N,N-dimethylbutylamine

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Cross-reference

Reason / purpose for cross-reference:

other: read-across target

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

It is considered justified to utilise information on this substance in a read across approach since it is a potential metabolite of the registered substance.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical signs of CNS depression (ataxia and hypoactivity)

Critical effects observed:

not specified

Conclusions:

The No Observed Adverse Effect Level was determined to be 125 mg/kg bw/day.

Executive summary:

It is considered justified to utilise information on n-butanol in a read across approach since it is a potential metabolite of the registered substance.

Four groups of male and female rats were administered the test material daily by gavage at 0, 30, 125 or 500 mg/kg bw/d for either 6 or 13 weeks. Dosing solutions of butanol in deionised water were used.

30 rats per sex per group were dosed, with a further 10 being sacrificed prior to dosing for determination of clinicopathological baseline levels. Ten male and ten female rats from each group were necropsied on study days 43 to 44 (interim sacrifice) and the remaining animals on study days 92 to 93.

Ataxia and hypoactivity (lasting less than 1 h) were observed 2 to 3 minutes after dosing in both sexes of the high-dose group (500 mg/kg bw/d) during the final 6 weeks of dosing. Such ataxia and hypoactivity are typically seen following high oral doses of alcohols. The rapid induction/remission of these effects and the reported increased incidence after the interim kill may be due to the fact that personnel were able to collect post-dose observations more quickly since fewer animals required dosing.

At the interim clinical pathological evaluation, red blood cell count (RBC), packed cell volume (PCV), and haemoglobin (HGB) averages of the 500 mg/kg/day dose group females were 5 % below control averages. Although these differences were statistically significant, they were small and no differences between the parameters were observed in the males of the interim evaluation or between control and treated groups of either sex at the final evaluation. Therefore, even if the lower red blood cell parameters in the 500 mg/kg/day females were an actual treatment-related effect, it was small and transitory and thus not considered as adverse.

Under the conditions of the study the No Observed Adverse Effect Level was determined to be 125 mg/kg bw/day.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1986

Reference 2

Reference Type:

secondary source

Title:

n-Butanol (CAS No. 71-36-3)

Author:

ECETOC

Year:

2003

Bibliographic source:

ECETOC JACC No. 41, ISSN-0773-6339-41, December 2003

Reference 3

Reference Type:

secondary source

Title:

OECD SIDS n-Butyl Alcohol

Author:

OECD

Year:

2001

Bibliographic source:

OECD SIDS, UNEP Publications

Materials and methods

Principles of method if other than guideline:

Four groups of male and female rats (30/sex/group) were administered the test material daily by gavage at 0, 30, 125 or 500 mg/kg bw/d for either 6 or 13 weeks.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butan-1-ol

EC Number:

200-751-6

EC Name:

Butan-1-ol

Cas Number:

71-36-3

Molecular formula:

C4H10O

IUPAC Name:

butan-1-ol

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, U.S.A.
- Age at study initiation: 36-37 d
- Mean weight at study initiation: males 90 g, females 86 g
- Housing: individually
- Diet (e.g. ad libitum): Purina Certified Rodent Laboratory Chow #5002 (pellet)
- Water (e.g. ad libitum): filtered municipal water
- Acclimation period: 7 days before the pre-treatment week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1
- Humidity (%): 48 ± 9
- Photoperiod (hrs dark / hrs light): 12:12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions of butanol in deionised water were used.

VEHICLE
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): 10 mL/kg was the constant dosing volume

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC-FI

Duration of treatment / exposure:

6 (interim sacrifice) or 13 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

125 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

30 (further 10 were sacrificed prior to dosing for determination of clinicopathological baseline levels)

Control animals:

yes, concurrent vehicle

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly

FOOD CONSUMPTION: Yes
-Time schedule: Food consumption was recorded weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmic examination was conducted prior to treatment and during week 13 before final necropsy.
- Dose groups that were examined: no data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the start of the study, during week 6 and during week 13
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 males and 10 females
- parameters: haemoglobin (HGB), haematocrit (PCV), erythrocyte count (RBC), mean cell volume (MCV), mean cell haemoglobin (MCH),mean cell haemoglobin concentration (MCHC) total and differential leucocyte counts (WBC), estimated platelet count (PLT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before the start of the study, during week 6 and during week 13
- Animals fasted: No data
- How many animals: 10 males and 10 females
- parameters: alkaline phosphatase (Alk phos) blood urea nitrogen (BUN), glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), glucose (Gluc), total protein (TP), albumin (Alb), A/G ratio (calculated), globulin (calculated), total bilirubin (Tot. bili.), sodium (Na), potassium (K), chloride (Cl), calcium (Ca), inorganic phosphate (Phos), carbon dioxide (TCO2), total serum cholesterol (Chol), creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: before the start of the study, during week 6 and during week 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- parameters: pH, specific gravity, glucose, protein, ketones, bilirubin, urobilinogen, microscopy of sediment

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes: Ten male and ten female rats from each group were necropsied on study days 43 to 44 and the remaining animals on study days 92 to 93. Gross pathology of all animals was assessed and organs from animals necropsied on study days 92 to 93 were weighed.

HISTOPATHOLOGY: Yes: A complete histopathological investigation was made of all animals of the control and high-dose groups. In the low and mid-dose groups, histopathology included the liver, kidney, and heart from all animals and all gross lesions. All animals found dead or killed in extremis were also microscopically examined.

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Ataxia and hypoactivity (lasting less than 1 h) were observed 2 to 3 minutes after dosing in both sexes of the high-dose group (500 mg/kg bw/d) during the final 6 weeks of dosing. Such ataxia and hypoactivity are typically seen following high oral doses of alcohols. The rapid induction/remission of these effects and the reported increased incidence after the interim kill may be due to the fact that personnel were able to collect post-dose observations more quickly since fewer animals required dosing.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No significant changes between treated groups and controls were observed concerning mortality (three rats were found dead or sacrificed in extremis, but these deaths could not be attributed to the test article.).

Body weight and weight changes:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

At the interim clinical pathological evaluation, red blood cell count (RBC), packed cell volume (PCV), and haemoglobin (HGB) averages of the 500 mg/kg/day dose group females were 5 % below control averages. Although these differences were statistically significant, they were small and no differences between the parameters were observed in the males of the interim evaluation or between control and treated groups of either sex at the final evaluation. Therefore, even if the lower red blood cell parameters in the 500 mg/kg/day females were an actual treatment-related effect, it was small and transitory and thus not considered as adverse.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Urinalysis findings:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

no significant changes between treated groups and controls were observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

2

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical signs of CNS depression (ataxia and hypoactivity)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level was determined to be 125 mg/kg bw/day.

Executive summary:

Four groups of male and female rats were administered the test material daily by gavage at 0, 30, 125 or 500 mg/kg bw/d for either 6 or 13 weeks. Dosing solutions of butanol in deionised water were used.

30 rats per sex per group were dosed, with a further 10 being sacrificed prior to dosing for determination of clinicopathological baseline levels. Ten male and ten female rats from each group were necropsied on study days 43 to 44 (interim sacrifice) and the remaining animals on study days 92 to 93.

Ataxia and hypoactivity (lasting less than 1 h) were observed 2 to 3 minutes after dosing in both sexes of the high-dose group (500 mg/kg bw/d) during the final 6 weeks of dosing. Such ataxia and hypoactivity are typically seen following high oral doses of alcohols. The rapid induction/remission of these effects and the reported increased incidence after the interim kill may be due to the fact that personnel were able to collect post-dose observations more quickly since fewer animals required dosing.

At the interim clinical pathological evaluation, red blood cell count (RBC), packed cell volume (PCV), and haemoglobin (HGB) averages of the 500 mg/kg/day dose group females were 5 % below control averages. Although these differences were statistically significant, they were small and no differences between the parameters were observed in the males of the interim evaluation or between control and treated groups of either sex at the final evaluation. Therefore, even if the lower red blood cell parameters in the 500 mg/kg/day females were an actual treatment-related effect, it was small and transitory and thus not considered as adverse.

Under the conditions of the study the No Observed Adverse Effect Level was determined to be 125 mg/kg bw/day.