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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Data on repeated dose toxicity are available for C10-DMA, C12-14-DMA, C16-DMA and C18-DMA. These studies were performed either according to OECD TG 422, OECD TG 407 or OECD TG 421. NOAEL/NOEL of between 50 and 180 mg/kg/d were obtained.


Subchronic/chronic toxicity of DMAs are assessed based on the data on read-across source substances DMAOs. A two-year study with C10-16 DMAO is currently used as key study to cover the endpoint subchronic/chronic toxicity. The NOAEL of 42.3 and 52.6 mg/kg/d were obtained for males and females respectively.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
repeated dose toxicity: oral, other
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint-specific justification, please see read-across justification document (category approach) in the linked category of dimethylalkylamines.
Frequency of treatment:
Daily
Organ weight findings including organ / body weight ratios:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
107 mg/kg bw/day (actual dose received)
Based on:
other: Read-across from C16-DMA; value converted based on MW
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Original data for the source: 100 mg/kg bw/d
Key result
Critical effects observed:
no
Executive summary:

The study used as source investigated the repeated oral toxicity of C16-DMA. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (category approach) is outlined in the read-across report in the linked category of dimethylalkylamines.

Endpoint:
repeated dose toxicity: oral, other
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint-specific justification, please see read-across justification document (category approach) in the linked category of dimethylalkylamines.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 192 mg/kg bw/day (actual dose received)
Based on:
other: Read-across from C12-14 DMA; value converted based on MW
Sex:
male/female
Basis for effect level:
other: No adverse effect up to the highest dose
Remarks on result:
other: Original data for the source: >= 150 mg/kg bw/d
Key result
Critical effects observed:
no
Executive summary:

The study used as source investigated the repeated oral toxicity of C12-14 DMA. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (category approach) is outlined in the read-across report in the linked category of dimethylalkylamines.

Endpoint:
repeated dose toxicity: oral, other
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint-specific justification, please see read-across justification document (category approach) in the linked category of dimethylalkylamines.
Key result
Dose descriptor:
NOAEL
Effect level:
233 mg/kg bw/day (actual dose received)
Based on:
other: Read-across from C10-DMA; value converted based on MW
Sex:
male/female
Basis for effect level:
other: No adverse effect found up to the highest dose level.
Remarks on result:
other: Original data for the source: 150 mg/kg bw
Critical effects observed:
no
Executive summary:

The study used as source investigated the repeated oral toxicity of C10-DMA. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (category approach) is outlined in the read-across report in the linked category of dimethylalkylamines.


 

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
read-across source
Details on study design:
-
Clinical signs:
no effects observed
Mortality:
no mortality observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no significant differences in survival at 104 weeks. There were no significant, compound-related differences in mean feed consumption, clinical chemistry or ophthalmology.

BODY WEIGHT AND WEIGHT GAIN
The high dose animals demonstrated >10% decreases in mean body weight. Animals in the 0.1% test substance group also showed reduced body weight, but the reduction was not as strong as in the high dose group.

HISTOLOGY
There were no compound-related effects on histopathic examination. There was no evidence of a carcinogenic response after chronic dietary administration of the test substance.
Dose descriptor:
NOAEL
Effect level:
42.3 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on decreased mean body weight in the highest dose group.
Dose descriptor:
NOAEL
Effect level:
52.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on decreased mean body weight in the highest dose group.
Critical effects observed:
not specified
Executive summary:

The study used as source investigated chronic toxicity after oral exposure. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given: comparable to guidelines/standards.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
no
Remarks:
original study performed in 1979, prior to the adoption of GLP compliance standards. However, it was reviewed and found acceptable by the laboratory´s Quality Assurance Department in accordance with US FDA´s GLP Regulation of June 20, 1979.
Limit test:
no
Species:
rat
Strain:
other: Charles River
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding laboratories Inc., Portage, Michigan, USA
- Age at study initiation: 4 weeks
- Housing: individually
- Diet: Zeigler NIH-07diet containing test substance, ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 46-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Zeigler NIH-07
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
not indicated
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily with the food
Remarks:
Doses / Concentrations:
0, 0.01, 0.1 and 0.2 % of the test compound (100% (w/v) active basis)
Basis:
nominal in diet
No. of animals per sex per dose:
60
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on the results from a 13 week study which showed the high dose causing about a 5 to 8 % reduction in body weight.
- Concentrations in the diet of 0, 0.01, 0.1 and 0.2 % test compound (100% (w/v) active basis) correspond to 0, 4.24, 42.3, or 87.4 mg/kg bw/day for males and 0, 5.23, 52.6, or 107 mg/kg bw/day for females according to OECD (2006).
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks of study, biweekly for the next 12 weeks and monthly thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/week: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once during pretest and at 3,6,12,16,19,22 and 24 months
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Animals fasted: No data
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Body weights, feed consumption, efficiency of feed utilization, clinical chemistry parameters and absolute and relative organ weights were compared by analysis of variance (one way classification), Bartlett´s test for homogeneity of variances, and at least significant differences criterion. If Bartlett´s test were significant, then pairwise comparisons were made by the Mann-Whitney U test. All statistical analyses were conducted at a 5 %, two-sided risk level, and each treatment group was compared with the main control group by sex.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
details see below
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no significant differences in survival at 104 weeks. There were no significant, compound-related differences in mean feed consumption, clinical chemistry or ophthalmology.

BODY WEIGHT AND WEIGHT GAIN
The high dose animals demonstrated >10% decreases in mean body weight. Animals in the 0.1% test substance group also showed reduced body weight, but the reduction was not as strong as in the high dose group.

HISTOLOGY
There were no compound-related effects on histopathic examination. There was no evidence of a carcinogenic response after chronic dietary administration of the test substance.
Dose descriptor:
NOAEL
Effect level:
42.3 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on decreased mean body weight in the highest dose group.
Dose descriptor:
NOAEL
Effect level:
52.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on decreased mean body weight in the highest dose group.
Critical effects observed:
not specified
Conclusions:
Under the conditions of the test, no substance related effects were observed in male and female rats after oral exposure for 104 weeks. The NOAEL is 42.3 (males) or 52.6 (females) mg/kg bw/day.
Executive summary:

Male and female Charles River rats were given a diet containing 0, 0.01, 0.1 or 0.2 % test substance ad libitum for 104 weeks. No substance related effect was observed in any concentration tested. The NOAEL is 42.3 (male) or 52.6 (female) mg/kg bw/day based on decreased mean body weight in the highest dose group.

Endpoint:
repeated dose toxicity: oral, other
Remarks:
Screening for reproductive / developmenral toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint-specific justification, please see read-across justification document (category approach) in the linked category of dimethylalkylamines.
Dose descriptor:
NOAEL
Effect level:
>= 174 mg/kg bw/day (nominal)
Based on:
other: Read-across from C18 DMA; value converted based on MW
Sex:
male/female
Basis for effect level:
clinical biochemistry
clinical signs
gross pathology
haematology
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
Remarks on result:
other: Original data for the source: >=180 mg/kg bw/d
Critical effects observed:
no
Executive summary:

The study used as source investigated the repeated oral toxicity of C18-DMA. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (category approach) is outlined in the read-across report in the linked category of dimethylalkylamines.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
good
System:
other: Body weight

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

Additional information

Toxicity after repeated oral application has been investigated with the following substances of the DMA category: C10-DMA, C12-14-DMA, C16-DMA and C18-DMA.


14-day repeated dose toxicity studies were performed on C10-DMA, C12-14 DMA, C16-DMA and C18-DMA. Mortality and lesions in GI-tract occurred at 300 mg/kg/day for C10-DMA, C16-DMA and C18-DMA. Further, body weight gain reduction and leucocytosis were found for C16-DMA and C18-DMA.


Studies according to OECD TG 422 were performed on C10-DMA, C12-14- DMA, C16-DMA and C18-DMA and comparable findings were obtained. Effects found at the highest dose tested (150 mg/kg/day for C10-DMA, C12-14 DMA and C16-DMA; 180 mg/kg/day for C18-DMA) included body weight gain reduction, leucocytosis and histopathologcal changes in GI tract. Only the body weight gain reduction found for males treated with C16-DMA was evaluated as adverse. The NOAEL of 150 mg/kg/day was obtained for C10-DMA, the NOAEL of 150 mg/kg/day for C12-DMA, the NOAEL of 100 mg/kg/day and 150 mg/kg/day for males and females treated with C16-DMA respectively, and the NOAEL of 180 mg/kg/day for C18-DMA.


Further, one 28-day toxicity study (OECD TG 407) and one reproduction/developmental toxicity screening study (OECD 421) are available for C12-14-DMA. Also in these studies consistent findings were obtained: Up to the dose levels associated with mortality (≥ 150 mg/kg/d), no apparent systemic effect was found. NOEL of 50 mg/kg/d were obtained in both studies.  


Currently no subchronic/chronic studies with members of the DMA-category are available. To fill this data gap, read-across to DMAOs is performed. In a two-year chronic study with C10-16 DMAO (Cardin et al., 1985, equivalent to OECD guideline 453) decreased body weights at the highest dose tested (87.4 mg/kg bw/d for males and 107 mg/kg bw/d for females) was reported. No other adverse effects were observed, resulting in a NOAEL of 42.3 and 52.6 mg/kg bw/d for males and females, respectively.


Further studies with repeated exposure to DMAOs are included as supporting evidence.


A study according to OECD TG 422 is available for C12-18 DMAO. The NOEL in this study was 40 mg/kg bw/d based on pathological changes in the forestomach and the mesenteric lymph nodes and signs of systemic toxicity (salivation) at dose levels of 100 and/or 200 mg/kg bw/d.


Lijinsky et al. (1984, reliability 3) reported a chronic study in rats. The animals were exposed for 93 weeks to ca. 250 mg C12-DMAO/kg bw/d. There was no effect on life span.  


A 90-day toxicity study with C10-16-DMAO in rats determined a NOAEL of 80 mg/kg bw/d (females) and 63 mg/kg bw/d (males) (The Procter & Gamble, 1980). The NOAEL for females was based on decreases in mean body weight at 150 and 301 mg/kg bw/d (no other effects observed). Opthalmoscopic examination revealed lenticular opacities pertaining to the posterior cortex of the lens in males at 112 and 236 mg/kg bw/d. The body weight of the males was reduced in the highest dose group (236 mg/kg bw/d).


In a 32-week feeding study with C10-16-DMAO in rabbits, a NOAEL of 40 mg/kg bw/d (males) is established (The Procter & Gamble, 1977A). Decreased alkaline phosphatase levels and an increased liver/body weight ratio were noted in males at 196 mg/kg bw/d.


In a two-generation study in rats (Lion Corporation, 1978B) reported a NOAEL > 40 mg/kg bw/d


 


For the chronic toxicity assessment of DMAs the use of 50 mg/kg/d as systemic NOAEL is considered to be sufficiently conservative, since there was no systemic effect present at this dose level. This approach is also in line with the approach taken by EFSA (2007), in which NOAEL of 50 mg/kg for DMAOs (based on Cardin et al, 1985) is used for the derivation of a TDI for DMAs in food contact materials.

Justification for classification or non-classification

In the recently generated subacute toxicity studies on DMAs (OECD TG 422 studies on C10-DMA, C12-14- DMA, C16-DMA, C18-DMA), NOAELs of ≥ 100 mg/kg/d were obtained. In the two-year chronic toxicity study on read-across source substances C10-16 DMAO, no severe toxicity were found up to the highest dose levels ( 87.4 mg/kg bw/d for males and 107 mg/kg bw/d for females), resulting in the NOAEL of 42.3 and 52.6 mg/kg bw/d for males and females, respectively.


Based on the category approach and read-across to DMAOs, members of the DMA category do not have to be classified for specific target organ toxicity – repeated exposure or repeated dose toxicity according to Regulation (EC) No 1272/2008.