3-nitrotoluene

Endpoint summary

Description of key information

Acute oral toxicity, OECD 401 eq. (Key, rel.2, Bayer, 1976), LD_50: 2121 mg/kg bw (male) / 1784 mg/kg bw (female)

Acute inhalation toxicity, OECD 403 eq. (rel.2, Kinkead, 1977), LD₅₀: > 880 mg/m³

Acute dermal toxicity, OECD 402 eq. (rel.2, Bayer, 1976), LD₅₀: > 1157 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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication/study report which meets basic scientific principles

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

No GLP study. Analytical purity not reported. Enviromental conditions not reported. No fasting period before treatment. Acclimation period not reported. Body weights not reported

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

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
- Weight at study initiation: 165-265 g
- Fasting period before study: no
- Housing: Makrolon cages type III
- Diet (e.g. ad libitum): Altromin Standard diet (Altromin GmbH, Lage/Lippe; Germany), ad libitum
- Water (e.g. ad libitum):ad libitum

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Justification for choice of vehicle:
- Lot/batch no. (if required):
- Purity:


MAXIMUM DOSE VOLUME APPLIED:


DOSAGE PREPARATION (if unusual):


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:

Doses:

250, 500, 1000, 1500, 2000, 2500, 3500 mg/kg

No. of animals per sex per dose:

15

Control animals:

other: not applicable

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: not reported
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, grosspathology

Statistics:

LD50 was calculated with the Probit Analysis (Fink et al, Methods of information in medicine 5, 19, 1966)

Sex:

male

Dose descriptor:

LD50

Effect level:

2 121 mg/kg bw

95% CL:

1 924 - 2 338

Sex:

female

Dose descriptor:

LD50

Effect level:

1 784 mg/kg bw

95% CL:

1 616 - 1 982

Mortality:

Mortality of the animals appeared within 24 hours after the treatment until 4 days

Clinical signs:

other: The poisoning symptoms appeared already between 2 and 35 minutes after dosing in form of sedation, cyanosis, reduction of general conditions. Sedation and cyanosis were observed until 3 days after the application. The decrease of the general conditions oc

Gross pathology:

Liver appeared spotted

		Symptoms of poisoning		Appereance of death
Dosis mg/kg	Toxicologicalresults	Start	End
Male rats
250	0/0/15	-	-	-
500	0/15/15	25´	2d	-
1000	0/15/15	15´	4d	-
1500	1/15/15	13´	5d	2d
2000	5/15/15	7´	6d	1-4d
2500	12/15/15	4´	6d	1-2d
3500	15/15/15	2´	-	1-2d
Female rats
250	0/0/15	-	-	-
500	0/15/15	35´	2d	-
1000	0/15/15	24´	4d	-
1250	1/15/15	14´	4d	3d
1500	5/15/15	10´	5d	2-4d
2000	10/15/15	10´	6d	1-2d
2500	13/15/15	9´	6d	1-3d
3500	15/15/15	5´	-	1-2d

 

Executive summary:

Bayer AG: Gröning & Kimmerle (1976):

The acute oral toxicity of 3-nitrotoluene was investigated on male and female rats, in a pre-GLP study equivalent or similar to OECD 401. 

 

Clinical observations appeared between 2 and 35 minutes after dosing in form of sedation, cyanosis, reduction of general conditions. Sedation and cyanosis were observed until 3 days after the application. A decrease of the general conditions occured from 2 to 6 days after the application. Deaths occurred within 24 hours to 4 days after application. At necropsy, the liver of mortalities was mottled in appearance.

 

After observation period of 14 days the LD₅₀ was calculated as:

• 2121 mg/kg bw (95% CL:1924 -2338) in male rats


• 1784 (95% CL: 1616 -1982), in female rats.

 

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 1 784 mg/kg bw

Quality of whole database:

A Klimisch rating of 2 has been applied. The study is pre-GLP but conducted to a relevant OECD test guideline using well-defined scientific procedures, therefore fulfilling the endpoint requirement.

Additional information

Acute Oral toxicity:

 

With a single oral administration to rats, the following symptoms occurred at doses of 500 mg/kg bw and above: sedation, cyanosis, impairment of the general condition and patchy livers in animals found dead [Gröning et al. 1976, Bayer AG. Unpublished report]. Doses ranging from 1000 to 4000 mg/kg bw also caused excitation, increased breathing frequency, short-term convulsions, debility and atony [Ciss et al., 1980. Dakar Medical 25:303-311; Ciss et al., 1978. Dissertation. Unversite´ Rene´Descartes de Paris, Serie E No. 17].

 

Acute Dermal toxicity:

 

In rats of both sexes a single dermal application of 1157 mg m-nitrotoluene/kg bw (exposure time: 24 hours) caused an impairment of general condition; no deaths occurred [Gröning et al. 1976.Bayer AG. Unpublished report]. A rabbit weighing 2.175 kg, treated with a single dermal application of 1 mL m-nitrotoluene (532 mg/kg bw) to the skin of the back, flanks and belly, exhibited a slightly increased breathing rate. The animal behaved normally during the 50-hour exposure period [Dambleff J: Beiträge zur Kenntnis der giftigen Wirkung nitrierter Benzole und Toluole insbesonder von der Haut aus. Dissertation, Würzburg, 1908].

 

Acute Inhalation toxicity: 

 

A 1-hour inhalation of m-nitrotoluene vapour (calculated concentration: 2417 mg/m³) was tolerated without symptoms by male rats and mice [Gröning et al. 1976.Bayer AG.Unpublished report].

Study on Methemoglobin formation: Two cats received a single intra peritoneal injection of 100 mg m-nitroroluene/ kg bw, maximum methemoglobin levels ranging from 9 to 52% were reached after 4 to 8 hours; the values differed greatly between individual animals and no dose dependency was seen. More Heinz bodies were also detected that with o-nitrotoluene. All the treated animals displayed reduced blood-clotting ability. At doses of 300 mg/kg bw and above, the following effects were observed: cramps in the extremities, trembling, baring of the teeth, breathing disorders, dilation of pupils, rigidity of the entire musculature on the day of administration and muscular laxity on the following day [Von Bredow et al., Naunyn-Schmiedeberg´s Arch. Exp. Path. Pharmak. 200, 335-355. 1942-1943].

Justification for classification or non-classification

Harmonised classification:

The substance does not currently have a harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP). 

 

Self-Classification:

The oral LD₅₀ value of the test item was established to exceed 2000 mg/kg body weight in male animals, but to be 1784 mg/kg bw in female animals. Based on the conditions of this test, the test item would be classified as acute toxic category 4, in accordance with CLP Regulation No 1272/2008 on Classification, Labelling and Packaging of Substances and Mixtures. Due to the impurity p-nitrotoluene (CAS 99-99-0; 0.2%; according to Table 3.1, annex VI of regulation No 1272/2008 Index No: 609-006-00-3) this substance will also be classified as Acute Tox Category 3.