reaction mass of sodium acetate, monoethylene glycol and diethylene glycol

Endpoint summary

Description of key information

ORAL VALUES
MEG rat: 33 day gavage NOAEL ~220mg/kg bw, 16 week dietary NOAEL (males only) 150mg/kg. Mouse oral 13 week feed 12500ppm (~3300mg/kgbw)
DEG: rat dietary study, week: NOAEL=936mg/kg bw.  rat oral feed study (225 day), NOAEL=100mg/kg bw
NaAc: drinking water study: NOAEL >500ppm in drinking water.  (Assuming water consumption of 10-12ml/100g/day =>NOAEL >50-60mg/kg/day
DERMAL
MEG: Dog 4 week studies, NOAEL=2220mg/kg (study 1), 4440mg/kg bw (study 2)
The sodium acetate data cannot be used to derive the oral NOAEL since the NOAEL is likely to be well in excess of the maximum dose tested in the only available study.  Therefore the oral NOAEL is based on the lowest value available for the other components, in this case DEG.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

2 200 mg/kg bw/day

Study duration:

subacute

Species:

dog

Additional information

There is no repeat dose data available on the multiconstituent substance, but data is available on the main components from which appropriate NOAELs can be established. Data on individual components:

 

Monoethylene glycol (ethan-1,2-diol) :

ORAL ROUTE

Schladt et al. (1998) tested ethylene glycol in an oral (gavage) study. Male and female rats were given doses of 220, 660 and 2000 mg/kg over a study period of 33 days. The daily application resulted in treatment-related effects on the kidneys. A slight derease in the urinary excretion of potassium, calcium and phosphate (males), a diminished pH value of the urine, and a slight increase in osmolality (females) were observed. In both sexes, excretion of oxalate was significantly increased and microscopic examination of urinary sediment revealed calcium oxalate crystals. Kidney weights of males and females were slightly elevated. Histopathology revealed crystals in renal tubuli, renal pelvis, and urinary bladder; tubulopathy and epithelial hyperplasia within the renal pelvis were also observed. The NOAEL could not be clearly determined, but was probably around 220 mg/kg.

Mertens (2002) reported a 16-week comparative dietary study using male rats. The animals were given doses of 50, 150, 500 and 1000 mg/kg. No direct test-article related effects on alpha 2u-globulin levels in immunohistochemically stained sections of the kidney were seen. The NOEL was found to be 150 mg/kg ,which is not significantly lower than that from the 28 day study.

NTP (1993) reported an oral feeding study with mice. Animals were given concentrations of 3200, 6300, 12500, 25000 and 50000 ppm for 13 weeks. All animals survived to the end of the study and final mean body weight of exposed mice did not differ significantly from those of the controls. Only male mice in the 25000 and 50000 ppm groups exhibited histopathologic lesions (nephropathy and hepatocellular hyaline degeneration). The NOAEL was found to be 12500 ppm.

DERMAL ROUTE

BASF (1991) reported a 4-week dermal application study according to OECD guideline 410. Male dogs were given the unchanged test substance (> 92.5% ethylene glycol and < 1.42% na-p-tert-butyl-benzoat; PTBBA) daily to the clipped skin in concentrations of 0.5, 2 and 8 ml/kg. Further studies followed to establish whether the severe testicular damage that was found in all dogs at 8 ml/kg and in one dog at 2 ml/kg was caused by na-p-tert-butyl-benzoic acid or whether it must be regarded as a direct or indirect consequence of ethylene glycol administration. Some urinary oxalate crystals were found at 2 ml/kg but due to the absence of histological findings, considered as not adverse. The NOEL was 2 ml/kg b.w . (2220 mg/kg b.w.). At this level, some urinary oxalate crystals were observed but considered as not adverse due to the absence of histological findings.

BASF (1991) reported an additional 4-week dermal application study according to OECD guideline 410. In this study, male dogs received the unchanged test substance (> 93.4% ethylene glycol and < 1.3% p-tert.butylbenzoic acid) daily to the clipped skin in amounts of 2 and 4 ml/kg. No testicular damage that was definitely induced by the test substance was detected in any of the dogs investigated. The NOEL was found to be 4 ml/kg b.w. (4440 mg/kg b.w.). At this level, urinary oxalate crystals were observed but considered as not adverse due to the absence of histological findings.

Diethylene glycol (2,2’-oxydiethanol)

ORAL ROUTE

BASF (1988) reported a 4-week study according to OECD guideline 407. DEG was administered in the diet to two groups of five males and five females rats per dose. Dose groups were 500, 2500, 10000 or 40000 mg/kg diet. One group was killed just after 28 days administration, the other group was killed after a 30-day observation period. At a dose of 40000 mg/kg diet, a significant concentration and amount of oxalic acid was found in the urea of both sexes, and oxalic acid stones in males after 28 days. However, these effects were not observed after the 30-day observation period. The NOAEL was 10000 mg/kg diet corresponding to 936 mg/kg body weight/day.

Gaunt et al. (1975) reported a 225-day oral feeding study. Male and female rats were given concentrations of 0.85, 0.17, 0.4 and 2.0% (= 64, 128, 300, 1500 mg/kg bw). The elevated levels of oxalic acid in urine in this study were considered to be a biomarker from metabolism and do not indicate toxicity. Mild defects of renal function at 0.4% DEG were therefore considered to define the NOAEL as 100 mg/kg/day.

Triethylene glycol (2,2’-(ethylenedioxy)diethanol):.

 

ORAL ROUTE

Bushy(1990) reported an OECD guideline study 408. Male and female rats were given orally (feed) doses ranging from 0 - 3849 mg/kg over a study period of 13 weeks. Small increases in kidney weight (high dose group females) and kidney weight relative to body weight (all groups of males and mid and high dose group females) were considered to be probably treatment related. Hematology measurements were altered at the 13-week measurement period. These changes were considered to be of questionable biological significance based on a lack of similar effect in the females, the small magnitude of the changes, and the lack of corresponding effects in other cell indexes. Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volulme in males from the high dose group were considered to be related to TEG treatment. Based on the lack of any other significant toxic effects, particularly the lack of histologic evidence of renal injury, hyperplasia, or hypertrophy, the altered urine measurements were considered to be most likely related to excretion of the large amounts of test material (or metabolites) during the course of this study. NOAELs were found to be 1522 mg/kg for male animals and 1699 mg/kg for female animals

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

EU-classification according to the criteria of directive 67/548 for repeated oral toxicity is not warranted as no effects are seen at dose of 50mg/kg bw or below. However, the evidence for oxalate nephrosis suggests that classification according to GHS for STOT-RE (repeated dose specific target organ toxicity) should be considered. The NOAEC in animals is outside the range for classification, but since humans are known to be more sensitive to the effects of MEG and TEG, it would seem appropriate to classify for repeat dose toxicity specific target organ toxicity (kidneys, oral route) based on human data according to regulation 1272/2008.