Dimethylamine

Carcinogenicity

Description of key information

Chemical Industry Institute of Toxicology" (1981), chronic inhalation of DMA by rats and mice, no carcinogenic effects.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981-1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no guideline followed but matherial and methods are results are good described. clinical chemistry and haematological information only at the end of the exposure period and not every 6 months, no satellite groups used

Qualifier:

no guideline followed

Principles of method if other than guideline:

experimental result

GLP compliance:

yes

Species:

rat

Strain:

other: Fischer rats CDF(F-344)/CrlBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories-Kingston
- Age at study initiation: 4-8 weeks
- Weight at study initiation: range 55-85 grams
- Fasting period before study:
- Housing:8 cubic meter whole body glass and stainless steel chamber
- Diet (e.g. ad libitum): pellets (NIH07); ad libitum except during exposure
- Water (e.g. ad libitum): Durham city water; ad libitum except during exposure
- Acclimation period:min 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): range 68-76 degrees F
- Humidity (%): range 40-60 %
- Air changes (per hr): approximately 2200 L/min
- Photoperiod (hrs dark / hrs light): lights on 7:00 to 19:00 hours; 12-hour light/dark

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:8m3 stainless steel and glass inhalation chambers operated under dynamic conditions at approximately 2200 l/min of HEPA-filtered air and a slightly sub-atmospheric pressure. CIIT has a unique inhalation toxicity settting in which chambers and anteroom service areas are completely separate units. Test atmospheres were generated by metering pure DMA directly from the cylinder via flowmeters into the supply air stream.
- Method of holding animals in test chamber: 1 per cage
- Air flow rate: 2200 L/min
- Method of particle size determination: no data



TEST ATMOSPHERE
- Brief description of analytical method used: analysis was performed by infrared spectrometry (MIRAN 801, Foxboro-Wilks, Norwalk, CT) and the concentrations were derived from calibration curves (optical desity vs. ppm DMA)
- Samples taken from breathing zone: yes with a Thermosorb sampling apparatus

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Ratio analytical to nominal concentration (%): 70% for the lowest test concentration (10 ppm) and 87% for the two highest test concentrations (50 and 175 ppm)

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 hours per day and 5 days per week

Post exposure period:

after 24 months of exposure, all surviving animals were fasted overnight and weighed just prior to necropsy

Dose / conc.:

175 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

Dose / conc.:

10 ppm (nominal)

Dose / conc.:

0 ppm (nominal)

No. of animals per sex per dose:

95

Control animals:

yes

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):

Positive control:

no data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once per week for the first thirteen weeks, and biweekly 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/day: No data
- 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: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after anesthetization after 24 months of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: approximately 20-40 per concentration
- Parameters checked in Appendix L were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:after anesthetization after 24 months of exposure
- Animals fasted: Yes overnight
- How many animals:approximately 20-40 per concentration
- Parameters checked in Appendix M were examined.

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: examination of gross abnormalities, organ (liver, kidney and brain) weight, microscopic examination

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Appendix I and J)
HISTOPATHOLOGY: Yes (see Appendix O)

Statistics:

data for body weights, serum chemistry, hematology, and organ weights: analysis of variance, Dunnett's test
red blood cell morphology: Kolmorgorov-Smirnov two-sample test
survival was estimated with product-limit procedure of Kaplan and Meier (1958)
all neoplastic findings: Kolmogorov-Smirnov one-tailed test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY: clinical observations noted for rats varied, with a predominance being associated with irritation in and around the eyes (summary table Appendix H). There was a limited unscheduled mortality in rats during the first 12 months of the study. However, mortalilty increased during the 12 to 18 month period and peaked in the 18 to 24 month period. Unscheduled mortality in rats exposed to DMA was not exposure related, with the exception that the high dose male rats and mice showed significantly improved mortality. Most deaths were probably associated with aging..

BODY WEIGHT AND WEIGHT GAIN: Throughout the 18 to 24 month period, male and female rats exposed to 175 ppm of DMA continued to have significantly depressed body weights compared to control (85-91% of control). On several occasions, the body weight of female rats exposed to 10 ppm of DMA were significantly higher than control weights. However, these results were not consistent throughout the 18-24 month time period. Body weight data for the entire study are shown graphically in Appendix G.




HAEMATOLOGY: the values of the hematology parameters of rats exposed to DMA were not significantly different from control values.


CLINICAL CHEMISTRY: serum chemistry was relatively unaffected by DMA exposure. Female rats exposed to 175 ppm of DMA had increased levels of alkaline phosphatase and SGOT. Male rats had clinical chemistry parameters within normal ranges.




ORGAN WEIGHTS: seee gross pathology


GROSS PATHOLOGY (see Appendices I and J): Only male rats exposed to 175 ppm of DMA had significantly decreased absolute liver weights. In addition, male rats in all exposure groups and females exposed to 175 ppm had significantly decreased kidney weights compared to controls. Relative organ weights are also reported. The only treatment-related gross observation was receding nasal turbinates in male and female rats exposed to 175 ppm DMA.


HISTOPATHOLOGY: NON-NEOPLASTIC: a large number of microscopic lesions were observed including benign and malignant neoplasms. However, only those lesions observed in the mucosal lining of the nasal cavity were considered to be treatment-related and the remainder lesions were those normally expected in rats over 2 years of age.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): chronic DMA exposure of rats was not associated with any increase in neoplasia of the nasal passage.





OTHER FINDINGS

Effect level:

other: no carcinogenicity

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity

Conclusions:

non carcinogenic

Executive summary:

DMA is not carcinogenic in rats or mice after exposure to DMA via inhalation for 24 month.

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981-1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

no guideline followed but matherial and methods are results are good described. clinical chemistry and haematological information only at the end of the exposure period and not every 6 months and nuerous unscheduled deaths in both male and female mice, no satellite groups used

Qualifier:

no guideline followed

GLP compliance:

yes

Species:

mouse

Strain:

other: B6C3F1 mice (C57B1/6NCrlBR x C3H/HeNCrlBR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories-Kingston
- Age at study initiation: 4-8 weeks
- Weight at study initiation: range 10-25 grams
- Fasting period before study: no data
- Housing:8 cubic meter whole body glass and stainless steel chamber
- Diet (e.g. ad libitum): pellets (NIH 07); ad libitum except during exposure
- Water (e.g. ad libitum): Durham city water; ad libitum except during exposure
- Acclimation period:min 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): range 68-76 degrees F
- Humidity (%): range 40-60 %
- Air changes (per hr): approximately 2200 L/min
- Photoperiod (hrs dark / hrs light): lights on 7:00 to 19:00 hours; 12-hour light/dark

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:8m3 stainless steel and glass inhalation chambers operated under dynamic conditions at approximately 2200 l/min of HEPA-filtered air and a slightly sub-atmospheric pressure. CIIT has a unique inhalation toxicity settting in which chambers and anteroom service areas are completely separate units. Test atmospheres were generated by metering pure DMA directly from the cylinder via flowmeters into the supply air stream.
- Method of holding animals in test chamber: 5 per cage
- Air flow rate: 2200 L/min
- Method of particle size determination: no data



TEST ATMOSPHERE
- Brief description of analytical method used: analysis was performed by infrared spectrometry (MIRAN 801, Foxboro-Wilks, Norwalk, CT) and the concentrations were derived from calibration curves (optical desity vs. ppm DMA)
- Samples taken from breathing zone: yes with a Thermosorb sampling apparatus

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Ratio analytical to nominal concentration (%): 70% for the lowest test concentration (10 ppm) and 87% for the two highest test concentrations (50 and 175 ppm)

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 hours per day and 5 days per week

Post exposure period:

after 24 months of exposure, all surviving animals were fasted overnight and weighed just prior to necropsy

Dose / conc.:

175 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

Dose / conc.:

10 ppm (nominal)

Dose / conc.:

0 ppm (nominal)

No. of animals per sex per dose:

95

Control animals:

yes

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):

Positive control:

no data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once per week for the first thirteen weeks, and biweekly 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/day: No data
- 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: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after anesthetization after 24 months of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: approximately 20-40 per concentration
- Parameters checked in Appendix L were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:after anesthetization after 24 months of exposure
- Animals fasted: Yes overnight
- How many animals:approximately 20-40 per concentration
- Parameters checked in Appendix M were examined.

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: examination of gross abnormalities, organ (liver, kidney and brain) weight, microscopic examination

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Appendix I and J)
HISTOPATHOLOGY: Yes (see Appendix O)

Statistics:

data for body weights, serum chemistry, hematology, and organ weights: analysis of variance, Dunnett's test
red blood cell morphology: Kolmorgorov-Smirnov two-sample test
survival was estimated with product-limit procedure of Kaplan and Meier (1958)
all neoplastic findings: Kolmogorov-Smirnov one-tailed test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY: There were discrepancies in mouse identification which caused concern in the interpretation of idividual body weights and clinical findings. Cause: 15 animals to a triple divided wire cage, mice lose often eartags. Over the study period, a total of 123 mice were noted as missing from their cages at one time or another. Male and female mice had a high incidence of alopecia. In addition, male mice had a high frequency of anogenital injuries. However, because the observations were distributed among exposed groups, as well as the control group, none of the clinical observations were considered to be treatment related. Serological tests of sentinel mice were negative during the 18-24 months period.

BODY WEIGHT AND WEIGHT GAIN: There were discrepancies in mouse identification which caused concern in the interpretation of idividual body weights and clinical findings. Cause: 15 animals to a triple divided wire cage, mice lose often eartags. Over the study period, a total of 123 mice were noted as missing from their cages at one time or another. Collective body weight data among the various dose groups of mice is still considered valid at all time points, as are all of the individual animal pathology findings. Only the 175 ppm exposed group remained significantly lower on a consistent basis compared to control animals (81 to 90% of control for females, 87 to 92% for males.Unscheduled mice mortality was 2 times that of the rats. Males accounted for 61% of the total unscheduled mortality. Renal failure was the most common cause of death in male mice.




HAEMATOLOGY: the values for exposed mice were not significantly different from control values except for a decrease in thrombocytes and mean platelet volume in male mice exposed to 175 and 50 ppm of DMA, respectively.


CLINICAL CHEMISTRY: male mice exposed to 175 ppm of DMA had significantly decreased levels of albumine, calcium, glucose, and total protein. Female mice had clinical chemistry parameters within normal ranges.




ORGAN WEIGHTS: see gross pathology


GROSS PATHOLOGY (see Appendices I and J): absolute liver and kidney weights were significantly decreased in male and female mice exposed to 175 ppm of DMA as was absolute brain weight in female mice exposed to that concentration. However, only the relative liver weight of male mice exposed to 175 ppm of DMA remained significantly decreased while the relative brain weight of female mice exposed to that concentration was significantly increased.


HISTOPATHOLOGY: NON-NEOPLASTIC: Nasal toxicity was similar in rats and mice of both sexes, affecting repiratory and olfactory epithelia. Lesions were focal and mild in animals exposed to 10 ppm, moderate at 50 ppm, and severe in rats and mice exposed to 175 ppm DMA.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): no treatment related increase in neoplasia were detected in rats or mice of either sex..





OTHER FINDINGS

Effect level:

other: no carcinogenicity

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity

Conclusions:

non carcinogenic

Executive summary:

DMA is not carcinogenic in rats or mice after exposure to DMA via inhalation for 24 month.

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981-1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no guideline followed but matherial and methods are results are good described. clinical chemistry and haematological information only at the end of the exposure period and not every 6 months, no satellite groups used

Qualifier:

no guideline followed

Principles of method if other than guideline:

experimental result

GLP compliance:

yes

Species:

rat

Strain:

other: Fischer rats CDF(F-344)/CrlBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories-Kingston
- Age at study initiation: 4-8 weeks
- Weight at study initiation: range 55-85 grams
- Fasting period before study:
- Housing:8 cubic meter whole body glass and stainless steel chamber
- Diet (e.g. ad libitum): pellets (NIH07); ad libitum except during exposure
- Water (e.g. ad libitum): Durham city water; ad libitum except during exposure
- Acclimation period:min 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): range 68-76 degrees F
- Humidity (%): range 40-60 %
- Air changes (per hr): approximately 2200 L/min
- Photoperiod (hrs dark / hrs light): lights on 7:00 to 19:00 hours; 12-hour light/dark

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:8m3 stainless steel and glass inhalation chambers operated under dynamic conditions at approximately 2200 l/min of HEPA-filtered air and a slightly sub-atmospheric pressure. CIIT has a unique inhalation toxicity settting in which chambers and anteroom service areas are completely separate units. Test atmospheres were generated by metering pure DMA directly from the cylinder via flowmeters into the supply air stream.
- Method of holding animals in test chamber: 1 per cage
- Air flow rate: 2200 L/min
- Method of particle size determination: no data



TEST ATMOSPHERE
- Brief description of analytical method used: analysis was performed by infrared spectrometry (MIRAN 801, Foxboro-Wilks, Norwalk, CT) and the concentrations were derived from calibration curves (optical desity vs. ppm DMA)
- Samples taken from breathing zone: yes with a Thermosorb sampling apparatus

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Ratio analytical to nominal concentration (%): 70% for the lowest test concentration (10 ppm) and 87% for the two highest test concentrations (50 and 175 ppm)

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 hours per day and 5 days per week

Post exposure period:

after 24 months of exposure, all surviving animals were fasted overnight and weighed just prior to necropsy

Dose / conc.:

175 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

Dose / conc.:

10 ppm (nominal)

Dose / conc.:

0 ppm (nominal)

No. of animals per sex per dose:

95

Control animals:

yes

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):

Positive control:

no data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once per week for the first thirteen weeks, and biweekly 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/day: No data
- 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: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after anesthetization after 24 months of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: approximately 20-40 per concentration
- Parameters checked in Appendix L were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:after anesthetization after 24 months of exposure
- Animals fasted: Yes overnight
- How many animals:approximately 20-40 per concentration
- Parameters checked in Appendix M were examined.

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: examination of gross abnormalities, organ (liver, kidney and brain) weight, microscopic examination

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Appendix I and J)
HISTOPATHOLOGY: Yes (see Appendix O)

Statistics:

data for body weights, serum chemistry, hematology, and organ weights: analysis of variance, Dunnett's test
red blood cell morphology: Kolmorgorov-Smirnov two-sample test
survival was estimated with product-limit procedure of Kaplan and Meier (1958)
all neoplastic findings: Kolmogorov-Smirnov one-tailed test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY: clinical observations noted for rats varied, with a predominance being associated with irritation in and around the eyes (summary table Appendix H). There was a limited unscheduled mortality in rats during the first 12 months of the study. However, mortalilty increased during the 12 to 18 month period and peaked in the 18 to 24 month period. Unscheduled mortality in rats exposed to DMA was not exposure related, with the exception that the high dose male rats and mice showed significantly improved mortality. Most deaths were probably associated with aging..

BODY WEIGHT AND WEIGHT GAIN: Throughout the 18 to 24 month period, male and female rats exposed to 175 ppm of DMA continued to have significantly depressed body weights compared to control (85-91% of control). On several occasions, the body weight of female rats exposed to 10 ppm of DMA were significantly higher than control weights. However, these results were not consistent throughout the 18-24 month time period. Body weight data for the entire study are shown graphically in Appendix G.




HAEMATOLOGY: the values of the hematology parameters of rats exposed to DMA were not significantly different from control values.


CLINICAL CHEMISTRY: serum chemistry was relatively unaffected by DMA exposure. Female rats exposed to 175 ppm of DMA had increased levels of alkaline phosphatase and SGOT. Male rats had clinical chemistry parameters within normal ranges.




ORGAN WEIGHTS: seee gross pathology


GROSS PATHOLOGY (see Appendices I and J): Only male rats exposed to 175 ppm of DMA had significantly decreased absolute liver weights. In addition, male rats in all exposure groups and females exposed to 175 ppm had significantly decreased kidney weights compared to controls. Relative organ weights are also reported. The only treatment-related gross observation was receding nasal turbinates in male and female rats exposed to 175 ppm DMA.


HISTOPATHOLOGY: NON-NEOPLASTIC: a large number of microscopic lesions were observed including benign and malignant neoplasms. However, only those lesions observed in the mucosal lining of the nasal cavity were considered to be treatment-related and the remainder lesions were those normally expected in rats over 2 years of age.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): chronic DMA exposure of rats was not associated with any increase in neoplasia of the nasal passage.





OTHER FINDINGS

Effect level:

other: no carcinogenicity

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity

Conclusions:

non carcinogenic

Executive summary:

DMA is not carcinogenic in rats or mice after exposure to DMA via inhalation for 24 month.

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981-1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

no guideline followed but matherial and methods are results are good described. clinical chemistry and haematological information only at the end of the exposure period and not every 6 months and nuerous unscheduled deaths in both male and female mice, no satellite groups used

Qualifier:

no guideline followed

GLP compliance:

yes

Species:

mouse

Strain:

other: B6C3F1 mice (C57B1/6NCrlBR x C3H/HeNCrlBR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories-Kingston
- Age at study initiation: 4-8 weeks
- Weight at study initiation: range 10-25 grams
- Fasting period before study: no data
- Housing:8 cubic meter whole body glass and stainless steel chamber
- Diet (e.g. ad libitum): pellets (NIH 07); ad libitum except during exposure
- Water (e.g. ad libitum): Durham city water; ad libitum except during exposure
- Acclimation period:min 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): range 68-76 degrees F
- Humidity (%): range 40-60 %
- Air changes (per hr): approximately 2200 L/min
- Photoperiod (hrs dark / hrs light): lights on 7:00 to 19:00 hours; 12-hour light/dark

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:8m3 stainless steel and glass inhalation chambers operated under dynamic conditions at approximately 2200 l/min of HEPA-filtered air and a slightly sub-atmospheric pressure. CIIT has a unique inhalation toxicity settting in which chambers and anteroom service areas are completely separate units. Test atmospheres were generated by metering pure DMA directly from the cylinder via flowmeters into the supply air stream.
- Method of holding animals in test chamber: 5 per cage
- Air flow rate: 2200 L/min
- Method of particle size determination: no data



TEST ATMOSPHERE
- Brief description of analytical method used: analysis was performed by infrared spectrometry (MIRAN 801, Foxboro-Wilks, Norwalk, CT) and the concentrations were derived from calibration curves (optical desity vs. ppm DMA)
- Samples taken from breathing zone: yes with a Thermosorb sampling apparatus

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Ratio analytical to nominal concentration (%): 70% for the lowest test concentration (10 ppm) and 87% for the two highest test concentrations (50 and 175 ppm)

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 hours per day and 5 days per week

Post exposure period:

after 24 months of exposure, all surviving animals were fasted overnight and weighed just prior to necropsy

Dose / conc.:

175 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

Dose / conc.:

10 ppm (nominal)

Dose / conc.:

0 ppm (nominal)

No. of animals per sex per dose:

95

Control animals:

yes

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):

Positive control:

no data

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once per week for the first thirteen weeks, and biweekly 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/day: No data
- 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: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after anesthetization after 24 months of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: approximately 20-40 per concentration
- Parameters checked in Appendix L were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:after anesthetization after 24 months of exposure
- Animals fasted: Yes overnight
- How many animals:approximately 20-40 per concentration
- Parameters checked in Appendix M were examined.

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: examination of gross abnormalities, organ (liver, kidney and brain) weight, microscopic examination

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Appendix I and J)
HISTOPATHOLOGY: Yes (see Appendix O)

Statistics:

data for body weights, serum chemistry, hematology, and organ weights: analysis of variance, Dunnett's test
red blood cell morphology: Kolmorgorov-Smirnov two-sample test
survival was estimated with product-limit procedure of Kaplan and Meier (1958)
all neoplastic findings: Kolmogorov-Smirnov one-tailed test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY: There were discrepancies in mouse identification which caused concern in the interpretation of idividual body weights and clinical findings. Cause: 15 animals to a triple divided wire cage, mice lose often eartags. Over the study period, a total of 123 mice were noted as missing from their cages at one time or another. Male and female mice had a high incidence of alopecia. In addition, male mice had a high frequency of anogenital injuries. However, because the observations were distributed among exposed groups, as well as the control group, none of the clinical observations were considered to be treatment related. Serological tests of sentinel mice were negative during the 18-24 months period.

BODY WEIGHT AND WEIGHT GAIN: There were discrepancies in mouse identification which caused concern in the interpretation of idividual body weights and clinical findings. Cause: 15 animals to a triple divided wire cage, mice lose often eartags. Over the study period, a total of 123 mice were noted as missing from their cages at one time or another. Collective body weight data among the various dose groups of mice is still considered valid at all time points, as are all of the individual animal pathology findings. Only the 175 ppm exposed group remained significantly lower on a consistent basis compared to control animals (81 to 90% of control for females, 87 to 92% for males.Unscheduled mice mortality was 2 times that of the rats. Males accounted for 61% of the total unscheduled mortality. Renal failure was the most common cause of death in male mice.




HAEMATOLOGY: the values for exposed mice were not significantly different from control values except for a decrease in thrombocytes and mean platelet volume in male mice exposed to 175 and 50 ppm of DMA, respectively.


CLINICAL CHEMISTRY: male mice exposed to 175 ppm of DMA had significantly decreased levels of albumine, calcium, glucose, and total protein. Female mice had clinical chemistry parameters within normal ranges.




ORGAN WEIGHTS: see gross pathology


GROSS PATHOLOGY (see Appendices I and J): absolute liver and kidney weights were significantly decreased in male and female mice exposed to 175 ppm of DMA as was absolute brain weight in female mice exposed to that concentration. However, only the relative liver weight of male mice exposed to 175 ppm of DMA remained significantly decreased while the relative brain weight of female mice exposed to that concentration was significantly increased.


HISTOPATHOLOGY: NON-NEOPLASTIC: Nasal toxicity was similar in rats and mice of both sexes, affecting repiratory and olfactory epithelia. Lesions were focal and mild in animals exposed to 10 ppm, moderate at 50 ppm, and severe in rats and mice exposed to 175 ppm DMA.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): no treatment related increase in neoplasia were detected in rats or mice of either sex..





OTHER FINDINGS

Effect level:

other: no carcinogenicity

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity

Conclusions:

non carcinogenic

Executive summary:

DMA is not carcinogenic in rats or mice after exposure to DMA via inhalation for 24 month.

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

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.

Additional information

The Chemical Industry Institute of Toxicology investigated in 1981 the carcinogenic potential of DMA. They administered DMA to rats and mice via inhalation in 3 different doses (10, 50 and 175 ppm) and could not show substance-related carcinogenic potential after an administration of DMA for a period of 2 years. The exhibited clinical signs were in high incidence: alopecia, anogenital injuries (♂), beside that irritation around the eyes occurred. A large number of microscopic non-neoplastic lesions were observed including benign and malignant neoplasms. However, only those lesions observed in the mucosal lining of the nasal cavity were considered to be treatment-related and the remainder lesions were those normally expected in rats over 2 years of age.Chronic DMA exposure of rats was not associated with any increase in neoplasia of the nasal passage. In conclusion, it is stated that DMA is not carcinogenic in rats or mice after inhalation exposure.