2-ethylhexanoic acid, iron salt

Endpoint summary

Description of key information

No acute toxicity studies with 2-ethylhexanoic acid, iron salt are available, thus the acute toxicity will be addressed with existing data on the individual assessment entities iron and 2-ethylhexanoic acid. No adverse effects were observed in acute oral toxicity studies with the assessment entity 2-ethylhexanoic acid. However, adverse effects were observed in acute oral toxicity studies with ferric chloride (trivalent Fe) and ferrous sulphate (divalent Fe). The reported LD50 values were 440 mg Fe/kg bw and 305 mg Fe/kg bw, respectively. Based on this, the calculated LD50 for 2-ethylhexanoic acid, iron salt is 911 mg/kg bw. No adverse effects were observed upon acute dermal exposure for both assessment entities iron and 2-ethylhexanoaic acid, thus the calculated LD50 is >2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Iron

Acute oral toxicity- Ferric

In an acute oral toxicity study (reliability score 2, not to GLP) in which a control group of mice (20 females) were given ferric chloride at doses of 186, 335, 604, 1087 mg Fe/kg bw (equivalent to 540, 974, 1,756, 3160 mg ferric chloride/kg bw) by oral gavage, and then observed for one month, the LD50 was 440 mg Fe/kg bw (equivalent to 1,300 mg ferric chloride/kg body weight). This value was based on 1/10, 2/10, 8/10 and 10/10 deaths in the 186, 335, 604, 1087 mg Fe/kg bw groups, respectively.

Acute oral toxicity- Ferrous

In a limited acute oral toxicity study (reliability score 2) conducted prior to the adoption of OECD test guidelines and GLP, mice (at least 10 males) were given a single oral gavage dose (doses not given) of ferrous sulfate solution. The mice were then observed for up to seven days and the rats for 24 hours. The acute oral LD50 for mice (males) was 1025 mg/kg salt (305 mg/kg Fe). Limited investigation of sex and strain differences in mice did not suggest any significant difference in response between the sexes or between different strains. Results obtained for the acute oral LD50 of ferrous sulphate in mice expressed as mg/kg Fe are reported as comparable to published oral LD50values.

In an additional supporting study two groups of 70 female mice received increasing doses of ferrous sulphate. The LD50 for female mice was calculated to be 680 mg ferrous sulphate/kg bw, equivalent to 250 mg Fe/kg bw. The LD50 for male mice was 670 mg ferrous sulphate/kg bw, which is equivalent to 246 mg Fe/ kg bw.

Acute dermal toxicity (ferric/ferrous)

A registration dossier shall contain information on the human health hazard assessment (regulation 1907/2006, Art.10). However, it is considered that the information requirements for iron (2+/3+) as laid down in annex VII to IX can be fulfilled by adaptation of the standard testing regime according to Annex XI, points 1.2. and 1.3. as presented in the following:

Considering the role of iron in human metabolic processes, it is highlighted that iron has several vital functions in the body. It serves as a carrier of oxygen to the tissues from the lungs by red blood cell haemoglobin, as a transport medium for electrons within cells, and as an integrated part of important enzyme systems in various tissues. It is an essential constituent of oxygen carriers, such as haemoglobin and myoglobin, and the iron contained within haem is essential for the redox reactions of numerous cytochromes. Insufficient intake results in the deficiency condition anaemia, adverse outcomes of pregnancy, impaired psychomotor development and cognitive performance and reduced immune function.

Beside of these important role in human health, acute dermal toxicity studies conducted with both iron species clearly demonstrate that iron has very low acute toxicity and is not of toxicological relevance.

According to the U.S. EPA Reregistration Eligibility Document (RED) for Iron Salts, published in 1993, an acute dermal toxicity test in rabbits with Iron (III) sulfate found an LD50 greater than 2000 mg/kg. No mortalities or other signs of toxicity were observed in male and female rats.

According to the OECD SIDS document for Iron Dichloride the dermal toxicity study performed by NIER (15) established an acute lethal dose (LD50) greater than 2,000 mg/kg body weight. Following the test guideline (TG 402), the limit test (2,000 mg/kg b.w.) was performed in 5 male and 5 female Sprague-Dawley rats. Because there was no animal death during the test period, the study was concluded. Yellowish-brown changes on the skin of applied sites were observed in all treated animals from day 2 but this was recovered during the test period, except for 3 females. 2 males and 4 females showed reddish nasal discharge on day 2. All rats gained normal body weight throughout the study. Regarding gross pathology, no abnormalities were observed in all animals.

Based on these results for both iron species no further testing is required.

 

2-ethylhexanoate

Acute oral toxicity

In an acute oral toxicity study 4 rats/sex/dose were dosed with 90, 722, 1445 or 2890 mg/kg bw. No mortality was observed in the 90, 722 and 1445 mg/kg bw dose groups. The test material caused mortality in rats administered a dose of 2890 mg/kg bw (4/4), and transitory weakness at lower doses in a dose-dependent manner. The LD50 was calculated to 2043 mg/kg bw.

 

In another acute oral toxicity study 5 rats/sex/dose have been administered 0.2, 1.6, 3.2 and 4.0 ml 2-ethylhexanoic acid/ kg bw. No substance related clinical signs nor mortality was observed at 0.2 and 1.6 ml/kg. However, 1/10 animals died. After administration of 3.2 ml/kg and 4 ml/kg apathy dyspnea abdominal position and re crusted eyes and snouts were observed. Mortality in these dose groups was 3/10, 5/10, respectively. LD 50 was estimated to be 4 mL/kg bw, being equivalent to 3640 mg/kg bw (density 0.91 g/ml). This result is supported by another study which however was poorly documented.e no signs of a toxicity response.  It is concluded that the LD50 is greater than 3640 mg/kg. This result is supported by another study which however was poorly documented.

 

Acute dermal toxicity

Dermal toxicity of 2-ethylhexanoic acid was tested in an OECD 402 guideline study. Five Wistar rats/sex/dose have been exposed dermally (semi-occlusive to a limit dose of 2000 mg/kg bw 2‑ethylhexanoic acid. No mortality and no clinical symptoms beside eschar formation have been observed.LD50 dermal therefore is > 2000 mg/kg bw.

 

2-ethylhexanoic acid, iron salt

No acute toxicity studies with 2-ethylhexanoic acid, iron salt are available, thus the acute toxicity will be addressed with existing data on the individual assessment entities iron and 2-ethylhexanoic acid. Under the assumption that the assessment entities of 2-ethylhexanoic acid, iron salt show their toxicological profile individually upon dissolution, the acute oral and dermal toxicity of 2-ethylhexanoic acid, iron salt can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1. The calculated LD50 for 2-ethylhexanoic acid, iron salt is 911 mg/kg bw. Thus, 2-ethylhexanoic acid, iron salt is classified according to regulation (EC) No. 1272/2008 for acute oral toxicity category 4 (H302: Harmful if swallowed). The calculated dermal LD50 for2-ethylhexanoic acid, iron salt is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute dermal toxicity. A study for acute toxicity via inhalation was not conducted with of 2-ethylhexanoic acid, iron salt, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

The calculated LD50 for 2-ethylhexanoic acid, iron salt is 911 mg/kg bw. No adverse effects were observed upon acute dermal exposure for both assessment entities iron and 2-ethylhexanoaic acid, thus the calculated LD50 is >2000 mg/kg bw. 2-ethylhexanoic acid, iron salt is therefore classified according to regulation (EC) No. 1272/2008 for acute oral toxicity category 4 (H302: Harmful if swallowed). No classification is required for acute dermal toxicity.