Dimethylamine

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Zeiger E. et al, 1987, test in Salmonella typhimurium species: no cytotoxicity, no genotoxicity

Hsie et. al., Multiple-endpoint mutagenesis with Chinese Hamster Ovary (CHO) cells: Evaluation with eight carcinogenic and non-carcinogenic compounds, Hemisphere Publishing Corporation) and (Ihidate, and Odashima, 1977) no cytotoxicity, no genotoxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: similar to guideline study; no data regarding GLP

Qualifier:

according to guideline

Guideline:

other: Haworth, S. et al.: Environ. Mutagen. 5, Suppl. 1, 3-142

Principles of method if other than guideline:

Use of S. typhymurium strain TA98, TA100, TA1535, TA1537 and/or TA97, but no E.coli strain.
not toxic chemicals tested up to a maximum dose of 10 mg/plate, poorly soluble chemicals were tested up to the dose defined by solubility, A maximum of 0.05 ml solvent was added to each plate, only 2-Aminoanthracene was used as the indicator of the efficacy of the S9-Mix, not every individual plate count is displayed, no justification that no confirmation of the negative result has been made

GLP compliance:

no

Type of assay:

bacterial reverse mutation assay

Target gene:

his-

Species / strain / cell type:

S. typhimurium, other: Salmonella Typhimurium TA98, TA100, TA1535, TA1537, TA97

Metabolic activation:

with and without

Metabolic activation system:

rat and hamster S9 (10% Aroclor 1254-induced)

Test concentrations with justification for top dose:

0.000, 33.000, 100.000, 333.000, 1000.000, 3333.000, 4500.000 µg/plate

Vehicle / solvent:

H2O

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

Remarks:

run with each trial

Positive controls:

yes

Remarks:

without S9: Sodium azide (TA1535, TA100), 9-aminoacridine (TA1537), 4-nitro-o-phenylenediamine (TA98) with S9: 2-aminoanthracene

Evaluation criteria:

An individual trial was judged mutagenic (+) if a dose-related increase over the corresponding solvent control was seen, and it was judged weakly mutagenic C+W) if a low-level dose response was seen. A trial was considered questionable (?) if a dose related
increase was judged insufficiently high to justify a call of " + W," if only a single dose was elevated over the control, or if a non-dose-related increase was seen.
The distinctions between a weak mutagenic response and a mutagenic response, or between a weak mutagenic response and a questionable mutagenic response are highly subjective.
A chemical was judged to be mutagenic (+), or weakly mutagenic (+W), if it produced a reproducible, dose-related increase in his+ revertants over the corresponding solvent controls in replicate trials. A chemical was considered to be questionable (?) if a reproducible increase of hist revertants did not meet the criteria for either a " + " or " + W," or if only single doses produced an increase in his+ revertants in repeat trials

Statistics:

no data

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: > 1000 µg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: > 1000 µg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: > 1000 µg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: > 1000 µg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 97

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: > 1000 µg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Table 82.1 DIMETHYLAMINE (LAB: EGG   SOLVENT: H2O)
DOSE	TA100						TA1535						TA1537						TA98
	NA		10% HLI		10% RLI		NA		10% HLI		10% RLI		NA		10% HLI		10% RLI		NA		10% HLI		10% RLI
ug/PLATE	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM
0.000	93	8.0	89	9.1	76	2.5	24	1.9	8	1.7	13	1.2	4	1.5	4	0.9	8	1.5	18	5.2	20	0.6	24	3.2
33.000	92	5.4					21	1.5					8	1.0					20	2.7
100.000	91	8.7	90	3.1	77	2.0	19	2.5	7	1.5	11	0.9	8	0.6	6	0.9	8	2.6	15	2.8	24	2.2	17	1.0
333.000	92	6.4	80	4.5	91	0.6	20	4.0	10	0.6	10	2.7	5	1.3	6	2.3	6	2.2	17	4.8	20	2.0	17	2.7
1000.000	88	6.3	92	7.0	88	5.2	16	2.3	7	1.2	8	1.7	5	1.5	8	0.3	5	1.7	17	1.2	20	3.9	24	3.0
3333.000	t		88	5.2	89	11.0	11s	1.5	8	1.2	9	1.3	6s	0.7	7	1.5	10	0.3	t		19	5.0	22	1.5
4500.000			82	6.7	86	2.5			9s	1.8	8	2.4			6	1.3	6	3.3			19	1.2	20	1.5
POS	2003	16.5	887	78.0	580	31.2	1176	36.1	80	1.9	51	2.7	573	199.4	94	4.2	58	8.7	840	81.5	1011	82.4	639	64.7

 

Table 82.2 DIMETHYLAMINE (LAB: EGG   SOLVENT: H2O)
DOSE	TA100						TA1535						TA1537						TA98
	NA		10% HLI		10% RLI		NA		10% HLI		10% RLI		NA		10% HLI		10% RLI		NA		10% HLI		10% RLI
ug/PLATE	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM	MEAN	SEM
0.000	117	10.1	107	6.2	132	16.2	21	3.5	13	1.5	10	0.7	7	2.0	8	0.9	8	0.6	22	4.4	34	2.9	28	3.2
100.000	126	4.8	124	3.2	106	7.0	14	1.2	10	1.2	15	4.2	8	1.9	8	0.3	9	1.5	25	2.7	25	2.9	28	1.5
333.000	112	9.5	116	5.0	120	0.9	15	3.9	15	1.8	10	0.0	8	1.3	7	1.2	10	2.2	21	1.7	28	1.7	26	1.2
1000.000	126	4.4	136	4.4	127	4.3	18	3.2	10	2.0	10	1.7	5	0.3	5	0.9	9	0.6	22	0.7	29	6.2	31	1.9
2000.000	108	7.6	115	5.1	113	16.4	15s	3.0	12s	1.9	14	1.5	9s	2.8	9	0.3	11	1.7	24s	1.8	26	1.2	27	1.2
3333.000	97s	11.5	129s	4.7	117	14.7	t		11s	1.2	11	1.2	t		7	0.6	8	0.6	20s	1.5	29	2.4	27	1.8
4000.000									16s	2.3
POS	2012	55.2	1503	72.7	1255	49.0	1205	65.2	116	7.2	60	1.7	535	18.1	184	21.0	133	2.1	2002	38.4	1270	40.2	1022	55.2

 

Conclusions:

Interpretation of results: negative

Dimethylamine was considered not mutagenic in the tests performed.

Executive summary:

This test was performed according to Haworth, S. et al.: Environ. Mutagen. 5, Suppl. 1, 3-142 with Salmonella typhimurium TA1535, TA1537, TA98, TA100, and TA 97. The concentrations of the test substance ranged from 0.000, 33.000, 100.000, 333.000, 1000.000, 3333.000 and 4000.000 or 4500.000 µg/plate using the pre-incubation method in either the presence or absence of 10% rat or hamster liver metabolic activation. The highest in some strains nontoxic dose tested was 1000.000 mg/plate and the test result was negative according to all strains, with and without metabolic activation. (Zeiger et al., 1987).

Reference 2

Endpoint:

in vitro gene mutation study in mammalian cells

Remarks:

and further multiple-endpoint mutagenesis tests

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well-described experimental result, no guideline followed

Principles of method if other than guideline:

CHO cells were treated with DMA in the presence of metabolic activation (Aroclor-1254 induced rat liver microsomes) and analyzed for cytotoxicity and specific gene mutation, and collected for chromosome aberration and SCE assays.

GLP compliance:

no

Type of assay:

other: Chinese Hamster Ovary (CHO) cells

Target gene:

hprt locus

Species / strain / cell type:

Chinese hamster Ovary (CHO)

Additional strain / cell type characteristics:

other: subclone CHO-KrBH4 of the CHO-K-, cell line, referred to as CHO cells

Metabolic activation:

not specified

Metabolic activation system:

no data

Test concentrations with justification for top dose:

0.5% (5 µL in 5 mL medium)

Vehicle / solvent:

details see below

Remarks:

details see below

Details on test system and experimental conditions:

details see below

Evaluation criteria:

details see below

Statistics:

details see below

Species / strain:

Chinese hamster Ovary (CHO)

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

other: no but tested up to a concentraton of 22 mM

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

all details are given below

The Mutagenicity and Toxicity of DMN and DMA

DMA did not exhibit cytotoxic and mutagenic effects up to 22 mM even with S9, and a marginal effect on SCE and chromosome aberration were seen in the presence of S9. The significance of this marginal cytogenetic activity needs to be further assesed. These results suggest that nitrosation is required for the genetic toxicity of DMN since its nonnitrosated analogue DMA is relatively inert. In addition, it shows that the carcinogenic chemical DMN causes cytotoxicity, gene mutation, chromosome aberration and SCE, while DMA, the noncarcinogenic analogue of DMN, is almost totally inert. A close examination of the SCE data indicated that DMA might exhibit a marginally weak response using the 2-fold criteria. Since DMA requires 5 times higher concentration than DMN to achieve a marginal response, it is not unreasonable to consider DMA as negative or nonpositive in the SCE assay.

Conclusions:

Interpretation of results: negative

DMA exhibits no cytotoxic and mutagenic effects.

Executive summary:

Hsie et al. reported in 1987 an multiple-endpoint mutagenesis test was performed. Chinese Hamster Ovary (CHO) cells were used with and without metabolic activation system. The test concentration of dimethylamine was up to 22 mM. Before performing this experimental study it was known that DMA is a noncarcinogen. It was used as analogue to the cancerogen DMN (dimehylnitrosamine).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Isakova et al., 1971. In vivo Mammalian Chromosome Aberration Assay; no genotoxicity

Link to relevant study records

Reference

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication which meets basic scientific principles.

Qualifier:

no guideline followed

Principles of method if other than guideline:

DMA was investigated on male Wistar rats weighing 150-200 g. These were subjected to long-term poisning by inhalation in 100-liter chambers, predetermined vapor concentrations being maintained around the clock for 3 month.

GLP compliance:

no

Remarks:

The study was conducted prior to the adoption of the OECD guidelines

Type of assay:

chromosome aberration assay

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

inhalation

Vehicle:

not applicable

Details on exposure:

Rats were exposed by inhalation in 100-L chambers

Duration of treatment / exposure:

15 and 90 days

Frequency of treatment:

daily

Post exposure period:

no

Dose / conc.:

0 mg/m³ air (nominal)

Dose / conc.:

0.5 mg/m³ air (nominal)

Dose / conc.:

1 mg/m³ air (nominal)

No. of animals per sex per dose:

no data

Control animals:

yes, sham-exposed

Tissues and cell types examined:

bone marrow cells

Details of tissue and slide preparation:

The preparation for cytological investigation were prepared by the method of Ford and Woolam (Ford C.E. and Woolam D.H. Stain technology, Vol.38, p.271, 1963).

Evaluation criteria:

The incidence of structural chromosome breakages and aneuploidy, recorded in metaphases of marrow cells, was used as the criterion of a mutagenic effect. The control was provided by the incidence of similar breakages in the marrow of intact rats of the same age and sex, maintained under identical conditions.

Statistics:

Student's test.

Sex:

male

Genotoxicity:

negative

Toxicity:

not specified

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not examined

Additional information on results:

The incidence of cells with structural chromosome breakages was similar to that in the control preparations (0-2%), and was independent of the duration of poisoning or the concentration of DMA. Analysis of the chromosome count in the same cells revealed that the incidence of aneuploid cells in the experimental animals was somewhat higher than in the controls, for both DMA concentrations and at various times after the beginning of exposure. Statistically significant differences from the controls (p < 0.01) were detected only after 3 month' poisoning, for both DMA concentartions. The incidence of aneuploid cells in the marrow after 90 days poisoning was nearly double that after 15 days poisoning. The significant increase in the incidence of aneuploidy with both DMA concentrations and after different poisoning periods was due to both hypoploid and hyperploid cells.

Conclusions:

Interpretation of results: negative
DMA did not produce cytologically detectable chromosome breakages.

Executive summary:

Male Wistar rats were exposed to 0.5 and 1 mg/cm³ dimethylamine via continuous inhalation for 15 and 90 days. 50 to 100 bone marrow cells were scored per animal. The incidence of cells with chromosomal breakage was did not exceed controls (0 -2%) in any experimantal variant but the incidence of aneuploid cells was significantly higher at both concentrations after 90 days. No decrease in mitotic activity was observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

In vitro

Gene mutation properties of dimethylamine were investigated in a bacterial reverse mutation assay (Ames test). This test was performed according to Haworth, S. et al.: Environ. Mutagen. 5, Suppl. 1, 3-142 with Salmonella typhimurium TA1535, TA1537, TA98, TA100, and TA 97. The concentrations of the test substance ranged from 0.000, 33.000, 100.000, 333.000, 1000.000, 3333.000 and 4000.000 or 4500.000 µg/plate using the pre-incubation method in either the presence or absence of 10 % rat or hamster liver metabolic activation. The highest in some strains nontoxic dose tested was 1000.000 mg/plate and the test result was negative according to all strains, with and without metabolic activation. (Zeiger et al., 1987).

Hsie et al. reported in 1987 an multiple-endpoint mutagenesis test was performed (Hsie et al., 1987). Chinese Hamster Ovary (CHO) cells were used with and without metabolic activation system. The test concentration of dimethylamine was up to 22 mM. Before performing this experimental study it was known that DMA is a noncarcinogen. It was used as analogue to the cancerogen DMN (dimehylnitrosamine).

Additionally, an in vitro mammalian chromosome aberration test with CHO cells testing among various other chemicals DMA-HCl showed no chromosomal aberrations and no mutations, therefore is stated that DMA is not genotoxic nor cytotoxic in concentrations um to 0.12 mg/mL (Ishidate et al., 1977).

In vivo

In an in Vivo Mammalian Chromosome Aberration Assay (Isakova et al., 1971), Wistar rats were exposed to vapours of DMA by inhalation at concentrations of 0.05 mg/m³ and 1 mg/m³ during 15 and 90 days. The incidence of structural chromosome breakages and aneuploidy, recorded in metaphases of marrow cells, was used as the criterion of a mutagenic effect. The control was provided by the incidence of similar breakages in the marrow of intact rats of the same age and sex, maintained under identical conditions. 50 to 100 metaphases were analyzed for each experimental and control animal.

The incidence of cells with structural chromosome breakages was similar to that in the control preparations (0 - 2 %), and was independent of the duration of poisoning or the concentration of DMA. Analysis of the chromosome count in the same cells revealed that the incidence of aneuploid cells in the experimental animals was somewhat higher than in the controls, for both DMA concentrations and at various times after the beginning of exposure. Statistically significant differences from the controls (p < 0.001) were detected only after 3 month' poisoning, for both DMA concentrations. The incidence of aneuploid cells in the marrow after 90 days poisoning was nearly double that after 15 days poisoning. The significant increase in the incidence of aneuploidy with both DMA concentrations and after different poisoning periods was due to both hypoploid and hyperploid cells.

Since only 50 to 100 metaphases from the bone marrow of each animal were evaluated, the increased aneuploidy and hyperploidy can not be evaluated.

Overall, it can be concluded that DMA is not genotoxic.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.