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EC number: 200-001-8
CAS number: 50-00-0
No studies were available which are directly related to this endpoint
(e.g. OECD Guideline 415, 416, or 422). However, no studies are needed
because it is not to be expected, that formaldehyde reaches the
reproductive organs and there is no evidence for effects on fertility
and gonads in experimental animals after long-term oral or inhalation
exposure. Toxicokinetic data (see summary end discussion Toxicokinetics)
suggested only local effects at the site of entry.
Effects on fertility
In a two-years drinking-water study in rats comparable with OECD
Guideline 453 (Til et al., 1989, Section Repeated dose toxicity: oral)
no adverse effects on the reproductive organs were recorded even at the
high dose level of 109 mg/kg bw/day in females and 82 mg/kg bw/day in
males that induced local effects in the stomach. These negative results
for reproductive organs are confirmed by the long-term drinking water
study of Tobe et al. (1989; Section Repeated dose toxicity: oral) in
rats or a chronic inhalation study in rats and mice (CIIT, 1981; Section
Repeated dose toxicity: inhalation) comparable to OECD Guideline 453 and
further oral and inhalation studies in rats, mice and dogs (see waiving
Section Effects on fertility). This lack of systemic effects to
reproductive organs (independent on the route of exposure) are in accord
with toxicokinetic data (see endpoint summary of section
repeated dose toxicity) suggesting only local effects at the site of
No conclusions can be drawn from the limited data in humans (see
waiving Section Effects on fertility).
A short summary and evaluation on reproductive effects is also
presented in a recent review by IARC (2006); details are given in the
following Section of the endpoint summary.
There is no evidence for adverse effects of formaldehyde on embryo and fetal development at dose levels inducing local maternal effects and secondary decrease in body weights and growth.
effects on behaviour, appearance, motility and muscular co-ordination in
dogs observed for a more prolonged period.
meets generally accepted scientific standards but limited number of
parameters examined. Further deficiencies: No data about purity
of the test substance; only low dose tested without maternal toxicity;
some evaporation of formaldehyde prior to consumption presumed
(resulting in lower dose levels). Study limited to a restricted number
of parameters (e.g. data on visceral or skeletal alterations only in
stillborn pups or pups which died later in post natal observation
period, no data on maternal weight gain). No statistical analysis.
Beagle dogs (9-10 pregnant bitches per dose) were exposed from day 4
after mating up to day 56 to a diet containing formaldehyde at dose
levels of 0, 3.1, or 9.4 mg/kg bw/day. The dose levels (max. 9.4 mg/kg
bw) and concentrations (max. 0.037% in the diet) were relative low (no
local effects expected). No toxic effects were reported in the bitches
(but no data on body weight gain). External malformations were examined
immediately after birth and after 8 weeks. Autopsy was performed on
stillborn pups and those lost before weaning. Further parameters: total
pups at birth, total live pups at birth, total pups at weaning, mean
live (or total) pups per litter at birth and at weaning, mean litter
size, sex ratio, mean pup weight (measured daily after birth for 8
days). Concerning the investigated parameters no developmental toxicity
developmental effects in dogs exposed via the diet to doses up to 9.4
mg/kg bw/day but limited number of parameters examined.
Developmental effects of formaldehyde in mice after oral exposure via gavage
Dose in mg/kg bw/day
No. of dams receiving the test substance
No. of dams alive on day 18
Number of pregnant dams
Average weight gain day 6-17
Mean number of implants/dam
Number of resorptions
Average % of resorptions/litter
Average % of foetal deaths/litter
Number of stunted fetuses
Average no. of live fetuses/dam
Average foetal weight in g
Study is comparable to OECD guideline 414 with acceptable
restrictions [partly without details on results (irritation, symptoms,
necropsy); co-application of methanol (used for stabilisation of
this gavage study 29 -76 pregnant
dose group were
exposed to 0, 74, 148, 185 mg/kg bw/day formaldehyde (concentration of
applied solution: 0, 0.7, 1.5, 1.8%) once daily at gestation day 6-15
(termination at gestation day 19). Maternal toxicity was obvious at
74 mg/kg bw/day (decreased body weight gain); data on local effects in
the gastro-intestinal tract are not available, however, these effects
are expected even at the low dose level (compare with data in Section
7.5.1). No embryo- or fetotoxic effects and no teratogenic effects were
reported at any dose level, although 185 mg/kg bw/day resulted in a high
mortality rate in pregnant mice.
No developmental toxicity in mice at dose
levels inducing maternal toxicity after oral exposure via gavage.
At a dose level of >=5 ppm local effects in the nasal cavity of dams are
expected (compare with data in Section 7.5.3 and endpoint summary in
Section 7.5). It can be speculated that 2 ppm is the NOAEC for maternal
toxicity (related to these local effects).
The study is comparable to OECD guideline 414 with acceptable
restriction (exposure restricted to gestation day 6-15; virus infection
in dams of all groups).
Pregnant Sprague-Dawley rats (25 per dose level) were exposed at
gestation day (GD) 6 -15 for 6 h/day to 0, 2, 5, 10 ppm. The study was
terminated at GD20. Maternal toxicity was detected only at 10 ppm
(decreased body weight gain and food consumption; no data about
irritation but local effects in the nasal cavity expected at >= 5 ppm).
No effects of toxicological relevance were found on parameters of
developmental toxicity, the NOAEC was 10 ppm.
Conclusion: No embryo- or fetotoxic effects in rats at concentrations
inducing maternal toxicity.
Developmental effects in rats exposed via inhalation for 6 h/day on gestation day 6-20Mean +- SD
Number of pregnant females
Incidence of pregnancy (%)
Body weight gain of dams (g)
Implantation sites per litter
Total foetal loss per litter
Resorption sites per litter
Live foetuses per litter
Foetal sex ratio
Mean weight of male pups
Mean weight of female pups
* : p<0.05; ** : p<0.01;
In this study the requirements of the OECD guideline 414 were fulfilled
except data on maternal toxicity (no data on food consumption, body
weight during exposure period and clinical symptoms[local effects
21 -24 pregnant Sprague-Dawley rats per dose level were exposed via
inhalation for 6 h/day on day 6 to day 20 of gestation to 0, 5, 10, 20,
or 40 ppm and sacrificed at gestation day 21. Significant effects on
maternal body weight were detected only at the high dose level
(determined only gestation day 6 and 21). However, maternal toxicity due
to local effects in the nasal cavity are expected at >= 10 ppm (compare
with data in Section 7.5.3). No developmental effects were found except
decreased fetal weight of males and females in the high dose group and a
slight but significant decrease in foetal weight of males at 20 ppm.
Conclusion: No teratogenic effects; effects on fetal weight at >= 20 ppm
might be due to maternal toxicity.
In a study comparable to OECD Guideline 414 (with acceptable
restrictions) pregnant Sprague-Dawley rats (25 per dose level) were
exposed at gestation day (GD) 6 -15 for 6 h/day to 0, 2, 5, 10 ppm
(Martin, 1990; FCC, 1985). The study was terminated at GD20. Maternal
toxicity was detected onlyat 10 ppm (decreased body weight gain and food
consumption; no data about irritation). At the 5 and 10 ppm levels, an
apparently significant concentration-related decrease in ossification
was detected in the bones of the pelvic girdle, but this was associated
with larger litter sizes with decreased fetal weights in both these
groups. The slightly lower fetal weights were considered to be due to
the larger litter sizes. Since noeffects of toxicological relevance were
found on parameters of developmental toxicity, the developmental
toxicity NOAEC was 10 ppm (Martin, 1990; FCC, 1985). In conclusion, no
embryo- or fetotoxic effects were detected in rats at concentrations
inducing maternal toxicity.
In a further teratogenicity study in rats (Saillenfait et al.,
1989) no teratogenic effects were detected even at inhaled
concentrations up to 40 ppm (0, 5, 10, 20, 40 ppm; 6 h/days at gestation
day 6-20). Only effects on fetal weight were reported at ≥ 20 ppm.
Significant reduction in body weight and absolute weight gain of dams
was found at 40 ppm. No data were reported on clinical signs or local
effects; however, local irritant effects are clearly to be expected at ≥
10 ppm (compare with data in Section Repeated dose toxicity)
In an oral developmental toxicity study (Marks, 1980) pregnant
mice were exposed via gavage to 0, 74, 148, or 185 mg/kg bw/day
formaldehyde (concentration of applied solution: 0, 0.7, 1.5, 1.8%) at
gestation day 6-15. Maternal toxicity was reported at 74 mg/kg bw/day or
greater (lethality and decreased body weight gain); data on local
effects in the gastro-intestinal tract are not available; however, these
local effects are expected even at the low dose level/concentration in
dams (compare with data in Section Repeated dose toxicity: oral). No
embryo- or fetotoxic effects and no teratogenic effects were reported at
any dose level, although 185 mg/kg bw/day resulted in a high mortality
rate in dams. In conclusion, no developmental toxicity was found in mice
at dose levels inducing maternal toxicity after oral exposure via gavage.
There were inconsistent findings in epidemiological studies on
spontaneous abortions; however, no conclusion can be drawn due to
limitations of these studies (see IUCLID Section 7.10.2; WHO, 1989;
A summary and evaluation on reproductive and developmental effects
is also presented in a recent review by IARC (2006): “Eleven
epidemiological studies have evaluated directly or indirectly the
reproductive effects of occupational exposures to formaldehyde. The
outcomes examined in these studies included spontaneous abortions,
congenital malformations, birth weights, infertility and endometriosis.
Inconsistent reports of higher rates of spontaneous abortion and lowered
birth weights were reported among women occupationally exposed to
formaldehyde. Studies of inhalation exposure to formaldehyde in animal
models have evaluated the effects of formaldehyde on pregnancy and fetal
development, which have not been clearly shown to occur at exposures
below maternally toxic doses. ”
A review on reproductive effects was identified in the
literature update up to April 20, 2015.
Dong et al. (2011, supporting) reviewed the literature on
reproductive effects in humans and animals starting from 450 references
including studies published iin Chinese language mostly in peer reviewed
journals. Animal studies by all routes of exposure were included. After
removal of abstacts, animal studies dating from before 1980, and
non-English publications (except Chinese and human studies), 18 human
and 46 animal studies were reviewed in detail. By a metaanalysis of the
mainly retrospective human studies the authors observed an increased
risk for spontaneous abortions (1.76, 95% CI 1.20-2.59; p=0.002) and all
adverse pregnancy outcomes (1.54, 95% CI 1.27-1.88; p<0.001) for
formaldehyde exposed women. But differential recall, selection bias, or
confounding cannot be ruled out. Animal studies suggest positive
associations between formaldehyde exposure and reproductive toxicity,
mostly in males. Potential mecchanisms are offered, like genotoxicity,
oxidative stress apoptosis, and alterations of enzymes, hormones, or
proteins. This review is a valuable collection of literature, including
studies from China, but as a critique, generally no effort is made to
analyse strengths and weaknesses of the single publications in order to
arrive at some weight of evidence assessment.
The available data on toxicity for
reproductiondo not trigger classification and labeling according to EU
Classification, Labelling and Packaging of Substances and Mixtures (CLP)
Regulation (EC) No. 1272/2008).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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