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EC number: 222-720-6
CAS number: 3586-55-8
study is conducted according to OECD guideline 408 with GLP. 10 male and
10 female Sprague-Dawley rats received via gavage once daily, 7 days per
week for 90 days 0, 30, 90, 270 mg/kg bw in corn oil (concentration 0,
0.6, 1.8, 5.4%). The
test substance induced local effects in the stomach at a dose level of ≥
90 mg/kg bw. Such effect is expected of a substance releasing
formaldehyde in situ. Other reported effects like reduced body weight
gain and some decrease in motor activity in the high dose groups and
alteration in haematology like increased leucocyte counts, shift in the
differential blood count at the high dose level are considered to be a
consequence of the chronic ulcerative gastritis & peritonitis. The
reduced pupil size detected in males and females and the negative pupil
response in males of the mid and high dose group (detected in functional
observation battery at week 13) might be a systemic effect of the test
substance but the toxicological relevance is unclear.
clinical chemistry parameters in the high dose group are recognized but
evaluation is limited without historical control data of the same
higher LOAELs can be expected if the test substance is applied via
drinking water or diet and not via gavage (bolus effect).
deficiencies include no data about the purity of the test substance
(responsibility of the sponsor, minor restriction); blood urea nitrogen
not determined in clinical chemistry and no data on significance at the
level p<0.05 (minor deficiencies).
Data on formaldehyde
Repeated oral exposure
The main effects in chronic drinking
water studies with rats are local lesions at a concentration of 0.19%
(Til et al. 1989) or 0.1% (Tobe et al. 1989). These
concentration-dependent effects included papillary epithelial
hyperplasia, hyperkeratosis and ulceration of the forestomach and the
glandular stomach.The NOAEC is 0.026% (Til et al. 1989) or 0.02% (Tobe
et al. 1989).Til et al.(1989) reported an increased incidence in
papillary necrosis of the kidney, but this effect was due to the reduced
water intake and is only indirectly treatment related. The decrease in
body weight is related to the reduced water & food consumption and/or is
secondary to lesions of the stomach. The NOAEL for systemic effects in
chronic studies is 82 mg/kg bw/day in males and 109 mg/kg bw/day in
females (Til et al. 1989; higher validity than Tobe et al., 1989). No
carcinogenic effects were reported (Til et al. 1989, Tobe et al. 1989).
Similar results concerning local effects were presented in a subacute
study, the NOAEL was 25 mg/kg bw/day (no data given about the
concentration; Til et al. 1988).
In the subchronic drinking water study
in rats (Johannsen et al., 1986) no local and no systemic effects were
detected at a dose levels up to 150 mg/kg bw/day. Concerning the missing
local effects at the high concentration of 0.1% in water the results are
in agreement with the chronic drinking water study of Tobe et al.
(1989). Local effects in the stomach could be clearly demonstrated at a
concentration of 0.5%. At a concentration of 0.1% only 1 out of 20 male
and 1 out of 20 female Wistar rats revealed these local effects (Tobe et
al., 1989). The concentration of formaldehyde in the subchronic drinking
water of Johannsen et al. (1986) was probably too low to induce local
effects in the gastro-intestinal tract of rats.
In a subchronic study no local and no
systemic effects were reported in dogs exposed via the diet to dose
levels up to 100 mg/kg bw/day.The NOAEL for systemic effects is 100
mg/kg bw/day.No data were given on the concentration, however, it can be
assumed thatthe concentration of formaldehyde in the diet was not
sufficient for induction of local effects in the gastro-intestinal tract.
In conclusion, the overall NOAEC for
the oral route based on chronic studies with rats is 0.026% in water
(LOAEC 0.1%). The NOAEL for systemic effects in rats is 82 mg/kg bw/day
in males and 109 mg/kg bw/day in females.
Repeated dermal exposure
Data available on this endpoint are of
limited validity due to restricted documentation. In mice only local
skin effects and no systemic toxicity were induced after topical
application of formaldehyde at a concentration of 10% and an amount of
200 µL. Slight hyperplasia of the epidermis was found and a few mice had
small ulcers and scratches (Iversen 1986). In another study there is
some evidence for local irritation at a concentration of >= 0.5%.
Repeated inhalation exposure
It has been shown in rats, mice, and
monkeys that the respiratory epithelium in the nasal cavity is the most
sensitive site. In rats and monkeys squamous metaplasia and hyperplasia
were reported, in mice rhinitis, dysplasia and squamous metaplasia.
Carcinogenicity data are evaluated in a separate chapter.
The NOAEL is 2 ppm in rats (e.g.
Monticello et al. 1996), and 1 ppm in monkeys (Rusch et al. 1983). Mice
are less sensitive, the NOAEL in a subchronic study is 4 ppm (Maronpot
et al. 1986); this might be related to the higher RD50value
in mice compared to rats. Lowest sensitivity was reported for hamsters,
no local or systemic effects were noted at 3 ppm (Rusch et al. 1983) and
slight effects at 10 ppm.
Studies with rats have shown that the
NOAEL and the LOAEL are independent of the exposure duration. In chronic
studies as well as in subacute studies with only a few days (measuring
cell proliferation) or weeks duration (measuring epithelial lesions) the
NOAEL was the same or even lower than in long term studies. Effects were
noted in the respiratory epithelium at a concentration of 2 ppm.
At dose levels above the LOAEL the
severity of the lesion in respiratory epithelium increased with the
concentration and the duration of the exposure period (cf. Monticello et
al. 1991). However, studies in rats (using the constant concentration x
exposure duration) revealed that the concentration rather than the
“total dose” is responsible for the effects (Wilmer et al. 1989). At
high dose levels (10-20 ppm) no complete reversibility of lesions in the
nasal cavity was reported in rats after 13 weeks of exposure and a post
exposure observation period of up to 126 weeks (Feron et al. 1988).
Not only the anterior part of the
nasal cavity but also more proximal parts of the upper respiratory tract
were affected with increasing formaldehyde concentrations in rats, mice
and monkeys: olfactory epithelium, larynx, trachea, and bronchus.
Increase in toxicity and severity is not linear but shows a sharp
increase at ca. 10 ppm.
Based on the studies described above
the overall NOAEL based on chronic studies with rats, mice, hamsters and
monkeys is 1 ppm corresponding to 1.2 mg/m³.
Effects in humans occupationally
exposed via inhalation
There is some evidence from a number
of survey studies that formaldehyde exposure may also induce squamous
cell metaplasia and hyperplasia in the respiratory epithelium of the
nasal cavity in long-term exposed humans (IARC 1995, Greim 2000, BfR
2006). However, the data base is not sufficient for conclusions on dose
or time response relationships. None of the studies were conducted with
sufficient methodological accuracy and no firm conclusion can be drawn
(WHO 2002, BfR 2006).
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