Nitrotoluene

Endpoint summary

Description of key information

There is no acute toxicity study available for nitrotoluene (CAS 1321-12-6), but a read-across can be made from 4 -nitrotoluene (CAS 99-99-0):

LD50, oral, rat: > 2250 mg/kg bw;  
LD50, dermal, rat: > 750 mg/kg bw;
LC50, inhalation, rat: > 4200 mg/m³/1h.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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

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

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-nitrotoluene
- Physical state: solid
- Analytical purity: not reported

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:

polyethylene glycol

Remarks:

Polyethylenglycol 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

Remarks on result:

other: No mortality occured

Mortality:

Deaths did not occur at the doses specified.
See "Remarks on results tables and figures".

Clinical signs:

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 to be r

		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

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 (oral, rat) > 2250 mg/kg bw.

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.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

There is no experimental test data available for nitrotoluene (CAS 1321-12-6), but a read-across can be made from its components. Nitrotoluene (CAS 1321-12-6) is a mixture of mainly 4-nitrotoluene (CAS 99-99-0) and/or 2-nitrotoluene (CAS 88-72-2). In addition, the mixture is containing small amounts of 3-nitrotoluene (CAS 99-08-1). A wealth of data is existing for the hazard assessment of 2- and 4-nitrotoluene, which can be used for the classification of nitrotoluene (CAS 1321-12-6). Key data and classification are derived from the isomer with the most critical hazard identified for each specific end point. The available experimental test data are considered reliable and suitable for the classification of nitrotoluene (CAS 1321-12-6) under Regulation 1272/2008.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 250 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

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

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

see "Any other information on material and method incl. tables"

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

Test type:

other: acute toxicity inhalation study, rats

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Nitrotoluene
- Physical state: solid (yellow crystalline substance)
- Analytical purity: no data

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: air

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Concentrations:

4167 mg/m³ air.

No. of animals per sex per dose:

5

Control animals:

not specified

Sex:

male

Dose descriptor:

LC50

Effect level:

> 4 167 mg/m³ air

Exp. duration:

1 h

Remarks on result:

other: No mortality occurred.

Mortality:

No martality occurred.

Clinical signs:

other: No signs of intoxication during the one hour exposure time or the 7 days post exposure observation period could be observed.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

LC50 (rat, inhaltion, 1h) > 4167 mg/m³ air.

Executive summary:

In an acute inhalation toxicity study male Wistar rats were exposed to the test-substance in a dose of 4167 mg/m³ air.

No signs of intoxication during the one hour exposure time or the 7 days post exposure observation period could be observed.

Therefore the LC 50 was > 4167 mg/m³ air/1h.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

There is no experimental test data available for nitrotoluene (CAS 1321-12-6), but a read-across can be made from its components. Nitrotoluene (CAS 1321-12-6) is a mixture of mainly 4-nitrotoluene (CAS 99-99-0) and/or 2-nitrotoluene (CAS 88-72-2). In addition, the mixture is containing small amounts of 3-nitrotoluene (CAS 99-08-1). A wealth of data is existing for the hazard assessment of 2- and 4-nitrotoluene, which can be used for the classification of nitrotoluene (CAS 1321-12-6). Key data and classification are derived from the isomer with the most critical hazard identified for each specific end point. The available experimental test data are considered reliable and suitable for the classification of nitrotoluene (CAS 1321-12-6) under Regulation 1272/2008.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 851 mg/m³ air

Exp. duration:

4 h

Remarks on result:

other: No mortality occurred.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

Method: other: 5 rats/sex/dose group, 1 dose only as 30 % emulsion covered by aluminium foil fixed by broad stripes of adhesive plaster to back and belly for a 24 hour-exposure period: cleaning with soap and water, observation period: 1 week

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

Test type:

other: Acute dermal toxicity study in rats

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Nitrotoluene
- Physical state: solid (yellow crystal)
- Analytical purity: no data

Species:

rat

Strain:

Wistar

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

polyethylene glycol

Remarks:

polyethylene glycol 400

Duration of exposure:

24 h

Doses:

750 mg/kg bw in polyethylene glycol 400

No. of animals per sex per dose:

10

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 750 mg/kg bw

Remarks on result:

other: No mortality occurred.

Mortality:

No mortalities could be observed.

Clinical signs:

other: After 18 hours after application of the test substance a decrease of general behavior could be observed in the animals. This condition persisted 5 days.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

LD50 (dermal, rat, occlusive, 24h) >750 mg/kg bw.

Executive summary:

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.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

There is no experimental test data available for nitrotoluene (CAS 1321-12-6), but a read-across can be made from its components. Nitrotoluene (CAS 1321-12-6) is a mixture of mainly 4-nitrotoluene (CAS 99-99-0) and/or 2-nitrotoluene (CAS 88-72-2). In addition, the mixture is containing small amounts of 3-nitrotoluene (CAS 99-08-1). A wealth of data is existing for the hazard assessment of 2- and 4-nitrotoluene, which can be used for the classification of nitrotoluene (CAS 1321-12-6). Key data and classification are derived from the isomer with the most critical hazard identified for each specific end point. The available experimental test data are considered reliable and suitable for the classification of nitrotoluene (CAS 1321-12-6) under Regulation 1272/2008.

Reason / purpose for cross-reference:

read-across source

Sex:

female

Dose descriptor:

LD50

Effect level:

> 20 000 mg/kg bw

Remarks on result:

other: No mortality occurred.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Mononitrotoluene is a mixture of mainly 4-nitrotoluene (CAS 99-99-0) and/or 2-nitrotoluene (CAS 88-72-2). In addition the mixture is containing small amounts of 3-nitrotoluene (CAS 99-08-1). A wealth of data is existing for the hazard assessment of 2- and 4-nitrotoluene. Key data and classification is derived from the isomer with the most critical hazard identified for each specific end point. For completeness key data of the other isomer is added as supporting information, if available.

Regarding acute toxicity classification is driven by 4-nitrotoluene.

Acute Toxicity

Oral

Groups of rats received different doses of 4-nitrotoluene ranging from 100 to 2250 mg/kg bw in polyethylene glycol 400. The LD50 was determined as > 2250 mg/kg bw (Bayer AG, 1976).

Similar oral toxicity was observed with 2 -nitrotoluene e.g. oral LD50 value of 890 mg/kg bw (Vernot et al., 1977) and approx. 2100 mg/kg b.w. (Ciss et al., 1980) in rats. Clinical signs of toxicity were related with methaemoglobin formation.

 

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 et al., 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).

 

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 4167 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 et al., 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: > 2250mg/kg bw; LD50, dermal, rat: > 750 mg/kg bw; LD50, dermal, rabbit: > 20000 mg/kg bw;

LC50, inhalation, rat: > 4167 mg/m³/1h, LC50 inhalation, rat > 851 mg/m³/1h; no information on particle size available).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There is no acute toxicity study available for nitrotoluene (CAS 1321-12-6), but a read-across can be made from 4-nitrotoluene (CAS 99-99-0). Like other nitrotoluenes, a primary toxic effect of 4-nitrotoluene is methaemoglobin formation. Taking into account that humans are much more sensitive to methaemoglobin producing substances than rats, 4-nitrotoluene is classified for acute oral toxicity Cat. 3 (H301: Toxic if swallowed.), acute inhalation toxicity Cat. 3 (H331: Toxic if inhaled.) and acute dermal toxicity Cat. 3 (H311: Toxic in contact with skin.) under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.

Furthermore, 4-nitrotoluene (CAS 99-99-0) is included in Annex VI of Regulation (EC) No. 1272/2008 with the following classification:

• Acute toxicity - oral Cat. 3 (H301: toxic if swallowed)
• Acute toxicity - dermal Cat. 3 (H311: toxic in contact with skin)
• Acute toxicity - inhalation Cat 3 (H331: toxic if inhaled).

Therefore, nitrotoluene (CAS 1321-12-6) is also classified for acute oral, acute dermal and acute inhalation toxicity Cat. 3 (H301, H311, H331).