Glycine, N,N'-1,2-ethanediylbis-, reaction products with formaldehyde, iron chloride (FeCl3) and phenol, potassium salts

Endpoint summary

Description of key information

An extended OECD 422 study with Fe-HBED was started in November 2021 and finished in May 2022; this study includes a duration of at least 90 days and all current 90-day study parameters were included so that it fulfills all requirements of an OECD 408 study. In this study no adverse effects were noted on parental, fertility, and developmental parameters at a level up to and including 1000 mg/kg bw/day.

Three repeated oral toxicity studies are available on the structurally related substance Fe-EDDHMA: one 90-day study and two 28-day studies. Additional information on oral toxicity is available for Fe-EDDHA. In contrast to Fe-HBED, in which no adverse findings were noted, the kidney was considered to be the target organ for Fe-EDDHA and Fe-EDDHMA, and some findings were noted in haematology parameters. Recently, an extended OECD 422 study with Fe-EDDHA was finished (including a high dose Fe-EDDHMA group) - for bridging purpose between Fe-EDDHA and Fe-EDDHMA. Although a significant difference in parental toxicity was noted between Fe-HBED on the one hand and Fe-EDDHA/Fe-EDDHMA on the other hand, all three compounds did not induce reproductive and developmental toxicity and could be used for read across purposes for these endpoints. 

In a key subacute 28-day dermal toxicity study with the structurally related substance Fe-EDDHA (CIBA-GEIGY Limited, 1996b), the NOEL was established at 100 mg/kg bw/day based on slight effects on the liver and skin and due to increased adrenal weight noted at the high dose level of 1000 mg/kg bw/day.

No data on repeated inhalation exposure are required. Exposure by the inhalation route is considered to be negligible.      

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The parental NOAEL in the extended OECD 422 study with Fe-HBED (with 90-day duration and 90-day parameters) was at least 1000 mg/kg bw/day.
The NOEL for the structurally related substance Fe-EDDHMA-Fe was 20 mg/kg bw/day in males and 100 mg/kg bw/day in females. In view of the absence of histopathological kidney effects in males treated with 100 mg/kg bw, and in view of the slight haematological changes, the NOAEL in male rats was considered to be close to 100 mg/kg bw and was conservatively set at 50 mg/kg bw. The results of this study with Fe-EDDHMA are supported by two oral 28-day studies and the results of a one-generation test and with studies performed with Fe-EDDHA, all showing a substantially lower NOAEL than for Fe-HBED.

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:

no study available

Additional information

Oral route (see also read across document in section 13).

An extended OECD 422 study with Fe-HBED (including a duration of at least 90 days and all current 90-day study parameters) was performed fulfilling  all requirements of an OECD 408 study. In this study no adverse effects were noted on parental, fertility, and developmental parameters at a level up to and including 1000 mg/kg bw/day.

In a 90-day oral (gavage) repeated dose toxicity study with the structurally related source compound Fe-EDDHMA-Fe in rats (Schoenmakers, 1996), the NOEL was established at 20 mg/kg bw/day in male rats and at 100 mg/kg bw/day in female rats. In this study, treatment with the test item resulted in slight haematological changes and a slightly increased relative kidney weight in male rats treated at 100 mg/kg bw/day. The slight increase in relative kidney weight was, however, not corroborated by histopathological renal effects, and was not seen in female rats at this level. Histopathological kidney effects were observed in both male and female rats at the next higher level of 500 mg/kg bw. In addition, two oral 28-day studies were available. The NOAEL in one of these oral 4 -week studies (Banks, 1988) was 200 mg/kg bw; in the second oral 4 -week study (Korn, 1990) 200 mg/kg bw was a LOAEL, however, the only change observed at that level consisted of slight fatty degenerations of renal tubular epithelial cells; no increase in relative kidney weight was observed at that level. Two other studies were available for the second source compound Fe-EDDHA. In the 90-day study the LOAEL was 50 mg/kg bw.

Dermal route

No study with Fe-HBED. In a repeated dose dermal toxicity study (CIBA-GEIGY Limited, 1996b), the structurally related substance Fe-EDDHA was administered to the skin of 5 Sprague-Dawley derived rats/sex/dose level at 10, 100 or 1000 mg/kg bw/day for 28 days (5 days/week). A concurrent control group was treated with the vehicle only. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. Based on the slight effects on the liver and skin and due to the increased adrenal weight noted at 1000 mg/kg bw/day, the NOEL was established at 100 mg/kg bw/day.

Inhalation route

Inhalation exposure of Fe-HBED is regarded negligible as the particle size distribution for particles below 100 µm was found to be 9.2% and only 0.7% of the particles was found less than 10 µm. In addition, the source substances showed only very low toxicity after acute inhalation exposure with a 4-h LC50 value in excess of 1.24 mg/L for Fe-EDDHMA (technically maximally attainable concentration), and a 4-h LC50 value in excess of 4.2 mg/L for Fe-EDDHA (also technically maximally attainable concentration) in the rat.

 

Justification for classification or non-classification

Based on the results of the repeated dose toxicity study resulting in a parental 90-day NOAEL of at least 1000 mg/kg bw/day, Fe-HBED is not subject to classification and labelling according to Regulation No 1272/2008 (CLP).