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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 entry.
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.
Ozen et al (2002 and 2005) performed subacute and subchronic inhalation studies with FA particularly addressing testes. Ozen et al. 2002 exposed rats to formaldehyde at different periods (subacute and subchronic) and concentrations (0; 12.2; 24.4 mg/L). Body and testis weights were recorded and compared with control groups. The metals described below were determined in rat testicular tissue by atomic absorption spectrometry by using wet ashing. It is concluded that that subacute or subchronic exposure to formaldehyde have caused growth retardation and altered levels of trace elements, including copper, zinc and iron, in testicular tissue, and may induce further oxidative damage on testicular tissue leading to spermatozoa abnormalities.
Ozen et al. 2005 used 18 albino Wistar rats divided into three groups, exposed to 0 (control), 5 and 10 ppm FA gas for a total of 91 days, 8 h/day, five days a week. Serum testosterone levels were determined using a chemiluminescent enzyme immunoassay. Testicular tissues were stained with Hematoxylin-Eosine and Hsp70 immunohistochemically. Diameters of seminiferous tubules and serum testosterone levels in animals inhaling FA were significantly decreased. In seminiferous epithelium stained for Hsp70, compared to those in the control group, the spermatogenetic cells in the experimental groups demonstrated an obvious increase in immunoreaction spermatides in the adluminal region and especially in the cytoplasm of spermatocytes. Immunoreaction of Hsp70 was detected in the spermatogonias of animals exposed to FA inhalation as opposed to those of the control group. Compared to the control, there was a significant increase in the immunoreactions observed not only in the cytoplasm of primary spermatocytes, but also spermatides in the adluminal region of the seminiferous tubules.Both studies lack reporting of key clinical data necessary for interpretation such as body and test weights, clinical data and symptoms etc. and no dose response relationship in testes was observed. It’s not clear whether Bouin’s solution was used for fixation of testes in order to avoid artefacts. However, it is clear that excessive systemic toxicity can be expected at the concentrations used which was reflected in all study groups in the few clinical parameters given in the publications (e.g. by body weight gains). As there is no experimental indication of systemic availability of FA, it can only be speculated that the effects observed are secondary to excessive general toxicity and irritation/corrosion.
There are many publications reporting adverse effects on male fertility with intraperitoneal (i.p.) application of aqueous FA solutions. Apart from the fact that these irritating or corrosive solutions might distribute directly into the scrotal sac causing local toxicity to the testes, i.p. administration is often accompanied with severe general toxicity leading to secondary effects such as testes effects. In addition, It should be noted that i.p. administration is a completely non-physiological and irrelevant route of exposure per se.
Taskinen et al. (1999) investigated whether exposure to formaldehyde, organic solvents or other chemicals in the wood-processing industry affects the fertility of women. For this purpose, a retrospective study on time to pregnancy was conducted among female wood workers who had given birth during 1985–1995. Data on pregnancy history, time to pregnancy, occupational exposures, and potential confounders were collected by a questionnaire; 64% (699/1,094) participated. The exposure assessment was conducted by an occupational hygienist. The data on time to pregnancy were analyzed with the discrete proportional hazards regression. Exposure to formaldehyde was significantly associated with delayed conception:
adjusted fecundability density ratio, FDR, was 0.64 (95% CI 0.43–0.92). At high exposure if no gloves were used, the FDR was 0.51 (% CI 0.28–0.92). Exposure to phenols, dusts, wood dusts, or organic solvents was not related to the time to pregnancy. Additionally, an association was observed between exposure to formaldehyde and an increased risk of spontaneous abortion (concerning previous spontaneous abortions, reported by the women). Associations between exposure to formaldehyde or to organic solvents and endometriosis, and between exposure to organic solvents or to dusts and salpingo-oophoritis were also suggested.
However, this publication shows a number of deficiencies:
- No analytical measurements. Exposures were estimated based on mailed questionnaires. Exposures were estimated from an undefined sampling time; when sampling was not available estimates relied upon sampling from an unrelated industry (i.e., cosmetology).
- Methanol is a co-exposure that was not accounted for.
- Pregnancy outcomes were evaluated based on recall, in a mailed questionnaire. The period of recall extended over a decade, likely introducing substantial recall bias.
- The number of women evaluated was not reported for the fecundability ratio; rather this report presented only FDR and 95% confidence limits.
- The highest risk in the study was calculated for those not wearing gloves (FDR = 0.51) when compared to formaldehyde exposure (FDR = 0.57) or other exposure categories (FDR = 1.09, 0.96 and 0.64 for low, medium and high exposure groups, respectively). This fact that not wearing gloves presents the greatest risks calls into question all conclusions related to any cause and effect for formaldehyde in the study.
- The exposure categories overlapped, raising serious concerns about assignment of individuals to the exposure bands.
Given these deficiencies, the conclusion of the study is questionable.
Duong et al. (2011, supporting) reviewed the literature on reproductive effects in humans and animals starting from 450 references including studies published in 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.
Khalil et al. (2017) investigated effects on the reproductive system after dosing male Swiss mice with 25 mg FA/kg bw/d over 65 consecutive days. A 40% solution of FA (possibly formalin) was diluted in water to “working stock solutions” without giving further details. The dosing volume per mouse was not specified. FA exposure affected steroidogenesis and several testicular enzymes. Under consideration of the bolus application severe effects on the stomach are to be expected with unknown systemic sequelae and missing data in this respect is a severe deficiency. This relatively new oral gavage study is hampered by several important drawbacks: detailed information is missing on the dosing solution, histopathology of the stomach, the primary portal of entry, was not carried out, and only one dose level of FA was used such that a dose response relationship cannot be assessed. Furthermore, the relatively steep rise in blood levels obtained by gavage leads to some uncertainty in risk assessment for humans exposed via food or liquid intake.
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; developmental toxicity).
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. ”
Merzoug and Toumi (2017) observed alterations of behavior and hemato-immune parameters in pregnant Wistar rats with significantly increased cortisol and decreased 17beta-estradiol. Offspring showed a significant decrease of several growth-related parameters and especially a nearly 90 % reduction of live fetuses. Rats were treated over 10 days before mating and then until GD 19. They were dosed with 2 mg FA/kg bw/d (from 37 % formalin) administered in a volume of 1 mL/kg bw corresponding to 2000 mg/L similar to the highest concentration used by Til et al. (1989). Under consideration of the bolus application severe effects in the stomach are to be expected but no information is available. However, detailed information is missing on the dosing solution, histopathology of the stomach, the primary portal of entry, was not carried out, and only one dose level of FA was used such that a dose response relationship cannot be assessed. Furthermore, the relatively steep rise in blood levels obtained by gavage leads to some uncertainty in risk assessment for humans exposed via food or liquid intake. So it remains unclear whether the effects observed are secondary to severe general toxicity and irritation.
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).
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