N,N-dimethylbutylamine

Endpoint summary

Description of key information

The substance is highly corrosive to the skin. Deaths occurred following oral and inhalation exposure. Local effects but no systemic effects or deaths were seen following dermal exposure up to 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05.10.1985 - 05.09.1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP guideline study. Restrictions: sesame oil instead of water; large differences in dose volume (0. to 3.2 mL/kg depending on dose).

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

Cited as Directive 84/449/EEC, B.1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

. Dose volume varied from 0.8 to 3.2 ml/kg bw, depending on dose level.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG
- Age at study initiation: males 6 weeks; females 9 weeks
- Weight at study initiation: males 168.2 +/- 6.7 g; females 188.7 +/- 9.7 g;
- Fasting period before study: 16 hours
- Housing: in groups of 5
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: min 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 50 +/- 20%
- Air changes (per hr): no data
- Photoperiod: (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5% at low dose; 25% at dose levels 200, 250, and 313 mg/kg bw
- Amount of vehicle (if gavage): 3.2 / 0.8 / 1.0 / 1.26 mL/kg bw at 160 / 200 /250 / 315 mg/kg bw
- Justification for choice of vehicle: not reported
- Purity: pharmaceutical grade

MAXIMUM DOSE VOLUME APPLIED: 3.2 mL/kg bw

DOSAGE PREPARATION: test substance was suspended in vehicle using a magnetical stirrer

Doses:

160, 200, 250, and 315 mg/kg bw (5 - 25 % in oil)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
-- observations: at 0.1, 0.5, 1, 2, 4, and 6 hours after dosing, then at least once a day during the 14-day observation period
-- weighing: day 0 (before dosing), days 7, 14, and 21 (females only) after dosing
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Probitanalysis

Sex:

male

Dose descriptor:

LD50

Effect level:

258 mg/kg bw

Based on:

test mat.

95% CL:

208 - 330

Remarks on result:

other: Free base. A combined male/female LD50 could not be generated

Sex:

female

Dose descriptor:

LD50

Effect level:

184 mg/kg bw

Based on:

test mat.

95% CL:

139 - 224

Remarks on result:

other: Free base

Mortality:

All deaths occurred within 0.5 to 2 hours after dosing. The LD50 was 258 mg/kg bw (95% CI 208 - 330) for males and 184 mg/kg bw (95% CI 139 - 224) for females.

Clinical signs:

Hunched posture, piloerection, bloody lacrimation, hypoactivity, rattling and forced respiration, at the higher doses (250 and 315 mg/kg bw), and convulsions and trembling in all female groups.

Body weight:

Surviing animals gained approx. 50% weight compared to body weight at study initiation.

Gross pathology:

In deceased animals, dark to black discoloration of the liver, petechial hemorrhage in the gastro-intestinal tract with bloody mucous in the stomach. No changes were noted in surviving animals.

MORTALITY

Dose mg/kg bw	male	female
160		2/5
200	0/5	2/5
250	3/5	5/5
315	4/5	5/5

 

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

N,N-dimethylbutylamine is acutly toxic. Under the conditions of the study the oral LD50 was 258 (males) and 184 (females) mg/kg (gavage, Wistar rats).

Executive summary:

The acute oral toxicity of N,N-dimethylbutylamine (160, 200, 250, 315 mg/kg bw; suspended in sesame oil) was examined in a guideline study (OECD 401) under GLP conditions. Young Wistar rats (5 per dose and sex) were treated and reactions were observed during the 14-day observation period.

Deaths occurred within 2 hours after dosing. The LD₅₀ was 258 mg/kg bw in males and 184 mg/kg bw in females. A combined LD₅₀ value could not be calculated. Signs of corrosion were seen in the gastro-intestinal tract of victims but not in animals that were sacrificed at the end of the observation period (Markert and Weigand, 1985)

 

Deviations from the test guideline include the use of a vehicle (sesame oil) instead of water. The dose volume varied largely across groups (0.8 to 3.2 mL/kg bw) and exceeded the recommended volume (1.0 mL/kg bw; OECD 401) in the low dose groups. The study is, however, considered to be valid and suitable for assessment, taking into consideration the lower LD₅₀ value (184 mg/kg bw) for both male and female rats.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

184 mg/kg bw

Quality of whole database:

Good and suitable for assessment.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

Low but suitable for assessment. 2 mg/L < LC50 < 200 mg/L

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23.07.1985 - 12.08.1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: A. Tuck & Sons Ltd, Battlesbridge, Essex, UK
- Age at study initiation: 10 - 14 weeks
- Weight at study initiation: males 223-258 g; females 190- 207 g
- Housing: individually during the 24 h exposure period and then in groups of 5 by sex for the remainder of of the study
- Diet: standard laboratory rodent diet ad libitum
- Water: ad libitum
- Acclimation period: min 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/-2°C
- Humidity: 60-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 6x12 cm
- % coverage: 10%
- Type of wrap if used: a patch of surgical gauze was held in palce with a strip of elastic adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing: yes; with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied: 2000 mg/kg bw; dose volume 2.78 mL/kg bw
- Constant volume or concentration used: na.a.; one dose only

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

10

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
-- observations: 0.5, 1, 2, 3, 4, and 5 hours following dosing, and then at least one per day
--weighing: on days 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Statistics:

not needed

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mL/kg bw

Based on:

test mat.

Remarks on result:

other: free base

Mortality:

No deaths occurred in the rangefinding or in the main study (i.e. 0 deaths in 14 exposed animals)

Clinical signs:

None of the rats showed clinical signs as repsonse to treatment.

Body weight:

Ther was no toxicologically significant effect on body weight in any rat.

Gross pathology:

No findings in final necropsies in any rat.

Other findings:

No local effects were reported.

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: other: lack of acute (systemic) toxicity; local skin effects (corrosion) was not reported but must be taken into consideration

Conclusions:

The dermal LD50 was >2000 mg/kg bw in the rat.

Executive summary:

The acute dermal toxicity of N,N-dimethylbutylamine (2000 mg/kg bw; free base) was examined in a rat study (5 male and female Sprague Dawley rats) that was conducted according to OECD 402 and under GLP conditions. There were no deaths or clinical signs of toxicity including body weight in any of the rats within the 14-day observation period. Local skin effects were not reported but must be assumed because of the corrosivity of the free base. Thus the dermal LD50 in the rat was >2000 mg/kg bw in this study (Hewitt and Collier,1985).

 

This study is considered to be valid and suitable for assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Suitable for assessment.

Additional information

The pH-value of N,N-dimethylbutylamine is considered to be >11.5 (see also section 4.20 of this dossier). According to OECD 404 (adopted 2002) the test substance is therefore considered to be corrosive to the intact skin and classification is proposed accordingly. In accordance with EC/1907/2006, No. 8.5 column 2, testing of substances that are corrosive to the skin for the acute toxicity endpoints is not needed. However, valid studies exist and can be taken into consideration whereas new studies are not required.

The substance was highly corrosive to the skin in-vivo and produced irreversible skin lesions within 3 minutes, i.e. the consideration based on the pKa value was correct. Outlines of the most valid available acute toxicity studies are given below. It should be noted that only the free base is corrosive, whereas the salt is generally not corrosive and consequently much less toxic. The studies below were all conducted with the free base.

Acute oral toxicity

The acute oral toxicity of N,N-dimethylbutylamine (160, 200, 250, 315 mg/kg bw; suspended in sesame oil) was examined in a guideline study (OECD 401) under GLP conditions. Young Wistar rats (5 per dose and sex) were treated and reactions were observed during the 14-day observation period.

Deaths occurred within 2 hours after dosing. The LD₅₀ was 258 mg/kg bw in males and 184 mg/kg bw in females. A combined LD₅₀ value could not be calculated.Signs of corrosion were seen in the gastro-intestinal tract of victims but not in animals that were sacrificed at the end of the observation period (Markert and Weigand, 1985)

 

Deviations from the test guideline include the use of a vehicle (sesame oil) instead of water. The dose volume varied largely across groups (0.8 to 3.2 mL/kg bw) and exceeded the recommended volume (1.0 mL/kg bw; OECD 401) in the low dose groups. The study is, however, considered to be valid and suitable for assessment, taking the lower LD₅₀ value (184 mg/kg bw) for both male and female rats into consideration.

Acute inhalation toxicity

The acute inhalation toxicity was determined in CD1 rats (5 per sex and dose) in a pre-guideline study without monitoring of the test substance concentration. All rats exposed at 2 mg/L survived until the end of the observation period while all rats exposed to nominal 200 mg/L died within 10 minutes after exposure initiation. Clinical signs indicated irritating effects both in the low dose and the high dose group (ocular and nasal discharge, corneal opacity in surviving animals; lung congestion and lung edema in victims). Thus the (LC50_{(4 hrs)} was between 2 mg/L and 200 mg/l in this study (Wazeter and Goldenthal, 1975).

The study does not allow estimating the LC₅₀-value. However, the described signs of toxicity clearly indicate that the primary mode of action is the irritating and corrosive effect of Dimethylbutylamine. The study is therefore considered to be supportive for assessment.

Acute dermal toxicity

The acute dermal toxicity of N,N-dimethylbutylamine (2000 mg/kg bw; free base) was examined in a rat study (5 male and female Sprague Dawley rats) that was conducted according to OECD 402 and under GLP conditions. There were no deaths or clinical signs of toxicity including body weight in any of the rats within the 14-day observation period. Local skin effects were not reported but must be assumed because of the corrosivity of the free base. Thus the dermal LD₅₀ in the rat was >2000 mg/kg bw in this study (Hewitt and Collier,1985). This study is considered to be valid and suitable for assessment.

Justification for selection of acute toxicity – oral endpoint
GLP guideline study: Lowest LD50 value

Justification for selection of acute toxicity – inhalation endpoint
The substance is corrosive to the skin. Results from a screening inhalation study are also available though a LD50-value was not derived.

Justification for selection of acute toxicity – dermal endpoint
The substance is corrosive to the skin. Local effects but no systemic effects were seen up to 2000 mg/kg bw.

Justification for classification or non-classification

Acute toxicity classification according to EC/1272/2008 and 2nd ATP (EC/286/2011 dated 2011 -03 -10) table 3.1.1 is proposed as follows, based on the effect levels described above.

 

Endpoint	Effect level	Category according to EC/286/2011, Table 3.1.1.
Acute oral toxicity	LD50: 184 mg/kg bw	3
Acute inhalation toxicity	LC50: 2 mg/L < LC50 < 200 mg/L	3 (vapour) EU071: corrosion to the respiratory tract
Acute dermal toxicity	LD50 > 2000 mg/kg bw	No classification