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Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
0.244 mg/m³
Additional information

No reproduction toxicity study was located for methyl formate, but there are several studies available using the supporting chemicals, formic acid and methanol. Methylformate is rapidly metabolized to formate and methanol. Considering that the primary effect of formic acid is corrosion, data on its neutralized salt are taken into consideration.

Sodium Formate:

The fertility toxicity potential of sodium formate was examined in a 2-Generation feed study (according to OECD 416 and GLP) using male and female Wistar rats (25/sex and dose) at dose levels of 0, 100, 300, and 1000 mg/kg bw/day.

There were no indications that sodium formate adversely affected fertility or reproductive performance of the F0 and F1 parental animals at dose levels as high as 1000 mg/kg body weight/day. Mating behavior, conception, gestation, parturition, lactation and weaning as well as sexual organ weights and gross findings of these organs were comparable between the rats of the test substance-treated test groups and the corresponding controls, and ranged within the historical control data of the test facility. There were no effects on male and female reproduction organs. Sperm parameters and estrous cycle were not affected.

Due to the absence of maternal toxicity and toxicity to reproduction in F0  animals and F1 pups at 1000 mg/kg bw and day, the NOAEL was set at 1000 mg sodium formate/kg bw/day for these endpoints.

The NOAEL for methyl formate (M= 60 g/mol) may be calculated, taking into account formula weights, and that two formate molecules result from one molecule of methyl formate:

Sodium formate (M = 69 g/mol): NOAEL = 1000 mg sodium formate/kg /69 = 14.5 mmol/kg bw/day

Methyl formate: 14.5 x (60/2) gives a NOAEL of approx. 435 mg methyl formate/kg bw/day.

Methanol:

Methanol was treated in the OECD-ICCA/HPV program in 2004 at SIAM 19. The final SIDS documents are available at the OECD website (Published OECD SIDS initial assessments of HPV chemicals;http://www.oecd.org/document/63/0,3343,en_2649_34379_1897983_1_1_1_1,00.html) and contain the studies quoted below.

Reproductive toxicity studies are available for methanol (supporting substance) in monkeys, rats, and mice. In monkeys, parents were exposed via inhalation prior to and during breeding as well as during pregnancy to concentrations of 0.26, 0.78, and 2.34 mg/L. A late wasting syndrome was observed at the highest concentration in 2 out of 7 female descendants, associated withsigns of severe malnutrition and gastroenteritis noted at autopsy. Mild neurobehavioral effects in offspring and some vaginal bleeding in mothers were observed at all concentrations. However, due to the normal variance in and the low number of animals, along with pre-term delivery of several mothers, the observed findings are difficult to interpret (Burbacher et al., 1999).

In a two-generation reproduction study, rats were exposed to methanol by inhalation for 19-20 hours/day (NEDO, 1987). No treatment-related alterations in general observations and reproductive parameters were found. None of the fertility indices including sexual cycle, days needed for insemination, insemination rate and pregnancy rate showed statistically significant differences. There were no differences for body weight, food consumption and water consumption during gestation and lactation period, either. No abnormalities were observed in findings on delivery and nursing behaviour and necropsy data of F0 animals. No firm conclusions can be drawn about fertility of either sex, as the copulation time of 21 days was comfortably long for successful insemination and gametogenesis was not considered. In the F1 and F2 progeny (both sexes), no histological changes and no effects on testes or ovaries were reported. However, a decrease in brain weights was evident at 1.3 mg/L methanol, but without noticeable histological changes and functional impairments. This phenomenon is believed to represent a change occurring during the prenatal period (Takeda and Katoh, 1988). However, no quantitative data and statistical level were documented for organ weights. The meaning of an apparent shift of testis descent in male offspring in relation to body weight development of the pups in the two following generations is unclear and was not directly addressed by Takeda and Katoh (1988), but detailed by NEDO (1987) and considered a significant difference from untreated controls. Furthermore, it is obvious that this parameter showed considerable variation also between the control groups of both generations.

Based in decreased brain weights in the first and second generation offspring (F1, F2), the NOAEC is 0.13 mg methanol/L (NEDO, 1987; Takedo et al., 1988). 

Obviously, the inhalation NOAEC for methanol is much lower than the oral formate NOAEL and should be used for further considerations. A conservative NOAEC for methylformate can be estimated to be 0.244 mg/L if one assumes that all the methyl formate is hydrolysed (one mole of methyl formate gives one mole of formate and one mole of methanol), and that the toxicity of methyl formate is dominated by methanol.



Short description of key information:
Methyl formate is rapidly cleaved by esterases (see chapter 7.1). Therefore, data on formic acid and methanol may be used. In the rat, the inhalation NOAEC for methanol (0.13 mg/L in a 2-generation study; Takeda et al, 1987) is much lower than the oral NOAEL of sodium formate (1000 mg/kg/d) and should be used for further considerations.

Effects on developmental toxicity

Description of key information
Methyl formate is rapidly cleaved by esterases. Therefore, data on formic acid and methanol may be used. In the rat, the inhalation NOAEC for methanol (6.5 mg/L) is much lower than the oral NOAEL of sodium formate (1000 mg/kg/d for rats and rabbits) and should be used for further considerations.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
12.9 mg/m³
Additional information

No developmental toxicity study was located for methyl formate, but there are several studies available using the supporting chemicals, formic acid (or its neutralized salt sodium formate) and methanol. Methylformate is rapidly metabolized to formate and methanol (see chapter 7.1).

Sodium Formate:

In a developmental study, time-mated female rats (25/dose, OECD TG 414) were given sodium formate via oral gavage at 0, 59, 236, and 945 mg/kg bw/day during gestation days 6 to 19.  Maternal toxicity was not seen. Gestational parameters were not influenced and there were no effects on the developing fetuses.  No malformations or skeletal variations were seen.  The NOAEL for maternal and developmental toxicity was 945 mg sodium formate/kg bw/day, the highest dose tested. 

The NOAEL for methyl formate may be calculated, taking into account formula weights, and that two formate molecules result from one molecule of methyl formate:

Sodium formate: NOAEL = 945 mg sodium formate/kg /69 = 13.7 mmol/kg bw/day

Methyl formate: 13.7 x (60/2)gives a NOAEL of approx. 410 mg methyl formate/kg bw/day.

Methanol:

Methanol was treated in the OECD-ICCA/HPV program in 2004 at SIAM 19. The final SIDS documents are generally available at the OECD website (Published OECD documents: http://www.oecd.org/document/63/0,3343,en_2649_34379_1897983_1_1_1_1,00.html), or may be directly accessed at http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=39B5D34A-2F5D-4D53-B000-E497B3A3EE89. For the ease of the reader these documents are also attached to section 13.

In a developmental study, rats were exposed to 270, 1330 and 6650 mg/m3 methanol by whole-body inhalation from gestation days 7 through 17 for 23 hours/day (NEDO, 1987). In the top dose, maternal toxicity was recorded. In the progeny, there was fetal malformation, increased perinatal mortality and developmental delay. Teratogenic effects occurred only at the maternally toxic exposure concentration. Exposure levels of 1.33 mg/L or less did not induce toxic symptoms in maternal animals, structural abnormalities or delay in growth or functional development in the F1-generation. Therefore, the NOAEC for maternal and developmental toxicity is considered to be 1.33 mg/L. Since the exposure time was far above the time recommended in the guideline (i.e. 6 h/d), thsi study was not taken into consideriation for further assessment.

In a second whole-body inhalation developmental study rats were exposed in chambers from gestation days 1 through 19 at 6650 and 13300 mg/m3 and from gestation days 7 through 15 towards 26.6 mg/L for 7 hours/day (Nelson et al., 1985). In the high dose group, significantly reduced food consumption without adverse effect on body weight gain was noted in maternal animals. No signs of maternal toxicity were observed in the lower dose groups. No influence on the number of corpera lutea and of implantations was reported. No effects on fetal lethality and resorption were found. There was no evidence of embryotoxic/teratogenic activity of methanol at 6.65 mg/L. At the highest concentration, an increased number of litters with skeletal and visceral malformations was noted. These included in particular rudimentary and extra cervical ribs and exencephaly and encephalocele, and, to minor extent, cardiovascular and urinary-tract defects. In this study a NOAEC for maternal and developmental toxicity of 6.65 mg/L was obtained.

In a further developmental whole-body inhalation study, mice were exposed to methanol (1330, 2660, 6650, 9970, 13300, 19940 mg/m3) on gestation days 6 to 15 for 7 hours/day. Additionally, an orally exposed group was included for comparison (Rogers et al., 1991, 1993). There were no signs of maternal toxicity. Developmental effects occurred after inhalation of 2.66 mg/L (Rogers et al., 1991, 1993). The dose related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2.66 mg/L. Significant increases in the incidence of exencephaly and cleft palate were observed at 6.65 mg/L At the highest dose, almost complete resorption of embryos in most litters occurred. Reduced fetal weight was noted at 13.3 mg/L and above. In this study, NOAECs for maternal toxicity was 19.9 mg/L and for developmental toxicity 1.3 mg/L, respectively.

 

Oral studies in mice resulted in various malformations at 4000 mg/(kg bw*d) (the LOAEL) and higher; no NOAELs could be established from these studies.

The NOAEC was 6.5 mg/L in the rat (preferred species) under exposure conditions that were comparable to those required for developmental toxicity studies according to OECD No. 414.

Obviously, the inhalation NOAEC for methanol is much lower than the oral formate NOAEL and should be used for further considerations. A conservative NOAEC for methylformate can be estimated to be 12.2 mg/L if one assumes that all the methyl formate is hydrolysed (one mole of methyl formate gives one mole of formate and one mole of methanol), and that the toxicity of methyl formate is dominated by methanol.

All these rodent studies on the endpoint developemental toxicity, though of scientific interest, are of limited relevance for a classification to humans (see also attachment) since methanol follows a different kinetic pattern in humans (see also chapter 7.1) and causes severe acute toxicity at rather low doses. In contrast, rodents do not respond to methanol in the same sense. Rodents tolerate high methanol doses without signs of toxicity and high doses are also required in order to achieve developmental effects. Humans are more prone to acute poisoning and show lethality (and blindness) at lower doses that do not induce any harm in rodents. Thus, the RAC concludes that there is robust evidence of developmental toxicity of methanol in rodents, but very limited indications of developmental toxicity from non-rodent species which have metabolic pathways more similar to humans. In addition, it is noted that the findings of developmental toxicity in rodents only occur at high exposure levels (with lowest LOAELs/LOAECs of 1000 mg/kg (Youssef, 1997) and 2000 ppm (Rogers, 1993), via the oral and inhalation route, respectively). It appears that in humans, blood concentrations similar to those seen in mice at inhalation concentrations leading to developmental toxicity findings which clearly meet the classification criteria (cleft palates were observed at 5000 ppm/6.65 mg/L and a blood concentration of 1650 mg methanol/L), would be lethal. Blood concentrations similar to those in the mouse at the LOAEC (increased incidence of cervical rib anomalies; 2.66 mg/L) would, in humans, be accompanied by signs of acute methanol intoxication (caused by formate). These signs could be nasal irritation, nausea, blurred vision, and mild CNS depression 6-30 hours later (NAS/COT Subcommittee for AEGLs (2005)) in severe cases, followed by acidosis and impaired vision (blindness). At an exposure level equivalent to the mouse NOAEC (1000 ppm), only slight effects may arise in humans. If this comparison was conducted using the rat LOAEC for developmental toxicity, such methanol concentrations may be acutely lethal to humans.

Based on the differences in kinetic between rodents and humans and due to the fact that only very high concentrations (that would be lethal in humans) induced developmental effects in rodents, the RAC concluded that methanol does not warrant classification for developmental toxicity (RAC opinion, CLH-O-0000004421-84-03/F, September 2014).

Justification for classification or non-classification

The developmental effects induced by methanol seen at high doses in rodents are not relevant for humans due to massive difference in metabolism. The RAC therefore concluded that methanol does not warrant classification for developmental toxicity. Furthermore, sodium formate, the neutralized salt of the second metabolic product of methyl formate that forms following ester cleavage, did also not induce reproduction toxicity. Thus, methyl formate does also not warrant classification for reproduction/developmental toxicity according to Directive 67/548/EEC (DSD) and Regulation EC1272/2008 (CLP).