Propanoic acid, 2-hydroxy-, ammonium salt (1:1), (2S)-

Endpoint summary

Description of key information

No data is available for ammonium-S-lactate itself. Therefore, available data from repeated dose toxicity studies conducted with suitable read-across partners were used in a weight-of-evidence approach to assess the specific target organ toxicity of the target substance. Based on the results, no classification for specific target organ toxicity is warranted for ammonium-S-lactate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

Regarding general conditions, no obvious findings were observed in any group.

Mortality:

no mortality observed

Description (incidence):

No mortality was found in any groups throughout the treatment period.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test-substance related change in the body weights was found.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test-substance related change in food intake was found, except for a tendency for increase of food intake in the male 3.0% group. The actual daily intakes of the test substance showed a good correlation with the expected dose.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No significant variation was found in erythrocytic parameters and Plt among the groups- Some slight changes were found in WBC parameters but therre was no dose-relation and these were therefore considered to be incidental.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No dose-related alteration was found in any of the serum biochemical parameters.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Absolute and relative kidney weights were increased or showed a tendency for increase at 3.0% in both sexes. Absolute spleen weights were decreased and relative liver weights were increased in the 3.0% male dose group. No dose-related changes were found in the other organs.

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no obvious macroscopic finding in any dose group.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Histopathologically, several non-neoplastic lesions, such as bile duct proliferation in the liver and focal myocarditis in the heart were noted in the control and 3.0% group.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

As neoplastic lesions, malignant pheochromocytoma of the adrenal in the male 3.0% group, two adenomas in the anterior pituitary in females of the 3.0% group and uterine endometorial stromal polyp in a female control was noted.

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

0.6 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects in the mid-dose

Dose descriptor:

LOAEL

Effect level:

3 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

3 other: %

System:

other: organ weight

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Conclusions:

In conclusion, based on the results obtained from a 52-week chronic feeding study in male and female Fisher rats with ammonium sulphate at dietary concentrations of 0, 0.1, 0.6 and 3.0%, the oral NOAEL is considered to be 0.6%, which is equivalent to 256 and 284 mg/kg bw/day in male and female rats.

Executive summary:

In a 52-week chronic feeding study in male and female Fisher 344/DuCrj rats (10/sex/dose group), ammonium sulphate was applied at concentrations of 0, 0.1, 0.6 and 3.0 % via the diet. Absolute and relative kidney weights were increased or showed a tendency for increase at 3.0 % in both sexes. Absolute spleen weights were decreased and relative liver weights were increased in the 3.0 % male dose group. No dose-related changes were found in other organs investigated. Moreover, no effects were found on mortality, body weight, hematological and serum biochemical parameters. Effects were neither seen in gross and histopathological examinations. Based on the results of this study, the oral NOAEL is considered to be 0.6 %, which is equivalent to 256 and 284 mg/kg bw/day in male and female rats.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

415 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Comparable to guideline study

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

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Remarks on result:

other: no adverse systemic effects observed

Critical effects observed:

no

Three control, one low-dose, and two high-dose animals, which died on study due to acute pneumonia and/or mucoid enteritis, were replaced. Feed consumption, body weights, hematology, clinical chemistry, and urinalysis were normal for all test groups. Absolute kidney weights of the low-dose group were significantly increased compared to controls, while the relative kidney weights were comparable. Both dose groups had mild irritation, described as a minimal to slight acanthosis, inflammatory cellular infiltration, and hyperkeratosis. Three of the high-dose animals developed minimal focal ulceration of the application areas.

Conclusions:

In a 90-day dermal study, 1 mL/kg bw/d of a 12 % ammonium lactate lotion, pH 5.0–5.5, was applied to the backs of six rabbits, three per sex, and 4 mL/kg bw/d were applied to the backs of eight rabbits, four per sex. Saline was applied to the backs of a control group of 10 rabbits, five per sex. Use of restraints was not specified. The backs of half of the animals were abraded.
Three control, one low-dose, and two high-dose animals, which died on study due to acute pneumonia and/or mucoid enteritis, were replaced. Feed consumption, body weights, haematology, clinical chemistry, and urinalysis were normal for all test groups. Absolute kidney weights of the low-dose group were significantly increased compared to controls, while the relative kidney weights were comparable. Both dose groups had mild irritation, described as a minimal to slight acanthosis, inflammatory cellular infiltration, and hyperkeratosis. Three of the high-dose animals developed minimal focal ulceration of the application areas.

Executive summary:

In a 90-day dermal study, 1 mL/kg bw/d of a 12 % ammonium lactate lotion, pH 5.0–5.5, was applied to the backs of six rabbits, three per sex, and 4 mL/kg bw/d were applied to the backs of eight rabbits, four per sex. Saline was applied to the backs of a control group of 10 rabbits, five per sex. Use of restraints was not specified. The backs of half of the animals were abraded.

Three control, one low-dose, and two high-dose animals, which died on study due to acute pneumonia and/or mucoid enteritis, were replaced. Feed consumption, body weights, haematology, clinical chemistry, and urinalysis were normal for all test groups. Absolute kidney weights of the low-dose group were significantly increased compared to controls, while the relative kidney weights were comparable. Both dose groups had mild irritation, described as a minimal to slight acanthosis, inflammatory cellular infiltration, and hyperkeratosis. Three of the high-dose animals developed minimal focal ulceration of the application areas.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data is available for ammonium-S-lactate itself. Therefore, available data from repeated dose toxicity studies conducted with suitable read-across partners (ammonium sulphate, ammonium chloride and calcium lactate) were used in a weight-of-evidence approach to assess the specific target organ toxicity of the target substance. As the target substance dissociates into ammonium and lactate ions in aqueous media, the assessment of the repeated dose toxicity potential can be based on available data of dissociable ammonium compounds and lactic acid. Lactic acid is a ubiquitous and integral element of mammalian metabolism and therefore of minor toxicological relevance in comparison to ammonium which is considered to be toxicologically more relevant than lactic acid. Further details on the read-across rationale are provided in IUCLID section 13.

In a 13-week subchronic oral toxicity study conducted similar to OECD 408, calcium lactate in drinking water was administered to Fischer 344/DuCrj rats. In this study, 5% calcium lactate in drinking water or diet does not result in adverse effects.

The repeated dose toxicity of ammonium chloride was examined in 28- and 90-day oral feeding studies. In the 28-day repeated dose toxicity the NOAEL was determined to be 2214.5 mg/kg bw/day for both sexes (corresponding to 4434 mg/kg bw/day ammonium-S-lactate). In the higher dose an effect on body weight and body weight gain was noted. In a 90-day repeated dose toxicity study the NOAEL was determined to be 1695.7 mg/kg bw/day for both sexes (corresponding to 3395 mg/kg bw/day ammonium-S-lactate). Further results were derived from a repeated dose toxicity study, in which ammonium chloride was administered to 10 male Sprague-Dawley rats/dose via the diet at a dose level of 12300 ppm for 70 days. Based on the results, the NOAEL was determined to be 12300 ppm (equivalent to 684 mg/kg bw/day; recalculated to 1369 mg/kg bw/day ammonium-S-lactate)

The repeated dose toxicity of ammonium sulphate was examined in a 52-week oral feeding study. In this chronic study, the NOAEL was determined to be 256 mg/kg bw/day for male rats and 284 mg/kg bw/day for female rats (corresponding to 415 and 461 mg/kg bw/day ammonium-S-lactate). In the high dose group, absolute and relative kidney weights were increased or showed a tendency for increase in both sexes. Absolute spleen weights were decreased, and relative liver weights were increased in male dose group. Moreover, supporting data is available from the review article by Anderson (1998). In this peer-reviewed publication, lactic acid and ammonium-DL-lactate were applied to the skin of rats or rabbits. No major systemic effects were noted. As the information provided was very limited, the data are not considered for assessing the repeated dose toxicity study of the target substance. Based on the results, no classification for specific target organ toxicity is warranted for the target substance ammonium-S-lactate.

Justification for classification or non-classification

Based on the available data from the read-across partners, the target substance ammonium-S-lactate does not warrant classification for specific target organ toxicity in accordance with CLP Regulation 1272/2008.