidental.
Salivation was seen after dosing in all high-dose rats. From the
temporary, short appearance immediately after dosing it is likely, that
this finding was induced by a bad taste of the test substance or local
affection of the upper digestive tract. Urine discoloration was also
observed for all high-dose rats which was most likely related to the
test compound. However, both types of findings were not considered to be
adverse, toxicologically relevant effects.
Fertility was severely impaired by test-substance administration at dose
levels of 150 and 450 mg/kg bw/d. Although mating (male and female
mating indices) was not influenced no lifeborn pups were delivered for
both test groups.
The deviated levels of clinical chemistry and haematology parameters
pointed to anemia and changed liver cell metabolism. The total protein
and the albumin levels were significantly higher in female rats starting
at test group 1 (50 mg/kg bw/d). As these were the only deviating
parameters in females of this test group the changes were regarded as
treatment-related, but non-adverse. The reason for the increase of the
sodium concentrations in rats of both sexes in test groups 2 (150 mg/kg
bw/d) and 3 (450 mg/kg bw/d) remains unclear, but a test
substance-related effect could not be excluded. The higher incidences of
leucocytes in the urine of rats of both sexes in test group 3 (450 mg/kg
bw/d) and, additionally, in males of the test group 2 (150 mg/kg bw/d)
as well as the increased incidence of higher transitional cell counts in
males of test group 3 (450 mg/kg bw/d) can be regarded as signs of an
affection of the urinary tract in treated rats.
Regarding pathology, after administration of the test substance the
terminal body weight was significantly lower in females of test group 2
(150 mg/kg bw/d) and in males and females of test group 3 (450 mg/kg
bw/d). The body weight reduction resulted in weight changes of adrenal
glands, brain, heart, seminal vesicle, and thymus. Target organs were
the kidney, testes, epididymides, ovaries, liver, and spleen. In kidneys
and testes, tubular degeneration was dose dependent and assessed as an
adverse effect. In ovaries, the occurrence of cysts and vacuolization of
sex cord stroma was related to treatment and was considered to be
adverse. In test group 3 (450 mg/kg bw/d), the infertility was linked to
the reduced number of sperms (oligospermia) caused by tubular
degeneration in testes. In addition, the occurrence of ovarian cysts and
vacuolization of the sex cord stroma in females may have influenced the
fertility. In test group 2 (150 mg/kg bw/d), the severity of the
findings in testes or ovaries was only minimal or slight and the
findings did not occur in all infertile animals. Nevertheless, these
lesions may have affected fertility. In the spleen, a dose-related
increase in incidence and severity of extramedullary hematopoiesis
occurred in males and females of test groups 2 (150 mg/kg bw/d) and 3
(450 mg/kg bw/d). In addition, in females of these test groups the
severity of hemosiderin storage was increased. These findings are
associated with the increased relative spleen weights in females of test
group 2 (150 mg/kg bw/d) as well as in males and females of test group 3
(450 mg/kg bw/d). They were induced in response to anaemia and related
to treatment. The liver weights were dose-related increased in males and
females of all treatment groups. The liver was enlarged in three males
and one female of test group 2 (150 mg/kg bw/d) as well as in three
males and five females of test group 3 (450 mg/kg bw/d). In females, the
liver enlargement correlated with a minimal central hepatocellular
hypertrophy that was observed in five animals of test group 2 (150 mg/kg
bw/d) and in 9 animals of test group 3 (450 mg/kg bw/d). In males,
mainly a minimal fatty change of hepatocytes was observed in two animals
of test group 1 (50 mg/kg bw/d), in 8 animals of test group 2 (150 mg/kg
bw/d), and in 7 animals of test group 3 (450 mg/kg bw/d). The liver
findings were related to treatment and considered to be adaptive.
Although, there were no clear histopathological correlates for the
increased liver weights in males of all treatment groups and in females
of test group 1 (50 mg/kg bw/d), a test substance-related effect could
not be ruled out. There was no correlation between erosion/ ulcer in the
stomach and erythrocytosis of the mesenteric lymph node (findings
occurred in different animals). However, a treatment-related effect
could not be ruled out but was assessed as non-adverse. All further
findings occurred either singly or were biologically equally distributed
over the control group and the treatment groups. They were considered to
be incidental or spontaneous in origin and without any relation to
Methylaminoethanol was administered orally via gavage to groups of 10
male and 10 female Wistar rats (F0 animals) at dose levels of 50, 150
and 450 mg/kg bw/d (BASF, 2010).
In conclusion, under the conditions of the present
reproduction/developmental toxicity screening test the NOAEL (no
observed adverse effect level) for reproductive performance and
fertility was 50 mg/kg bw/d for the parental rats. The NOAEL for
general, systemic toxicity of the test substance was 50 mg/kg bw/d for
females and less than 50 mg/kg bw/d for males based on the tubular
degeneration in the kidneys of six male animals.
caused severely impaired fertility in rats treated at dose levels of 150
and 450 mg/kg bw/d in the Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test (OECD 422; BASF,
2010). Although mating (male and female mating indices) was not
influenced no lifeborn pups were delivered for both test groups. Signs
of general toxicity were observed in animals of only the highest dose
group (450 mg/kg bw). Changed levels of clinical chemistry parameters
together with histopathological findings in organs of treated animals
points to the systemic toxicity hazard by prolonged exposure. This is a
summary of the most relevant findings which are very likely accountable
for these effects:
group 3 (450 mg/kg body weight/day):
of 10 animals):
tubular degeneration (8 out of 10 animals)
tubular degeneration (10)
urea clearance (mean of test group)
in urine (mean of test group)
central fatty change (5)
peripheral fatty change (2)
albumin level (mean of test group)
extramedullar haematopoiesis (8)
anaemia (mean of test group)
stomach: erosion/ulceration (2)
of 10 animals):
vacuolization of sex cord stroma (10 out of 10 animals)
tubular degeneration (9)
central hypertrophy (9)
lymph nodes: sinus erythrocytosis (5)
group 2 (150 mg/kg body weight/day):
peripheral fatty change (5 out of 7 animals)
vacuolization of sex cord stroma (4 out of 7 animals)
extramedullar haematopoiesis (1)
lymph nodes: sinus erythrocytosis (1 out of 2 animals)
group 1 (50 mg/kg body weight/day):
tubular degeneration (6)
kidneys of males of all treatment groups as well as in females of test
groups 2 (150 mg/kg bw/d) and 3 (450 mg/kg bw/d) revealed a minimal to
severe tubular degeneration (see next table) which was regarded to be
treatment-related. The severity increased dose-dependently:
degeneration in the kidney:
Test group(mg / kg bw / day)
Number of animals
degeneration in the testes / epididymides:
(mg / kg bw / day)
Diffuse tubular degeneration
degeneration in kidneys and testes was dose dependent and assessed as an
adverse effect. This is probably a key factor in the fertility effects.
Furthermore, the effects in kidneys are probably related to anaemia.
Since serum bilirubin was high, some amount of haemoglobin in the urine
can be present, especially if the kidneys are damaged. It was manifested
in discoloured urine of the treated animals.
of sex cord stroma
Occurrence of cysts
Vacuolization of sex cord stroma
occurrence of cysts and vacuolization of sex cord stroma in ovaries was
related to treatment and was considered to be adverse. This is another
key factor to fertility effects.
on classification and labelling:
on the findings observed in the Combined Repeated Dose Toxicity Study
with the Reproduction/Developmental Toxicity Screening Test (OECD 422;
BASF, 2010) classification with a “hazard category 2” for “Specific
Target Organ Toxicity Repeated Exposure” (STOT RE Cat. 2) is
warranted for Methyl-Monoethanolamine (MMEA; CAS 109-83-1) according to
the criteria of EU Classification, Labelling and Packaging of Substances
and Mixtures (CLP) Regulations No 1272/2008. The substance will be
labelled accordingly with “H373: May cause damage to organs
through prolonged or repeated exposure”. Target organs are the
kidney, testes, epididymides, ovaries, liver, and spleen.
rationale is as follows:
and treatment-related adverse effects on kidneys (i.e. tubular
degeneration) after repeated dose exposure occur in the range of the low
dose (i.e. 50 mg/kg bw/day).
and treatment-related adverse effects on blood (i.e. haemolytic anaemia)
occurred in the range of the mid and high doses (150 and 450 mg/kg
is not subject for classification as being toxic to male and female
fertility. Adverse effects on fertility are considered to occur
secondary to the specific target organ toxicity (i.e. adverse effects on
kidney and anaemia).
on the rationale:
exerted treatment-related and adverse effects on the kidneys in males
and females (i.e. tubular degeneration was observed at all doses tested.
Additionally, changes in urine parameters were reported that corroborate
the impaired functionality of the renal system at 150 and 450 mg/kg
bw/day (e.g. occurrence of blood in the urine, reduction in urea
clearance). The effects may be secondary to anaemia.
anaemia has been reported to be caused substance- and treatment-related
by MMEA. A significant decrease in red blood cell count and in total
haemoglobin content could be observed in the mid and high doses. In
consequence, a decrease in haematocrit was observed in line with the
before mentioned findings representing anaemia. Further indications for
a haemolytic anaemia can be derived from the fact that an increase in
hemosiderin storage in the spleens has been reported. Additionally, an
increase in bilirubin levels was reported to occur in the urine
indicative for the haemolytic character of the anaemia.
is not subject for classification for adverse effects on fertility, as
the effects on testes and epididymides, as well as effects on the
ovaries did not occur isolated and in the absence of other toxic
effects. The adverse effects on fertility were reported to occur in the
range of other significant toxic effects (i.e. kidney toxicity and
haemolytic anaemia as described above). Thus, the adverse effects on
reproduction affecting male and female fertility are considered to be
secondary to the general toxicity effects observed and to result from a
non-specific mechanism. The adverse and significant toxic effects on the
kidneys occurs in the lowest dose of 50 mg/kg bw/day whereas fertility
was impaired only at higher dose levels (= 150 and 450 mg/kg bw/day.
Furthermore, haemolytic anaemia represents an adverse and significant
effect which occurs in the same range as effects on fertility are being
and fertility have been linked with kidney failure in male rats and
kidney functional impairment (Nazian and Dietz, 1987, Menjívar et al.,
2000). In these available studies male fertility was reported to be
impaired by liver insufficiency as a secondary consequence (e.g. chronic
nephrosis, uraemia in consequence of partial nephrectomy). Especially
chronic nephrosis as an umbrella term for degenerative tubular kidney
disease represents a comparable situation to what has been observed for
MMEA. Ortiz et al. (1999) reported decreased male fertility in
consequence of chronic nephrosis.
the possible mechanism, effects on the choline-homeostasis could play a
role. Various alkanolamines are known to produce choline-deficiency
(e.g. diethanolamine DEOA CAS 111-42-2). Choline is a vitamin-like
compound with various physiological functions (i.e. building block of
phospholipids and acetyl-choline, one-carbon-metabolism and
DNA-methylation etc.). It could be demonstrated that certain
alkanolamines exert an inhibitory effect on either choline-uptake and/or
choline-metabolism. Thereby, alkanolamines cause a choline-depletion. A
hallmark of choline-depletion is a fatty liver change (Zeisel, 1994). In
line with this, liver enlargement concurrent with an increase in
absolute absolute and relative liver weight has been reports in all dose
groups after MMEA-treatment. Furthermore, minimal fatty changes and
central hepatocellular hypertrophy have been observed in parallel.
Similar effects have also been reported for DEOA, where
choline-deficiency caused liver and kidney effects (Melnick, 1992) in
repeated dose toxicity tests. In long-term studies with DEOA, liver and
kidney tumours developed in mice but not in rats (NTP, 1992). In depth
investigation on the possible mode-of-action revealed that the liver
tumours formation could be attributed to an increase in hepatocellular
proliferation probably due to a DEOA-induced choline-depletion
(Lehman-McKeeman and Gamsky, 2000; Lehman-McKeeman et al., 2002).
However, an increase in hepatocellular proliferation has been reported
for rodent hepatocytesin vitroonly whereas human primary
hepatocytes did not respond. This indicates that rodent cell might be
more sensitive and prone towards choline-depletion than human
hepatocytes are. Thus, the human relevancy of the findings is
questionable as no increase in proliferation was observed in the human
hepatocytes (Stott, 2000; Kamendulis and Klaunig, 2005). Therefore, the
mode-of-action of MMEA causing kidney lesions might rely on
choline-depletion (as reported for various alkanoalmines as well). This
mode-of-action has been demonstrated in the context of liver tumour
formation to lack human relevance. It is thus concluded that
MMEA-induced adverse kidney effects might arise in addition from a
toxicokinetic difference with rodents being most sensitive species.This
“choline” issue may also be causing some specific effect on membrane
integrity that is resulting in a spectrum of toxic effects (anaemia,
testes tubule degeneration, and possibly kidney tubule degeneration). This
was considered to be part of the DEA toxicity spectrum as well, since
some anemia was noted at the high dose levels of the DEA chronic studies.
the dramatic reduction in male and female fertility (10 and 11%,
respectively) occurred in the range of morbidity already in the high
dose of 450 mg/kg bw/day. Twenty per cent of the males (2/10) were
either found dead (1/10) or had to be sacrificed due a poor general
status (1/10). In the mid dose (150 mg/kg bw/day) reduction in fertility
was still evident in the presence of adverse and severe kidney effects
and haemolytic anaemia. However, no animal died treatment related in the
mid dose group.
together, MMEA should be classified for specific target organ toxicity
affecting kidney and blood. Effects on fertility are considered to occur
as a secondary consequence and are thus not subject to classification.
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