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

Endpoint summary

Description of key information

In the absence of repeated dose toxicity data following administration of the reaction mass, this endpoint is evaluated on the basis of repeated dose toxicity data for the hydrolysis products formic acid and ethane-1,2-diol and considering the corrosive properties of the reaction mass.

For ethane-1,2-diol, the oral NOAEL in rats is 150 mg/kg bw/d after chronic administration with the kidney as the target organ. The NOAEC for inhalation toxicity for formic acid is 32 ppm (0.06 mg/L) based on histopathological changes in the nasal cavity due the corrosivity of formic acid. Due to the corrosive properties of the reaction mass, it is considered that local effects prevail over systemic effects on all exposure routes, indicating that the data on formic acid are more relevant than the data on ethane-1,2 -diol.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Database is reliable, justifying the assessment factor of 1 for quality of data base.

System:

urinary

Organ:

kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

244 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Database is relialbe, justifying the assessment factor of 1 for quality of data base.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

61 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Database is relialbe, justifying the assessment factor of 1 for quality of data base.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

Due to the corrosive properties of the reaction mass, local effects are considered to be most relevant - as it is the case for the hydrolysis product formic acid.

Additional information

In the absence of repeated dose toxicity data following administration of the reaction mass, this endpoint is evaluated on the basis of repeated dose toxicity data for the hydrolysis products formic acid and ethane-1,2-diol and considering the corrosive properties of the reaction mass.

Ethane-1,2 -diol

A chronic toxicity study in male Wistar rats, which is the most sensitive strain and sex for ethane-1,2-diol toxicity, was conducted administering ethylene-1,2-diol via the diet at 0, 50, 150, 300, or 400 mg/kg bw/day for up to twelve months. Subgroups of animals were included for metabolite analysis and renal clearance. Mortality occurred in 5 of 20 rats at 300 mg/kg bw/day (days 111-221) and 4 of 20 rats at 400 mg/kg bw/day (days 43-193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg bw/day presumably due to osmotic diuresis. Calculi (calcium Oxalate crystals) occurred in the bladder or renal pelvis at >300 mg/kg bw/day. Rats dying early at >300 mg/kg bw/day had transitional cell hyperplasia with inflammation and hemorrhage of the bladder wall. Crystal nephropathy affected most rats at 300 mg/kg bw/day, all at 400 mg/kg bw/day, but none at <= 150 mg/kg bw/day. No significant differences in kidney oxalate levels, the metabolite responsible for renal toxicity, were observed among control, 50 and 150 mg/kg bw/day groups. At 300 and 400 mg/kg bw/day, oxalate levels increased proportionally with the nephrotoxicity score supporting the oxalate crystal-induced nephrotoxicity mode of action. The NOAEL of 150 mg/kg bw/day is the same as that reported after 16-week exposure (Cruzan et al., 2004) and appears to be a threshold dose below which no renal toxicity occurs, regardless of exposure duration. (Corley et al., 2008).

Formic acid

In an OECD guideline No. 413 test conducted under GLP conditions, 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.

There were no mortalities nor clinical signs or systemic toxicity in male and female rats exposed to 8, 16, 32, 64, or 128 ppm for 13 weeks (5 days/week, 6 h/day). There were no unusual gross lesions noted during necropsy, organ weights were not affected by treatment. Male and female reproductive parameters (sperm motility, density, testicular or epididymal weight, length of the estrous cycle) were not affected. Histopathology revealed increased incidences of squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium in the high-dose male and female rat groups where most of the animals were affected. The severity was generally minimal to mild.

Adverse systemic effects were not observed. Thus, the NOAEC for systemic effects was 128 ppm (244 mg/m³), the highest concentration tested.

Based on the local histopathological changes in the respiratory tract the NOAEC in this study was determined to be 64 ppm (122 mg/m³). (Thompson, 1992).

In the two-week repeated dose inhalation toxicity study where rats were exposed to formic acid concentrations of 0, 31, 62.5, 125, 250, or 500 ppm (5 days/week, 6h/day)

the results were comparable to the 13 -week study. Toxicity was due to local effects in the upper respiratory tract and no adverse systemic toxicity was seen at non-lethal concentrations. A NOAEC of 31 ppm (60 mg/m³) was derived. (Thompson, 1992).

Considering both repeated dose inhalation toxicity studies an overall NOAEC for the local effects in the upper respiratory tract of 32 ppm (61 mg/m³) and an NOAEC of 128 ppm (244 mg/m³) for systemic toxicity can be derived.

Conclusion on the repeated dose toxicity of the reaction mass

Due to the corrosive properties of the reaction mass, it can be assumed that local effects at the port of entry dominate its toxicity. Local effects can be caused by the reaction mass and its hydrolysis product formic acid. The formic acid NOAEC in the rat is 61 mg/m³ for local effects in the upper respiratory tract after repeated inhalation exposure. The NOAEC was not influenced by exposure duration. The second hydrolysis product of the reaction mass, ethane-1,2 -diol, does not possess relevant local toxicity. Thus, the NOAEC of 61 mg/m³ is considered to be applicable for the reaction mass and to represent a conservative value as the molecular weight of formic acid is lower than that of the major components of the reaction mass.

Due to the rapid hydrolysis of the reaction mass, the relevance of systemic toxicity can be assessed on the basis of data on the hydrolysis products formic acid and ethane-1,2-diol. Formic acid did not show relevant systemic toxicity in the inhalation toxicity studies. The repeated dose toxicity of ethane-1,2 -diol is characterised by renal toxicity (oxalate crystal nephropathy) with a chronic NOAEL of 150 mg/kg bw/day. This oral NOAEL corresponds to an inhalation concentration of 724 mg/m³ when rats would be exposed 6 hours/day (respiration volume of 0.29 m³/kg bw) and 5 days/week (150 mg/kg bw/d / 0.29 m³/kg bw x 7d/5d = 724 mg/m³). Since this value is much higher than the NOAEC of 61 mg/m³ for local effects, it can be concluded for the reaction mass that local toxicity prevails over systemic toxicity.

Justification for classification or non-classification

The repeated dose toxicity of the reaction mass is characterised by local toxicity caused by its corrosive properties. Its classification for skin corrosion Cat. 1 is considered as sufficiently protective for local effects after repeated exposure and an additional classification for repeated dose toxicity is not required under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/918.