4-nitrotoluene

Endpoint summary

Description of key information

Acute oral toxicity: LD₅₀, oral, rat: > 2250 mg/kg bw (key, rel.2, OECD 401 eq, pre-GLP);
Acute dermal toxicity: LD₅₀, dermal, rat: > 750 mg/kg bw; LD₅₀, dermal, rabbit: > 20,000 mg/kg bw
Acute inhalation toxicity: LC₅₀, inhalation, rat: > 851 mg/m³/4h

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:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given (No OECD guideline or GLP defined; no necropsy and no histopathological examinations were performed)

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. Animals were not fasted before the treatment. Enviromental conditions not reported. Acclimation period not reported. Body weights not reported. No necropsy and no histopathological examinations were performed

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:

other: Wistar-II-R

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 160-245 g
- Housing: animals were housed in Makrolon cages, type 3
- Diet (e.g. ad libitum): Altromin-Standarddiät (Altromin GmbH, Lage/Lippe, Germany) ad libitum
- Water (e.g. ad libitum): ad libitum

Route of administration:

oral: gavage

Vehicle:

other: Polyethylene glycol 400

Doses:

100, 250, 500, 1000, 2250 mg/kg bw

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
- Other examinations performed: clinical signs

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 250 mg/kg bw

Mortality:

see "Remarks on results tables and figures"

Clinical signs:

other: other: Symptoms of poisoning began in rat from 4 to 40 minutes after application in the form of disordered breathing and a reduced general condition. The respiratory disturbances were observed until 3 days after application, and the general condition was

		Symptoms of poisoning		Appereance ofdeath
Dosis mg/kg	Toxicological results	Start	End
Male rats
100	0/0/15	-	-	-
250	0/15/15	29´	2d	-
500	0/15/15	21´	4d	-
1000	0/15/15	18´	4d	-
2250	0/15/15	4´	6d	-
Female rats
100	0/0/15	-	-	-
250	0/15/15	40´	3d	-
500	0/15/15	35´	4d	-
1000	0/15/15	20´	5d	-
2250	0/15/15	12´	5d	-

 

In this table in the column "Toxicological results" the numbers have the following meaning:

1^stnumber= amount of dead animals

2^ndnumber = amount of animals with symptoms

3^rdnumber = amount of animals used

Executive summary:

In an acute oral toxicity study male rats received the test substance in a dose of 100, 250, 500, 1000 or 2250 mg/kg bw in Polyethylenglycol 400. Symptoms of poisoning began in rat from 4 to 40 minutes after application in the form of disordered breathing and a reduced general condition. The respiratory disturbances were observed until 3 days after application, and the general condition was to be reduced to 6 days. No mortalities were observed. Therefore the LD 50 was >2250 mg/kg bw (Bayer AG, 1976).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 250 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

OECD SIDS 2003

 

Acute Toxicity

 

 Oral

Groups of rats received different doses of 4-nitrotoluene ranging from 100 to 2,250 mg/kg bw in polyethylene glycol 400. The LD50 was determined as > 2,250 mg/kg bw (Bayer AG, 1976). In other rat studies, in which 4-nitrotoluene was administered in 1% aqueous methylcellulose, an LD50 value of 3,200 mg/kg bw was found in females, and a value of 4,700 mg/kg bw in males (Ciss, 1978; Ciss et al., 1980b). Clinical signs included poor condition, tachypnea, somnolence, atony, convulsions and wheezing for up to 24 hours. Survivors appeared normal one week after administration of the test substance. In a further study, an LD50 of 2,144 mg/kg bw was determined in male rats, with cyanogenic effects reported at 3,400 mg/kg bw and above (DuPont Chem, 1972).

 

Dermal

Neat 4-nitrotoluene (up to 20,000 mg/kg bw) was applied to the clipped back of 3 rabbits and kept in place by occlusive dressing for 24 hours. No rabbit died. No local or systemic effects were reported during treatment or after removal of the dressing and the following 14-day period (Kinkead, 1977). When applied as an emulsion in polyethylene glycol 400 at a dose level of 750 mg/kg bw to the back of 5 rats/sex/group, no deaths during the 24 hour treatment period and during the one week observation period were noted, but the rats showed poor general condition from 18 hours post application up to 4 days after application (Bayer AG, 1976). In a poorly documented study with rats, application of up to 16,000 mg/kg bw caused methemoglobinemia of up to 25 % within 72 hours which was reported to be reversible; no deaths occurred. No further details were described (Sisa et al., 1959).

 

Inhalation

Five male rats and 10 male mice were exposed to 4-nitrotoluene dust for one hour and then observed for 7 days to determine LC50-values. At the highest exposure level of 4,167 mg/m³, no animal died and no signs of intoxication were noted during or post exposure (Bayer AG, 1976). In other studies 10 rats and 10 mice were exposed to an atmosphere essentially saturated with 4-

nitrotoluene for four hours (rat: 152 ppm = 851 mg/m³; mouse: 228 ppm = 1,277 mg/m³). No death occurred during exposure or during the subsequent 14 day post exposure observation period. No lesions attributable to exposure could be discovered during gross pathological evaluation, neither in rats nor in mice (Kinkead, 1977). For none of the studies was information on particle size available.

 

Conclusion

4-Nitrotoluene is a methemoglobin forming chemical. Tachypnea, wheezing, somnolence and cyanosis were the predominant clinical signs following oral doses near to or exceeding the LD50 value. Methemoglobinemia was reported in rats after dermal exposure to high dose levels (LD50, oral, rat: 2,144 - 4,700 mg/kg bw; LD50, dermal, rat: > 750 mg/kg bw; LD50, dermal, rabbit: > 20,000 mg/kg bw; LC50, inhalation, rat: > 851 mg/m³/4h; no information on particle size available).

 

Justification for classification or non-classification

Harmonised classification:

The substance is classified in Category 3 (H301 – Toxic if swallowed) according to the Regulation (EC) No. 1272/2008 (CLP). 

The substance is classified in Category 3 (H311 – Toxic in contact with skin) according to the Regulation (EC) No. 1272/2008 (CLP). 

The substance is classified in Category 3 (H331 – Toxic if inhaled) according to the Regulation (EC) No. 1272/2008 (CLP). 

 

Self-Classification:

The oral LD₅₀ value of the test item was established to exceed 2250 mg/kg body weight. Based on the conditions of this test, the test item would not be classified for acute oral toxicity, in accordance with CLP Regulation No 1272/2008 on Classification, Labelling and Packaging of Substances and Mixtures. Since p-nitrotoluene has a harmonised classification, the substance will be classified accordingly even though the LD₅₀ suggest otherwise.