Reaction mass of ethane-1,2-diol and 2-hydroxyethyl formate and ethylene diformate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the absence of studies on reproduction and developmental toxicity/teratogenicity with the reaction mass, this endpoint is evaluated on the basis of data for the hydrolysis products formic acid and ethane-1,2 -diol. Ethane-1,2 -diol did not induce reproductive toxicity in a three-generation reproduction toxicity study. There was no signs indicative of an adverse effect on fertility in a repeated dose toxicity study with formic acid where organ weights, histopathology, and reproductive organ function, i.e. sperm parameters and estrous cycle length, were not affected at the end of the 13 -week exposure period. As neither ethane-1,2 -diol nor formic acid cause adverse effects regarding reproduction it can be concluded that the reaction mass is not a reproductive toxicant.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Quality of whole database:

Similar to Guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

122 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP and guideline compliant

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the absence of experimental data on the reproduction toxicity of the reaction mass, this endpoint is evaluated on the basis of the data available on the hydrolysis products formic acid and ethane-1,2-diol.

 

Ethane-1,2-diol

In a three-generation reproduction study in which F344 rats (both sexes) received 40, 200, or 1000 mg ethylene-1,2-diol/kg bw/d in the diet, there were no treatment-related parental effects (based on survival, body weight, food consumption, appearance, behaviour, and histopathology in major organs) or effects on fertility index, gestation index, gestation survival index, pup weight, appearance, behaviour, or histopathology in major organs (DePass et al., 1986).

 

Formic acid

In an OECD guideline No. 413 test conducted under GLP conditions (Thompson, 1992a, see also section on repeated dose toxicity), 10 rats per sex and dose were exposed to formic acid vapor at 0, 0.015, 0.030, 0.062, 0.122, or 0.244 mg/L (0, 8, 16, 32, 64, or 128 ppm; dose selection based on results of a range finding study) via whole-body inhalation 6 hours/day, 5 days/week for 13 weeks.

In addition to the parameters required for the subchronic studies, sperm motility and morphology was examined in both species at termination in all males and the estrous cycle of all females was examined during the last two weeks of exposure. Male and female reproductive organs were weighed and subjected to histopathology. Organ weights, histopathology, and reproductive organ function, i.e. sperm parameters and estrous cycle length, were not affected at the end of the 13 -week exposure period.

Thus there were no findings that point towards adverse effects of formic acid on male and female reproductive organs at any dose including the highest test dose (NOAEC = 128 ppm or 0.244 mg/L) in the rat 13-week inhalation study.

 

Conclusion on the reproduction toxicity of the reaction mass

Due to the rapid hydrolysis of the reaction mass, its reproduction toxicity can be assessed on the basis of data on the hydrolysis products formic acid and ethane-1,2-diol. The available data for both substances do not indicate an adverse effect on reproduction. This is further supported by the fact that both substances are not classified for effects on reproduction in Annex VI of Regulation (EC) No 1272/2008. Thus, it can be concluded that - based on read-across - the reaction mass is not a reproductive toxicant.

Effects on developmental toxicity

Description of key information

In the absence of studies on developmental toxicity/teratogenicity with the reaction mass, this endpoint is evaluated on the basis of developmental toxicity data for the hydrolysis products formic acid and ethane-1,2 -diol.

Formic acid did not cause developmental toxicity or teratogenic effects in mice, when administered on day 8 of gestation, the sensitive phase of methanol-induced exencephaly. Ethane-1,2-diol was tested in numerous developmental toxicity studies. It caused teratogenic effects in rats and mice, but not in rabbits. A thorough evaluation of the mechanism leading to the teratogenic effects revealed that the rabbit is the most relevant for humans. Thus, the effects seen in rats and mice have been considered as non- relevant for humans and no classification regarding developmental toxicity has been proposed.

It can be concluded that the reaction mass is not a developmental toxicant.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Non-guideline compliant

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

150 mg/m³

Study duration:

subacute

Species:

mouse

Quality of whole database:

Non-guideline compliant

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Ethane-1,2 -diol

Rabbit

Rabbits were administered doses with 0, 100, 500, 1000 and 2000 mg/kg bw/d by gavage during gestation days 6 -19 (Tyl RW et al., 1993).

At 2000 mg/kg bw/d, severe maternal toxicity (mortality and degenerative changes in the kidney were observed but no developmental or reproductive effects (pre-or post-implantation loss, number of fetuses, fetal body weight, sex ratio per litter, external, visceral or skeletal malformations and variations) in fetuses.

No developmental effects were observed at 2000 mg/kg bw/day, the highest dose tested.

 

Mouse

Mice were dosed at 0, 50, 150, 500 or 1500 mg/kg bw/day by gavage during gestation days 6 -15 (Neeper-Bradley TL et al, 1995).

There was no apparent treatment related maternal toxicity. Developmental effects observed at 1500 mg/kg bw/d included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra 14th rib. At 500 mg/kg/d, slight reductions in fetal body weight and increased incidences of extra ribs were observed.

Under the conditions of this study, the NOAEL for developmental toxicity in mice is at 150 mg/kg bw/d and the LOAEL is 500 mg/kg bw/d.

Mice were exposed to an aerosol (whole-body) at 0, 150, 1000 or 2500 mg/m³ on gestational days 6 -15 for 6 hours per day (Tyl RW et al, 1995). In maternal animals, absolute and relative liver weights were significantly increased at 2500 mg/m³. At 1000 mg/m³ and above, skeletal variations, malformations of the head, face and skeleton were observed. However, it is assumed that considerable intake occurred due to ingestion after grooming and/or percutaneous absorption. The NOAEL for developmental toxicity was determined to be 150 mg/m³.

 

Rat

Rats were exposed to 0, 50, 150, 500, 1000, or 2500 mg/kg bw/day during gestation days 6 -15 (Neeper-Bradley TL et al., 1995).

There was no apparent treatment related clinical maternal observations. In the 2500 mg/kg bw/day group, dams had significantly decreased body weight, increased water consumption, decreased uterine weight, increased kidney weight, and increased relative liver weight. Developmental effects observed at 500 mg/kg bw/day included reduced body weights, extra or missing ribs, missing arches, and poor ossification in thoracic and lumbar centra. At 2500 mg/kg bw/day, in addition to skeletal malformations, there was gastroschisis, hydrocephaly, lateral ventricle dilated (tissue depressed), umbilical hernia, and atelectasis. Maternal toxicity was observed at 2500 mg/kg bw/day and fetotoxicity and teratogenicity at 1000 and 2500 mg/kg bw/day.

For maternal toxicity, the NOAEL was determined as 1000 mg/kg bw/day and for developmental toxicity as 500 mg/kg bw/day.

Rats were exposed to an aerosol (whole-body) at 0, 150, 1000 or 2500 mg/m³ on gestational days 6 -15 for 6 hours per day (Tyl RW et al., 1995). Exposure of rats during organogenesis resulted in minimal maternal toxicity at 2500 mg/m³ and minimal fetotoxicity at 1000 and 2500 mg/m³. There was no maternal or embryofetal toxicity at 150 mg/m³ (the no observable effect level) and no teratogenicity at any aerosol concentration employed.

Relevance for human health

As explained in detail in the REACH dossier (CSR and IUCLID) of ethane-1,2-diol (CAS 107-21-1) its developmental toxicity can be attributed to the formation of glycolic acid. In the same dossier it has been demonstrated that the rabbit should be considered as the species which is the most relevant for humans, based on the fact that the disposition of glycolic acid between the maternal blood and the embryo is driven by the polarity of the proton-linked monocarboxylate transporters MCT1 and MCT4 in the placenta, that glycolic acid is sequestered in the rat but not the rabbit and that the rabbit and human placenta show similar polarity to each other and opposite to that of the rodent. Consequently, no proposal for the classification of ethane-1,2 -diol as developmental toxicant has been made.

Formic acid

Formic acid is not classified as a developmental toxicant in Annex VI of Regulation 1272/2008. There is no evidence that formic acid causes developmental toxicity.

Single gavage doses of sodium formate of 750 mg/kg body weight were administered to CD-1 mice on day 8 of gestation (sensitive phase of methanol-induced exencephaly). After administration, the formate concentrations determined in plasma were 1.05 mmol/l and in the decidua 2 mmol/l. The foetuses were examined on days 10 and 18 of gestation.

No effects were found on the neural tube, head or body lengths, or weight of the foetuses (Dorman et al., 1995 as summarised by MAK (2002)). Formic acid. Published Online: 31 JAN 2012 DOI: 10.1002/3527600418.mb6418e0019.

Conclusion on the developmental toxicity of the reaction mass

Due to the rapid hydrolysis of the reaction mass its developmental toxicity can be assessed on the basis of data on the hydrolysis products formic acid and ethane-1,2 -diol.

There is no experimental evidence that formic acid causes developmental toxicity. Ethane-1,2 -diol induced teratogenic effects in the mouse and rat, but not in the rabbit. As it has been demonstrated that the rabbit is the species with the highest relevance for human health (see above), it is concluded that ethane-1,2 -diol does not need to be classified for developmental toxicity.

Justification for classification or non-classification

The available experimental test data on ethane-1,2 -diol and formic acid are reliable and suitable for read-across and classification purposes of the reaction mass under Regulation (EU) 1272/2008. Since neither formic acid nor ethane-1,2 -diol are reproductive or developmental toxicants (for ethane-1,2 -diol the rabbit is the most appropriate species regarding human relevance ), the reaction mass is not classified for reproductive or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/918.