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Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Waiver
Type of information:
other: Waiver, based on expert evaluation of the datasets for physical chemistry amd toxicology
Adequacy of study:
other information
Study period:
2017-2018
Reliability:
other: Expert judgement and interpretation based on detailed examination of the current database for Aetoacetamide
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
no guideline required
Principles of method if other than guideline:
Waiver based on the expert judgement and interpretation of a detailed examination of the current database for Acetoacetamide.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable
Type:
absorption
Results:
predicted: 80%
Type:
excretion
Results:
predicted: primarily via the urine and faeces
Type:
distribution
Results:
predicted: widley distributed
Type:
metabolism
Results:
predicted: mostly in the liver and the thyroid
Type:
other: dermal absorption
Results:
predicted: low due to the physical chemical characteristics of Acetoacetamide
Conclusions:
The physical chemical characteristics of Acetoacetamide and the data from the re-peated dose toxicity study clearly suggest and demonstrate that Acetoacetamide is likely to be adequately absorbed, distributed and excreted with limited or no bioac-cumulation. The data suggest that the thyroid and liver are likely target organs and that enhanced metabolism is predicted to occur, although the toxicity of metabolites is predicted to be limited, as in the genotoxicity studies metabolic activation was without demonstrable effect.
Considering these attributes, the most likely route of excretion would be primarily via the urine and secondarily the faeces. Acetoacetamdie was not acutely toxic via the oral route, was not a skin or eye irritant or a skin sensitizer. The data from the repeat dose study demonstrated systemic exposure and that Acetoacetamide was unlikely to be toxic to reproduction, in utero development of the foetus or post-natal survival and development of neonatal rats.
Executive summary:

Opinion on TK/ADME (absorption, distribution, metabolism and excretion).

No compound specific toxicokinetic or ADME investigations, or studies on potential metabolites, were available at the time of this review. However, physical chemical data on the test substance and mammalian toxicity data were available for evaluation from which a reasoned scientific opinion on the ADME parameters of Acetoacetamide can be predicted.

The physical chemical data were generated specifically on the test substance and were generally GLP and regulatory compliant studies.

1. Key physical chemical data on Acetoacetamide

The data demonstrated (preliminary test) that the test substance is miscible with water (>1000 glL at 20 °C) and had a partition coefficient (Log Kow) of -1.4 at 23°C pointing to a relatively lipophobic substance. The vapour pressure was 0.93 Pa at 20°C, the melting point was 52.5°C. Acetoacetamide is not flammable and not surface active.

The particle size was 228.9µm (D50). These findings do not suggest that this substance would present a risk of inhalation exposure under ambient environmental conditions.

 

2. Mammalian toxicity data on Acetoacetamide 

The mammalian toxicity data evaluated were:

-      acute oral and dermal toxicity

-      in vivo skin corrosion/irritation

-      in vivo eye corrosior/irritation

-      in vivo skin sensitization

-      Ames test, in vitro chromosome aberration test and in vitro gene mutation test (HPRT)

-      OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction and Developmental Toxicity Screening Test (oral gavage study)

 

Most of the studies were GLP compliant respectively meets generally accepted scientific principles and therefore acceptable for assessment.

 

The acute oral LD50 was determined to be >15000 mg/kg bw (25% solution). The calculated value for the pure substance is LD50 = 3750 mg/kg bw. There were no abnormal findings or deaths. Thus, it may be reasonably concluded that

Acetoacetamide is not acutely toxic. Furthermore, the test item was neither a skin or eye irritant nor a skin sensitizer.

The in vitro genotoxicity studies (with and without S9 metabolic activation) demonstrated that there was no evidence for genotoxic potential.

In an OECD 422 study, combined repeat dose toxicity and reproductive/developmental screening study (oral gavage dosed), where the dosages tested were 0, 100, 300 and 1000 mg/kg bw/day (there was also a 14-day dose range finding

study at these dosages) the systemic NOAEL was 100 mg/kg bw/day. No mortality occurred in this study.

No adverse effects were found on male and female clinical observations, functional observations, body weight, food consumption, haematology and coagulation, clinical biochemistry, urinalysis and gross pathological findings at necropsy.

There were also no test item-related effects on estrous cyclicity, nipple retention, anogenital distance, precoital interval and duration of gestation, reproductive indices, pup thyroid weight and pup thyroxine hormone, pup external findings on PND 0 and at death. No test item-related effects on number of corpora lutea, implantation sites, % pre and post implantation loss, litter data, litter weights, reproductive indices and number of live pups on PND 0, 4 and 13 in HD group were observed when compared with controls.

For organ weight thyroid / parathyroid a test item-related dose dependent increase with statistical significance (absolute and relative for male and female HD group and relative for male MD group) was seen. Absolute and relative organ weight for liver was decreased in all male groups and male thyroxine hormone was statistically significant decreased in the male HD group compared to control group. Test item-related minimal to slight follicular hypertrophy for thyroid glands in male and female HD group and male MD group was found at histopathological evaluation. Additionally, test item-related hepatocellular hypertrophy in male HD group was recorded.

Adverse effects of Acetoacetmide were noted at a dose level of 100 mg/kg body weight/day for general systemic toxicity (in terms of histopathological finings in thyroid and liver in parental males and females at 300 and 1000 mg/kg). Thus, the NOAEL for general systemic toxicity could be established at 100 mg/kg body weight/day.

Nevertheless, the historical control data on histopathology for thyroid and liver have to be compared with the histopathological findings to confirm the NOAEL. 

No adverse effects of Acetoacetmide were noted at a dose level of 1000 mg/kg body weight/day for reproductive and developmental toxicity. Thus, the NOAEL for reproductive and developmental toxicity screening could be established at 1000 mg/kg body weight/day.

  

3. Opinion on TK/ADME of Acetoacetamide

Absorption and distribution 

The relative lipophobicity, and water solubility, indicates that the substance may not be rapidly absorbed across lipid bilayer cell membranes (limiting systemic availability), when compared to more lipophilic substances, after either oral or dermal exposure. Although absorption via aqueous channels and passive diffusion, and the fact that Acetoacetamide has a molecular weight of 101.1 glmol, suggest that some absorption

would be expected.

With a water solubility greater than >1000 g/L (miscible with water) and a Log Pow of -1.4, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and as such dermal uptake for this substance might be expected to be low. The data from the acute toxicity studies do not confirm nor refute evidence of acute absorption via the GI tract or skin.

The OECD 422 study demonstrated systemic toxicity in terms of histopathological finings. The findings in thyroid and liver of male and rats at 300 and 1000 mg/kg bw/day indicates that systemic exposure was evident.

The data suggest some systemic exposure and indicate that distribution, bioavailability and bioaccumulation might be limited. The physical chemistry data suggest that it is unlikely that acute inhalation exposure

(i.e. would not present an exposure risk as significant exposure would not be expected) would result in toxicity considering the very low toxicity evident in the studies presented.

 

Metabolism

It is predicted, from the physical chemistry and toxicity data, that metabolism would be via the liver and the thyroid.In the OECD 422 study at a dosage level of 300 mg/kg minimal to slight follicular hypertrophy was seen for thyroid glands in males and additionally, increased minimal hepatocellular hypertrophy was noted in males at 1000 mg/kg bw. No findings for female rats.

These findings suggests an increase in metabolic activity in relation to systemic exposure of Acetoactamide.The substance is likely to be extensively metabolised in the liver. Regarding potential metabolites, as no genotoxicity was

seen either with or without the addition of metabolic activation (+/- liver S9-mix), that data support the view that potential metabolites of Acetoacetamide may be of limited mammalian toxicity.

 

Excretion

Given the physical chemical properties of the substance, the nature of the effects seen in the repeated dose toxicity study and probable limited bioaccumulation, it is predicted that excretion would be primarily via the urine and faeces. It is likely that urinary excretion would be the primary route.

Description of key information

1. Key physical chemical data on Acetoacetamide

The data demonstrated (preliminary test) that the test substance is miscible with water (>1000 glL at 20 °C) and had a partition coefficient (Log Kow) of -1.4 at 23°C pointing to a relatively lipophobic substance. The vapour pressure was 0.93 Pa at 20°C, themelting point was 52.5°C. Acetoacetamide is not flammable and not surface active.

The particle size was 228.9µm (D50). These findings do not suggest that thissubstance would present a risk of inhalation exposure under ambient environmental conditions.

 

2. Mammalian toxicity data on Acetoacetamide 

The mammalian toxicity data evaluated were:

-      acute oral and dermal toxicity

-      in vivo skin corrosion/irritation

-      in vivo eye corrosior/irritation

-      in vivo skin sensitization

-      Ames test, in vitro chromosome aberration test and in vitro gene mutation test (HPRT)

-      OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction and Developmental Toxicity Screening Test (oral gavage study)

 

Most of the studies were GLP compliant respectively meets generally accepted scientific principles and therefore acceptable for assessment.

 

The acute oral LD50 was determined to be >15000 mg/kg bw (25% solution). The calculated value for the pure substance is LD50 = 3750 mg/kg bw. There were no abnormal findings or deaths. Thus, it may be reasonably concluded that

Acetoacetamide is not acutely toxic. Furthermore, the test item was neither a skin or eye irritant nor a skin sensitizer.

Thein vitrogenotoxicity studies (with and without S9 metabolic activation) demonstrated that there was no evidence for genotoxic potential.

In an OECD 422 study, combined repeat dose toxicity and reproductive/developmental screening study (oral gavage dosed), where the dosages tested were 0, 100, 300 and1000 mg/kg bw/day (there was also a 14-day dose range finding

study at these dosages) the systemic NOAEL was 100 mg/kg bw/day. No mortality occurred in this study.

No adverse effects were found on male and female clinical observations, functional observations, body weight, food consumption, haematology and coagulation, clinical biochemistry, urinalysis and gross pathological findings at necropsy.

There were also no test item-related effects on estrous cyclicity, nipple retention, anogenital distance, precoital interval and duration of gestation, reproductive indices, pup thyroid weight and pup thyroxine hormone, pup external findings on PND 0 and at death. No test item-related effects on number of corpora lutea, implantation sites, % pre and post implantation loss, litter data, litter weights, reproductive indices and number of live pups on PND 0, 4 and 13 in HD group were observed when compared with controls.

For organ weight thyroid / parathyroid a test item-related dose dependent increase with statistical significance (absolute and relative for male and female HD group and relative for male MD group) was seen. Absolute and relative organ weight for liver was decreased in all male groups and male thyroxine hormone was statistically significant decreased in the male HD group compared to control group. Test item-related minimal to slight follicular hypertrophy for thyroid glands in male and female HD group and male MD group was found at histopathological evaluation. Additionally, test item-related hepatocellular hypertrophy in male HD group was recorded.

Adverse effects of Acetoacetmide were noted at a dose level of 100 mg/kg body weight/day for general systemic toxicity (in terms of histopathological finings in thyroid and liver in parental males and females at 300 and 1000 mg/kg). Thus, the NOAEL for general systemic toxicity could be established at 100 mg/kg body weight/day.

Nevertheless, the historical control data on histopathology for thyroid and liver have to be compared with the histopathological findings to confirm the NOAEL. 

No adverse effects of Acetoacetmide were noted at a dose level of 1000 mg/kg body weight/day for reproductive and developmental toxicity. Thus, the NOAEL for reproductive and developmental toxicity screening could be established at 1000 mg/kg body weight/day.

  

3. Opinion on TK/ADME of Acetoacetamide

Absorption and distribution 

The relative lipophobicity, and water solubility, indicates that the substance may not be rapidly absorbed across lipid bilayer cell membranes (limiting systemic availability), when compared to more lipophilic substances, after either oral or dermal exposure. Although absorption via aqueous channels and passive diffusion, and the fact that Acetoacetamide has a molecular weight of 101.1 glmol, suggest that some absorption

would be expected.

With a water solubility greater than >1000 g/L (miscible with water) and a Log Pow of -1.4, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and as such dermal uptake for this substance might be expected to be low. The data from the acute toxicity studies do not confirm nor refute evidenceof acute absorption via the GI tract or skin.

The OECD 422 study demonstrated systemic toxicity in terms of histopathological finings. The findings in thyroid and liver of male and rats at 300 and 1000 mg/kg bw/day indicates that systemic exposure was evident.

The data suggest some systemic exposure and indicate that distribution, bioavailability and bioaccumulation might be limited.The physical chemistry data suggest that it is unlikely that acute inhalation exposure

(i.e. would not present an exposure risk as significant exposure would not beexpected) would result in toxicity considering the very low toxicity evident in the studies presented.

 

Metabolism

It is predicted, from the physical chemistry and toxicity data, that metabolism would be via the liver and the thyroid.In the OECD 422 study at a dosage level of 300 mg/kg minimal to slight follicular hypertrophy was seen for thyroid glands in males and additionally, increased minimal hepatocellular hypertrophy was noted in males at 1000 mg/kg bw. No findings for female rats.

These findings suggests an increase in metabolic activity in relation to systemic exposure of Acetoactamide.The substance is likely to be extensively metabolised in the liver.Regarding potential metabolites, as no genotoxicity was

seen either with orwithout the addition of metabolic activation (+/- liver S9-mix), that data support the view that potential metabolites of Acetoacetamide may be of limited mammalian toxicity.

 

Excretion

Given the physical chemical properties of the substance, the nature of the effects seen in the repeated dose toxicity study and probable limited bioaccumulation, it is predicted that excretion would be primarily via the urine and faeces. It is likely that urinary excretion would be the primary route.

4. Conclusions

The physical chemical characteristics of Acetoacetamide and the data from the re-peated dose toxicity study clearly suggest and demonstrate that Acetoacetamide is likely to be adequately absorbed, distributed and excreted with limited or no bioac-cumulation. The data suggest that the thyroid and liver are likely target organs and that enhanced metabolism is predicted to occur, although the toxicity of metabolites is predicted to be limited, as in the genotoxicity studies metabolic activation was without demonstrable effect.

Considering these attributes, the most likely route of excretion would be primarily via the urine and secondarily the faeces. Acetoacetamdie was not acutely toxic via the oral route, was not a skin or eye irritant or a skin sensitizer. The data from the

repeat dose study demonstrated systemic exposure and that Acetoacetamide was unlikely to be toxic to reproduction, in utero development of the foetus or post-natal survival and development of neonatal rats.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
80
Absorption rate - dermal (%):
50

Additional information

Oral absorption

The physical chemistry and mammalian toxicity data suggest that oral absorption occurs but that it may be limited. Applying expert judgement to the evaluation of these data a conservative estimate of 80% for oral absorption is suggested.

Dermal absorption

Dermal absorption is likely to be very low but in the absence of experimental data a default value of 50% is suggested based on EFSA guidance - EFSA Journal 2017;15(6):4873).

 

Inhalation

The physical chemistry data clearly suggest that Acetoacetamide is unlikely to present an inhalation hazard and therefore absorption via this route may be considered negligible. 

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