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Administrative data

Description of key information

Oral: Three acute oral toxicity studies according or similar to OECD 401 were conducted in Sprague-Dawley rats (5/sex/dose). BASF (1985) reported LD50 values of 1470 mg/kg in females and 2220 mg/kg in males, applying an aqueous solution of 92 % Na3NTA. Monsanto (1986, BD-85-255) reported LD50 values of 3800 mg/kg in females and 5300 mg/kg in males, applying 40 % aqueous solution of Na3NTA. In a second study Monsanto (1986, BD-85-230) reported LD50 values of 1300 mg/kg in females and 1600 mg/kg in males dosing NTA as 99 % Na3NTA monohydrate
As part of a mutagenicity study a LD50 of 1250 mg/kg bw was estimated in male NMRI mice (RCC2000) using a small group size of 2 mice/dose. Several other less reliable studies conducted in rats report oral LD50 values between 1000 mg/kg and 2000 mg/kg (Dow, 1970, 1968, 1967) or at 3715 mg/kg (Monsanto 1968). Nixon (1971) reported acute oral toxicity in different species. A LD50 of 1100 mg/kg were found when applying 20 % NA3NTA to 5 SD rats/sex/dose (998, 1400, 2060, and 1730 mg/kg). In rhesus monkeys a LD 50 of 750 mg/kg was estimated based on deaths at 1000 mg/kg and 2000 mg/kg. Na3NTA was applied as 50 % aqueous solution. In mongrel dogs (4/per dose, 80 % aqueous solution) no death occurred within the observation period of one week after application of 5000 mg/kg Na3NTA (80 % solution), but dogs vomited immediately after application. In addition Nixon (1971) assessed intraperitoneal toxicity in SD rats that is not considered to be relevant for human risk assessment.
Dermal: Monsanto tested acute dermal toxicity in 6 New Zealand rabbits up to 10.000 mg/kg (1968) and as limit test with 2000 mg/kg (1966). Both did not cause mortality.
Inhalation: A comprehensive study on inhalation toxicity is available from P&G (1971). In addition a sensory irritation assay was conducted by TNO (2007) applying Na3NTA close to the technically highest attainable concentration.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
Value:
1 300 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion
Dose descriptor:
LD50
Value:
10 000 mg/kg bw

Additional information

Oral

LD50 values were found in a range of 750 to above 5000 mg/kg. The data available demonstrate considerable species differences: An approximate LD50 value of 750 mg/kg is reported in rhesus monkeys after application of 50 % aqueous solution of Na3NTA (Nixon 1971). One monkey received the lowest dose of 500 mg/kg. This animal was sacrificed after 11 days. No unusual lesions were noted. Two monkeys received 1000 mg/kg. One animal vomited within 1 min after dosing. The second animal died after 70 minutes. This dose level produced a slight decrease in motor activity within 50 minutes after dosing, followed by paralysis and by death. Both animals treated with 2000 mg/kg each died approximately 30 minutes after dosing. A decrease in motor activity was noted 15 minutes after dosing, followed in 5 minutes by paralysis and death. The only unusual lesions noted grossly at autopsy were hemorrhagic areas in the stomach.

In dogs an LD0 >5000 mg/kg was found after application of 80 % aqueous solution of Na3NTA (Nixon 1971). However, dogs vomited in less than 1 min after application raising concerns about the systemic availability of the substance.

Oral LD50 values in SD rats range from 1300-1470 mg/kg (females) and 1600-2220 mg/kg bw (males) (BASF 1985, Monsanto 1986). Application of 40 % aqueous solution leads to an LD50 of 3800 mg/kg in females and 5300 mg/kg in males (Monsanto 1986, BD-85-255). This suggests an almost linear dose-dependency. Several other studies conducted in SD rats report LD50 values in the range of 1000 – 2000 mg/kg (Dow 1967, 1968, 1970).

For risk assessment the result of a reliable rodent study applying defined pure test substance is taken (1300 mg/kg; Monsanto 1986) leading to a classification as Acute Tox 4. The LD50 in monkeys is derived in a poorly reported study with a low number of animals. In addition the test substance was applied as 50 % aqueous solution and one low dose animal vomited immediately after administration. According to the dose-dependency found in rat studies, a LD50 of ~ 750 mg/kg (50 % Na3NTA) would equal 375 mg/kg (pure Na3NTA). This less reliable study would trigger the same classification. Hence, it does not raise higher concern. 

Dermal

The minimum lethal dose by skin absorption was evaluated in 6 New Zealand rabbits (Monsanto 1968). No deaths occurred at 10.000 mg/kg NA3NTA monohydrate (25 %) within 3 days. No nervous or muscular incoordination was developed. Activity and appetite were reduced for 2-3 days at the highest level. No local symptoms were reported. The main weakness of this study is the poor level of documentation, especially information on observation time was insufficient. However, the lack of deaths at such a high dose seems to be sufficient to assess a possible hazard. The result was confirmed by a limit test (Monsanto, 1966). Application of 2000 mg/kg as 10% aqueous solution to 6 New Zealand rabbits for 24 h did not cause any deaths.

Inhalation

A comprehensive study on inhalation toxicity is available (P&G, 1971). A pulmonary screening was performed with mice, which were exposed to NTA aerosols at a maximum concentration of 7.6 mg/l for 5 minutes. No death occurred. In an acute inhalation toxicity study, 10 male albino rats were exposed for 4 hours to either micronized or non-micronised NTA at levels up to 5.0 mg/l (5.0 mg/l were reported to be the highest attainable concentration for non-micronized NTA, using a cyclone dust generator). Animals were observed for 14 days. No mortalities occurred. After termination of exposure, all animals recovered and appeared healthy throughout the remaining observation period. Weight gain of exposed animals was normal and there were no pathological findings.

In a 4-day repeated exposure study, 10 male rats were exposed to a maximum of 2 mg/l of micronized NTA for 6 hours/day on 4 consecutive days. Animals were necropsied after a 14-day observation period. No deaths occurred.

In a 4-week repeated exposure study, monkeys, rats and guinea pigs were exposed to measured concentrations of up to 0.342 mg/L non-micronised NTA for 6 hours/day, 5 days/week for 4 weeks followed by a 2 week observation period. At the highest concentration 2/12 rats and 4/12 guinea pigs showed dyspnea during the first 2 weeks of exposure; the monkeys exhibited diarrhea but no respiratory irritation or general discomfort. No deaths occurred in any of these treatment groups.

An Alarie test was conducted by TNO (1997) exposing 4 rats/dose to Na3NTA for 30 min [IUCLID 7.9.3]. Overall, the results of this study show sensory irritation to be present in rats at levels of 2.86 and 4.25 mg/L Na3NTA. The RD50 value was estimated to be close to the technically highest attainable concentration. Due to the short exposure period this result cannot be used to determine a LC0.

Intraperitoneal

The i.p. LD 50 values in rats were found to be 254 mg/kg (50 % Na3NTA) and 446 mg/kg (20 % Na3NTA). No unusual symptoms were observed in any of the animals following injection.All surviving animals appeared normal 24 h after dosing.

Justification for classification or non-classification

Based on the available data on oral toxicity the substance is classified Acute Tox 4 according to regulation (EC)1272/2008. Acute dermal toxicity seems to be low as inferred from a study on New Zealand rabbits treated with 25 % aqueous solution. The dermal LD0 is above 10.000 mg/kg exceeding the limit dose of 2000 mg/kg. Acute inhalation toxicity seems to be low as exposure close to the maximum technically attainable concentration (5 mg/m3) did not cause any deaths.