Carbamic acid, (2-hydroxypropyl)-, compd. with 1-amino-2-propanol (1:1)

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: peer reviewed toxicological assessment of category 'C1-C13 primary amines'

Data source

Reference

Reference Type:

publication

Title:

2-Propanol, 1-amino-, CAS-No. 78-96-6; SIDS Initial Assessment Profile for SIAM 32, 2011-04-19; Investigated in a Category C1-13 Primary Amines

Author:

OECD SIDS

Year:

2011

Bibliographic source:

OECD SIDS documents (Chemicals Screening Information Dataset for High Volume Chemicals); Conclusions agreed; available via web-page

Materials and methods

Type of study / information:

peer reviewed toxicological assessment of category 'C1-C13 primary amines' (summary)

Test material

Test material information

Constituent 1

Reference substance name:

1-amino-2-propanol

IUPAC Name:

1-amino-2-propanol

Constituent 2

Reference substance name:

1-aminopropan-2-ol

EC Number:

201-162-7

EC Name:

1-aminopropan-2-ol

Cas Number:

78-96-6

IUPAC Name:

1-aminopropan-2-ol

Details on test material:

The C1-C13 primary amines category is limited to the eleven sponsored substances as mentioned above. It excludes C12-C16 primary fat amines.
(74-89-5) Methylamine; (75-04-7) Ethylamine; (75-31-0) Isopropylamine; (109-73-9) Butylamine; (13952-84-6) sec-Butylamine; (75-64-9) tert-Butylamine; (111-86-4) Octylamine; (104-75-6) Hexylamine, 2-ethyl; (5332-73-0) Propylamine, 3-methoxy-; (1761-71-3) Cyclohexylamine, 4,4’-methylenebis; (78-96-6) 2-Propanol, 1-amino-

The C1-C13 Primary Amines category is represented by the structure with a single and primary amino-group R-NH2, where R is an alkyl group that may be linear, branched or alicyclic; the alkyl group may include an atom or group that will not react with or substantially affect the properties of the amine function. The tendency to share the nonbonded electron pair on the nitrogen underlies the chemical behavior of amines as a group.
The C1-C13 Primary Amines category members are structurally similar showing trend in physical-chemical properties and ecotoxicity and similar toxicological properties. This category is defined as below:
• A structure that contains only aliphatic organic substituents that are linear, branched or cyclic;
• Molecular weights from approxiamtely 30 to 250 Dalton, classifying these primary amines as low molecular weight aliphatic amines.
• Incremental structural change across the group consisting of an increasing number of atoms in the molecular backbone; moderate branching is acceptable. The change is restricted to adding elements that do not greatly change the physicochemical properties of the amino moiety, as evidenced by the consistency of pKa values within the narrow range of 9.86 to 10.87.
Observed corrosive properties overwhelm the systemic toxicity of the primary amines in most cases, including acute toxicity; the known acute oral and dermal effects are generally related to the alkaline properties and are expected to be a general feature of the category. Structure-activity similarities for mammalian toxicity and structure-activity relationships (SAR) shown for aquatic toxicity endpoints lend support to the category.
In general, members of the C1-C13 primary amines can be considered to be comparable in metabolism. However, there are known outliers for which own data are available to cover the endpoints (due to structural differences, methylamine, tert-butlylamine may be metabolized by different pathways than the rest of the category). Read-across approach has been used for addressing the mammalian toxicity endpoints where no data were available on individual substances.

Applicant's summary and conclusion

Executive summary:

Category rationale

The C1-C13 primary amines category is limited to the eleven sponsored substances as mentioned above. It excludes C12-C16 primary fat amines.

(74-89-5) Methylamine; (75-04-7) Ethylamine; (75-31-0) Isopropylamine; (109-73-9) Butylamine; (13952-84-6) sec-Butylamine; (75-64-9) tert-Butylamine; (111-86-4) Octylamine; (104-75-6) Hexylamine, 2-ethyl; (5332-73-0) Propylamine, 3-methoxy-; (1761-71-3) Cyclohexylamine, 4,4’-methylenebis; (78-96-6) 2-Propanol, 1-amino-

 

The C1-C13 Primary Amines category is represented by the structure with a single and primary amino-group R-NH2, where R is an alkyl group that may be linear, branched or alicyclic; the alkyl group may include an atom or group that will not react with or substantially affect the properties of the amine function. The tendency to share the nonbonded electron pair on the nitrogen underlies the chemical behavior of amines as a group.

The C1-C13 Primary Amines category members are structurally similar showing trend in physical-chemical properties and ecotoxicity and similar toxicological properties. This category is defined as below:

• A structure that contains only aliphatic organic substituents that are linear, branched or cyclic;

• Molecular weights from approxiamtely 30 to 250 Dalton, classifying these primary amines as low molecular weight aliphatic amines.

• Incremental structural change across the group consisting of an increasing number of atoms in the molecular backbone; moderate branching is acceptable. The change is restricted to adding elements that do not greatly change the physicochemical properties of the amino moiety, as evidenced by the consistency of pKa values within the narrow range of 9.86 to 10.87.

Observed corrosive properties overwhelm the systemic toxicity of the primary amines in most cases, including acute toxicity; the known acute oral and dermal effects are generally related to the alkaline properties and are expected to be a general feature of the category. Structure-activity similarities for mammalian toxicity and structure-activity relationships (SAR) shown for aquatic toxicity endpoints lend support to the category.

In general, members of the C1-C13 primary amines can be considered to be comparable in metabolism. However, there are known outliers for which own data are available to cover the endpoints (due to structural differences, methylamine, tert-butlylamine may be metabolized by different pathways than the rest of the category). Read-across approach has been used for addressing the mammalian toxicity endpoints where no data were available on individual substances (as indicated in the table below).

 

 

 

Toxicokinetics

The C1-C13 primary amines may be absorbed through the skin up to chain length of about six carbon atoms. The charged form will hinder absorption across biological membranes, and the corrosive properties of the substances may also affect absorption. Dermal exposures to dilute solutions, aerosols and vapors might not have sufficient base capacity to overwhelm the skin's natural acidity and only a few of these molecules exist as the uncharged free base. In situations where the majority of the molecules would exist as the free base on the skin, the individual would experience a chemical burn. At the pH of the GI tract, only limited, non-ionized compound would be absorbed. Following inhalation, the C1-C13 primary amines will be removed by dissolution in the upper respiratory tract and swallowed. Vapors or particulates that get to the deep lungs will be primarily in the charged form which is expected to slow absorption somewhat and contribute to the local metabolism of these C1-C13 primary amines by alveolar and bronchiolar tissues. The major routes of metabolism of C1-C13 primary amines involve various processes including oxidation, conjugation, and other enzyme-catalyzed reactions leading to detoxification and excretion. Additionally, N-acetylation may occur, but represents only a very minor pathway in the metabolism of aliphatic amines. Methylamine, which has the amino group is attached to a methyl group rather than a methylene group, is not a substrate for monoamine oxidase. Pharmacokinetic studies have indicated that a substantial amount of methylamine is oxidized to carbon dioxide, even though some is excreted unchanged in expired air and urine. Although metabolic pathways have not been identified for tert-butylamine, it is expected, based on its structure, to have a different metabolic pathway than the other members of the category.

In some cases (repeated dose and reproductive toxicity), the tested substance was the salt of amines to avoid damage to the gastrointestinal tract following gavage administration due to the caustic mode of action. Testing the salt also provides the ability to distinguish between symptoms caused by local effects such as irritation or corrosion and symptoms that are due to systemic toxicity.

 

Irritation

Reliable skin irritation studies are available for all category memebrs except cyclohexylamine, 4,4’-methylenebis. All tested category members were corrosive to skin. Based on the available acute dermal toxicity study with cyclohexylamine, 4,4’-methylenebis and data from other category memebers, this substance is also considered to be corrosive to the skin. Based on the available data and known eye irritation potential of alkyl amines in general, it is expected that all the amines in the category are corrosive to the eye. The C1-C13 primary amines are known irritants of the human respiratory tract; supporting animal data confirm this finding.

 

Sensitization

There was no evidence of positive sensitization results at the concentrations tested in animal studies for isopropylamine, butylamine, octylamine, propylamine, 3-methoxy-, or 2-propanol, 1-amino-. There were no data located for methylamine, ethylamine, sec-butylamine, tert-butylamine, hexylamine, 2-ethyl, cyclohexylamine, 4,4’-methylenebis; a similar lack of skin sensitization potential is expected for these substances.

 

Repeated dose toxicity

Local effects (irritation of the respiratory tract and mucous membranes) are the major effects following repeated inhalation exposure (methylamine, ethylamine, isopropylamine and tert-butylamine). This occurred in rats exposed to 96 mg/m3 of methylamine for 10 days, or to 200 mg/m3 of tert-butylamine for 13 weeks, and at higher concentrations of ethylamine and isopropylamine. Systemic effects (changes in clinical chemistry parameters) were also noted following repeated dose inhalation of tert-butylamine at 200 mg/m3. The oral NOAELs in rats were 15 mg/kg bw/d for cyclohexylamine, 4,4’-methylenebis-, 500 mg/kg bw/day as methylamine hydrochloride; CAS No. 593-51-1; 100 mg/kg bw for octylamine (as the hydrochloride, CAS No 142-95-0), 300 mg/kg bw/ d for 2-propanol, 1-amino (as the hydrochloride; CAS No. 7780-04-3) and 1000 mg/kg bw/day (females) for propylamine, 3-methoxy- (as the hydrochloride; CAS No. 18600-41-4). The effects observed in these studies included reductions in body weight, body weight gain, and food consumption; and/or changes in blood, urine and clinical chemistry parameters, as well as histopathological findings in various organs with cyclohexylamine, 4,4’-methylenebis- . Similar effects following repeated exposure are expected for the remaining members (sec-butylamine, butylamine and hexylamine, 2-ethyl) are expected. For those category members for which read-across is applied, the lowest NOAEC/NOAEL level is used.

 

Genetic toxicity

All of the members of the category have been tested in the Ames test and no evidence of mutagenic potential was detected with the exception of 2-propanol, 1-amino-, which was positive in one bacterial mutagenicity assay withSalmonellaTA1535 with activation; the second bacterial mutagenicity assay was negative. Of the five compounds evaluated in a mouse lymphoma assay, all but methylamine gave negative results. Four of these five, including methylamine, have been examined in micronucleus tests in rodents and none showed any evidence of clastogenic activity. 2-Propanol, 1-amino- was negative in a mammalian gene mutation assay and an in vitro chromosomal aberration assay. Cyclohexylamine, 4,4’-methylenebis- was negative in twoin vivomicronucleus assays. A third micronucleus assay (with methodological limitations) was positive; data for clastogenicity are equivocal for this substance. The weight-of-evidence suggests the category members are not mutagenic.

 

Carcinogenicity

No data are available for the carcinogenicity of the C1-C13 Primary Amines.

 

Reproductive toxicity

Effects on fertility

Reproductive toxicity has been directly investigated following inhalation or oral (gavage) exposure on eight members of the category. Following oral (gavage) exposure, no reproductive toxicological potential was detected for octylamine, propylamine, 3-methoxy or 2-propanol, 1-amino- (each tested as the hydrochloride). Cyclohexylamine, 4,4’-methylenebis- reduced the number of implantation sites in an OECD 422 study in rats at an oral dose of 50 mg/kg bw/day that also produced other indications of parental systemic toxicity. No reproductive or systemic toxicity occurred at 15 mg/kg bw/day. Methylamine (as the hydrochloride), in an oral (gavage) OECD 422 study did produce adverse reproductive effects at 1000 mg/kg bw/day, a dose that also produced overt indications of parental toxicity. The NOAEL for systemic and reproductive toxicity was considered to be 500 mg/kg bw/day. Following inhalation exposure, no reproductive toxicological potential was detected for isopropylamine in a one generation study with rats. Reproductive toxicity has also been investigated as part of repeated dose inhalation studies. In a 24-week repeated dose inhalation toxicity study, ethylamine did not adversely effect male and female gonads up to 922 mg/m3. In a 13-week repeated dose inhalation toxicity test, tert-butylamine produced no adverse effects on the testes up to 2000 mg/m3. Substances that have not been tested for reproductive toxicity (butylamine, sec-butylamine, and hexylamine, 2-ethylhexyl) are not expected to be reproductive toxicants based on read across to other category members.

 

Developmental toxicity

Developmental toxicity has been investigated following inhalation and oral (gavage) exposures in rats. An inhalation study found isopropylamine not to be fetotoxic in rats at test concentrations that also produced maternal toxicity; administration of butylamine by the inhalation route was associated with significant respiratory tract (portal of entry) irritation of the dams at even the lowest tested concentration of 50 mg/m3, while fetal effects were not observed at the highest test concentration of 450 mg/m3. Rat studies involving repeated oral exposures to methylamine, octylamine, propylamine, 3-methoxy and 2-propanol, 1-amino- (each tested as the hydrochloride) or cyclohexylamine, 4,4’-methylenebis during pregnancy identified no evidence of developmental toxicity potential. Butylamine (tested as the hydrochloride, CAS 3858-78-4) produced fetal malformations in rats at an oral gavage dose of 400 mg/kg bw/day that was not overtly toxic to the dams. Rat studies involving repeated inhalation exposures to isopropylamine, or butylamine during pregnancy identified no evidence of developmental toxic potential. The reported developmental effects of butylamine (as the hydrochloride salt) are therefore expected to be route specific occurring only after oral exposure. For those substances where data exist for developmental toxicity, the results indicate a lack of effect with the exception of butylamine, which was negative by inhalation but positive when administered as the hydrolchoride salt by oral (gavage). Taking a precautionary approach, ethylamine, sec-butylamine, tert-butylamine and hexylamine, 2-ethyl, are regarded as potential developmental toxicants when administered by the oral (gavage) route.

 

The C1-C13 Primary Amines possess properties indicating a hazard for human health (acute toxicity, irritating/corrosive properties). Cyclohexylamine, 4,4’-methylenebis (oral gavage) and tert-butylamine (inhalation) may exhibit additional potential hazardous properties for human health (repeated dose toxicity). Butylamine may exhibit additional potential hazardous properties for human health (developmental effects when tested as the salt by the oral route); based on read-across, ethylamine, sec-butylamine, tert-butylamine and hexylamine, 2-ethyl may also cause similar developmental effects by the oral route. Adequate screening-level data are available to characterize the hazard to human health for the purposes of the OECD HPV Chemicals Programme.