Di(µ-2,2´,2´´-nitrilotris(ethanol)-diperchlorato)dinatrium

Endpoint summary

Description of key information

NOAEL (oral) = 1.0 mg/kg bw/day (perchlorate, rat)

NOAEL (dermal, systemic effects) = 250 mg/kg bw/day (triethanolamine, rat)

NOAEL (dermal, local effects) = 125 mg/kg bw/day (triethanolamine, rat)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

endocrine system

Organ:

thyroid gland

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

urinary

Organ:

kidney

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.7 mg/cm²

Study duration:

subchronic

Species:

rat

Mode of Action Analysis / Human Relevance Framework

Thyroid function and regulation are qualitatively similar in rats and humans, but important differences in serum thyroid hormone binding and clearance rates lead to important quantitative differences between the two species: rats have more than 100 times lower serum thyroid hormone binding affinity contributing to higher thyroid hormone clearance rates and the need for a higher rate of thyroid hormone production per unit of body weight. Therefore the potency of perchlorate is lower in humans than in animals, because of the substantial differences in the dynamics of the two systems.

Additional information

No data are available for the assessment of the toxicity potential of the substance after repeated exposure. Available data from literature for the dissociation substances are used for the assessement of the toxicity of the substance. Justification for Read Across is given in Section 13 of IUCLID.

Repeated dose toxicity: oral

The potential effects of perchlorate when administered to rats in their drinking water over the course of 14 or 90 days were investigated in agreement with EPA test guideline OPPTS 870.3100 . A nontreatment recovery period of 30 days was also included to assess the reversibility of substance-induced effects. No toxicologically meaningful differences were observed between the control and treated groups with respect to survival, clinical observations, body weights, food consumpton, opthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters or bone marrow micronucleus formation. Administration of the substance for 90 days did not induce any test article- related gross or microscopic changes in tissues and organs besides the thyroid. Increased absolute and relative thyroid weight was observed at the 10 mg/kg/day group, while decreased T3 and T4 levels, increased TSH levels and thyroid histopathological changes were also noted in the higher dose group. Despite the fact that changes in the hormone levels were also noted in levels below 10 mg/kg/day, there were no indications of a thyroid growth response at dose levels ≤ 1.0 mg/kg/day. Based on these findings, 1.0 mg/kg bw/day (nominal) is regarded as the NOAEL (males/female rats). LOAEL is therefore considered to be 10 mg/kg bw/day.

An available study on triethanolamine, even if not a lot of details are provided, can also be used. The substance was administered via the feed for 28 days to male albino rats in concentrations of 498, 1076, 2251 mg/kg/day. Body weights were measured; organ weights and macroscopical observations were noted at autopsy. No mortality was observed in any of the treated groups or control. At autopsy, a moderate incidence of mottled, congested liver was noted at the 2251 mg/kg/day and a lesser extent at the 1076 mg/kg/day levels, but not at the 498 mg/kg/day or control levels. Liver, kidney and tests weights to body weight ratios at the 2251 mg/kg/day group were significantly higher from control (p=0.05). Also, the kidney/body weight ratio at the 498 mg/kg/day level was significantly higher from control. No LOAEL was specified/determined in the current study, but based on the available data a LOAEL of 498 mg/kg/day could be established. As per a secondary source (NTP 1999), in a 90-day study in Carworth-Wistar rats administered triethanolamine in feed at daily doses of 5 to 2610 mg/kg, the NOEL was 80 mg/kg. Decreased body weight gains were observed in rats administered 1270 mg/kg or above. Microscopic lesions of the kidney, liver, lung, or small intestine and a low incidence of mortality occurred at a concentration of 730 mg/kg or above. Liver and kidney weight effects occurred at concentrations as low as 170 mg/kg (Smyth et al., 1951).

Repeated dose toxicity: dermal

Two studies are available for the assessment of the cummulative effects of triethanolamine to rats and mice after a repeated exposure for 13 weeks. Groups of 10 rats and mice were topically administered with 125 - 1000 and 250 - 4000 mg/kg bw respectively. Clinical observations, body weight, hematology, urinanalysis, clinical chemistry, organ weights and histopathology were examined in both animal groups. Sperm morphology and vaginal cytology evaluation were also examined.

All rats survived to the end of the study. Final mean body weights and weight gains of males and females administered 2000 mg/kg and the mean body weight gain of females administered 1000 mg/kg were significantly less than those of the vehicle controls. Clinical observations included irritation, scaliness, and crustiness of the skin at the site of application for males and females. Males also had discoloration, and two males administered 2000 mg/kg had ulceration at the site of application. Changes in clinical pathology parameters were minor and consistent with inflammation at the site of application. Kidney weights were generally greater in males and females administered 500, 1000, or 2000 mg/kg than in the vehicle controls. Microscopic lesions attributed to the substance administration included acanthosis and inflammation at the site of application nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in males and females. These lesions generally occurred with dose-related increases in incidence and severity in males and females. No NOAEL was determined in the current study. However, the NOAEL (systemic effects) of 250 mg/kg bw/day is adopted based on evidence of effects on the kidneys in males (increased organ weights and nephropathy) and a NOAEL (local effects) of 125 mg/kg bw/day based on skin lessions in males. This is in accordance with eMSCA conclusion for repeated dose toxicity of triethanolamine by using the same data, as stated in the Substance Evaluation Report- CoRAP (version 1.1, dated August 2015).

All mice also survived to the end of the study.  The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls.  Clinical findings were observed only in mice in the 4000 mg/kg groups and included scaliness, irritation, and discoloration at the site of test material application for males and females and skin erosion at this site in one male. The absolute kidney and liver weights of males and females administered 4000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 4000 mg/kg groups and in one female in the 2000 mg/kg group. No NOAEL was determined/specified in the current study. However, the LOAEL (systemic effects) of 2000 mg/kg bw/day is adopted based on the magnitude of the kidney weight changes at the top dose, noting the absence of any histopathological findings associated with these changes at any dose level. A LOAEL (local effects) of 250 mg/kg bw/day is established based on skin lessions. These values are in accordance with eMSCA conclusion for repeated dose toxicity of triethanolamine by using the same data, as stated in the Substance Evaluation Report- CoRAP (version 1.1, dated August 2015).

The NOAEL from the rat study will be used to establish the DNEL long-term dermal local. This dose will be adjusted to mg/cm²/d to enable comparison with human exposure. The modification from NOAEL_test in mg/kg of body weight to NOAEL_modified in mg/cm²/day takes in consideration the below (ECHA guidance on information requirements, Chapter R.8, Appendix R.8.9, 2012):

- Average weight of rats = 250 g

- Dose is applied over approximately 10 % of the total body surface.  

- The total body surface area of rats is on average 44.5 cm².

The modification from NOAEL_testin mg/kg of body weight to NOAEL_modifiedin mg/cm²/day is therefore:  125 mg/kg x (0.25cm²/44.5cm²) = 0.7 mg/cm²

National Toxicology Program (1999). NTP Technical report on the toxicology and carcinogenesis studies of Triethanolamine (CAS no. 102-71-6) in F344/N rats and B6C3F1 mice (dermal studies). NTP TR 449, NIH Publication No. 00-3365 

Smyth, H.F., Jr., Carpenter, C.P., and Weil, C.S. (1951). Range-finding toxicity data: List IV. AMA Arch. Ind. Hyg. Occup. Med. 4, 119-122

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008 substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed:

Category 1: substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of: reliable and good quality evidence from human cases or epidemiological studies; or observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided in 3.9.2.9, to be used as part of a weight-of- evidence evaluation.

Category 2: substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations.

To evaluate whether the substance should be classified or not for specific target organ toxicity-repeated exposure, the available data from sub-chronic studies on perchlorate and triethanolamine are used. However, for the assessment of the classification of the substance after repeated exposure via the oral route, perchlorate data are predominantly used; data on triethanolamine are obtained from a study that no sufficient details are provided nor a guideline is followed. Furthermore, besides following a standard guideline and GLP Requirements the duration of the study on perchlorate is higher, also including a recovery period. Based on the results of the study, a NOAEL of 1.0 mg/kg bw/day and a LOAEL of 10 mg/kg bw day are established. This NOAEL is determined based on thyroid organ weight increases and corresponding histopathological changes in the thyroid after 14 and 90 days at a dosage level of 10 mg/kg/day. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at dosage levels as low as 0.01 mg/kg/day, however no thyroid organ weight or histopathological effects were observed at dosage levels of ≤ 1.0 mg/kg/day. Since significant toxic effects observed in the 90-day repeated-dose study occur at the guidance values (C ≤10 mg/kg bw/day) the substance should be classified in Category 1, as per the CLP Regulation. However, taking in consideration the relevance of these results to humans and the position of eMSCA as stated in the Substance Evaluation Conclusion Document of sodium perchlorate (dated 10/08/2016) the substance should be classified as STOT RE2, H373, with the thyroid as the target organ. According to the Guidance on the Application of the CLP Criteria, chapter 3.9.2.3.2 “Any information pertaining to the relevance of findings in animals to humans must be taken into account and may be used to modify the classification from how it would be if based on the available animal data (CLP Guidance 2015). Humans are expected to be less susceptible to disruption of thyroid function and antithyroid effects, leading to a decrease in the classification assigned, if taken into account.

In order to evaluate whether or not to classify the substance after the repeated exposure by the dermal route, the subchronic study on triethanolamine is used (no data on perchlorate are available). A LOAEL (systemic effect) of 500 mg/kg bw/day and a LOAEL (local effect) of 250 mg/kg bw/day were determined. These values allow the non-classification of triethanolamine since significant toxic effects observed in the 90-day repeated-dose study occurs above the guidance value ranges. Consequently the substance is not classified as a STOT-RE based on data retrieved from a subchronic dermal study on the dissociation substance, triethanolamine. However, the substance is classified as STOT-RE 2, H373, based on available data on perchlorate from a 90 -day repeated dose study via the oral route.