Tolylene diisocyanate

トリレンジイソシアナート


[CAS No. 26471-62-5]

Methyl-1,3-phenylene diisocyanate/Toluene diisocyanate

メチル-1,3-フェニレンジイソシアナート/トルエンジイソシアナート

Molecular formula: C9H6N2O2　Molecular weight: 174.16

ABSTRACT

Tolylene diisocyanate was studied for oral toxicity in rats of both sexes in a single dose toxicity test at doses of 0 and 2000 mg/kg. The single dose toxicity test revealed an LD50 value of more than 2000 mg/kg for both sexes.

Tolylene diisocyanate was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 30, 100 and 300 mg/kg.

During the administration period, salivation was observed in both sexes given 100 and 300 mg/kg. Body weight gain tended to be suppressed in males given 100 and 300 mg/kg, but recovered or tended to recover during the recovery period. On hematological examination, changes suggestive of inflammation were found in males given 300 mg/kg on days 29 and 43. On blood chemistry examination, changes suggesting effects on the liver were found in males given 100 and 300 mg/kg and females given 300 mg/kg on day 29 and in males given 300 mg/kg on day 43. Pathological examination revealed changes in the stomach and small intestine in males given 300 mg/kg at necropsy on day 29. With the animals examined on day 29, microscopic changes in lungs were found in males given 100 mg/kg or more and females given 30 mg/kg or more. In the trachea, microscopic changes were found in males and females given 30 mg/kg or more. In glandular stomach, spleen and liver, microscopic changes were found in both males and females given 300 mg/kg. With the animals examined on day 43, no effects of tolylene diisocyanate were detected at necropsy. However, changes in spleen were found in both males and females given 300 mg/kg. The changes in lungs, trachea, stomach, small intestine and liver were considered to be reversible.

The NOEL for repeat dose toxicity is considered to be less than 30 mg/kg/day for both sexes.

Tolylene diisocyanate was mutagenic in Salmonella typhimurium TA100 with an exogenous metabolic activation system.

Tolylene diisocyanate induced structural chromosomal aberrations in CHL/IU cells after 6 hr short-term treatment without S9 mix. Polyploidy was not induced in any treatment group.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:>99 wt%
Test species/strains:Rat/Crj:CD(SD)
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Doses:0, 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
GLP:Yes

　Test results:

No deaths occurred of either sex during the observation period. Hypoactivity was observed in both sexes as an effect of the test substance.
The LD50 values were more than 2000 mg/kg for both sexes.

2. Repeat Dose Toxicity 1)

Purity:More than 99 wt%
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:Guideline for 28-Day Repeated Dose Toxicity Test in Mammalian Species (Chemical Substances Control Law of Japan)
　Route:Oral
　Doses:0(vehicle), 30, 100, 300 mg/kg/day
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
　Administration period:Males and females, 28 days
　Terminal kill:Males and females, on days 29 and 43
GLP:Yes

　Test results:

No deaths occurred in either sex. During the administration period, salivation was observed in both sexes given 100 and 300 mg/kg. Body weight gain tended to be suppressed in males given 100 and 300 mg/kg, but recovered or tended to recover during the recovery period. Neutrophilic leukocytes and reticulocytes were increased, and platelets tended to be increased in males given 300 mg/kg on days 29 and 43 but with tendencies for recovery for leukocytes and platelets on day 43. In females given 300 mg/kg, the reticulocyte rate was increased on day 43. Total protein and albumin were decreased and total cholesterol and ALT were increased in males given 300 mg/kg on day 29. Moreover, total protein demonstrated a tendencies for decrease and ALT was increased in males given 100 mg/kg, while total cholesterol was increased in females given 300 mg/kg. On day 43, ALT was increased in males given 300 mg/kg but the other changes found on day 29 had disappeared. On pathological examination, thickening of the walls of the stomach and small intestine was found at necropsy in males given 300 mg/kg on day 29. With the animals examined on day 29, bronchial pneumonia in lungs was found in males given 300 mg/kg and females given 30 or 100 mg/kg. Regeneration and deciliation of bronchial epithelium in lungs were evident in males given 100 mg/kg or more, and females given 30 mg/kg or more. Regeneration and deciliation in the trachea were found in both males and females given 30 mg/kg or more. Erosion in the glandular stomach was found in both males and females given 300 mg/kg. Pigmentation in the spleen was apparent and fatty change in liver was decreased in both males and females given 300 mg/kg. With examination on day 43, no effects of tolylene diisocyanate were detected at necropsy. However, spleen weights were increased in males given 300 mg/kg. Moreover, pigmentation in spleen was increased in males and females given 300 mg/kg more than in the administration period. Changes in lungs, trachea, stomach, small intestine and liver were considered to be reversible.

The NOEL for repeat dose toxicity is considered to be less than 30 mg/kg/day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.8 %
Test species/strains:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals(Chemical Substances Control Law of Japan) and OECD Test Guideline 471
　Procedures:Pre-incubation method
　Solvent:DMSO
　Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98), Sodium azide (TA1535), 9-Aminoacridine (TA1537) and N-Ethyl-N'-nitro-N-nitrosoguanidine (WP2 uvrA)
+S9 mix; 2-Aminoanthracene (all strains)
　Doses:-S9 mix; 78.1, 156, 313, 625, 1250, 2500 and 5000 μg/plate(TA100 and TA1535)
-S9 mix; 156, 313, 625, 1250, 2500 and 5000 μg/plate(WP2 uvrA)
-S9 mix; 313, 625, 1250, 2500 and 5000 μg/plate(TA98 and TA1537)
+S9 mix; 9.77, 19.5, 39.1, 78.1, 156, 313, 625, 1250, 2500 and 5000 μg/plate(TA100 and TA98)
+S9 mix; 78.1, 156, 313, 625, 1250, 2500 and 5000 μg/plate(TA1535)
+S9 mix; 156, 313, 625, 1250, 2500 and 5000 μg/plate(WP2 uvrA)
+S9 mix; 313, 625, 1250, 2500 and 5000 μg/plate(TA1537)
+S9 mix(additional test I, II and III, 30 % S9 mix); 78.1, 156, 313, 625, 1250, 2500 and 5000 μg/plate(TA100 and TA98)
+S9 mix(additional test IV and V, 30 % S9 mix); 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000 μg/plate(TA100 and TA98)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:2
GLP:Yes

　Test results:

This chemical induced gene mutations in Salmonella typhimurium TA100 with metabolic activation (30 % S9). Toxicity was observed at 5000 μg/plate (TA100, TA1535 and WP2 uvrA) with and without metabolic activation.

Genetic effects:
Salmonella typhimurium TA100
+?-
　Without metabolic activation:[ ][ ][*]
　With metabolic activation:[*][ ][ ]

Salmonella typhimurium TA1535, TA98 and TA1537
+?-
　Without metabolic activation:[ ][ ][*]
　With metabolic activation:[ ][ ][*]

Escherichia coli WP2 uvrA
+?-
　Without metabolic activation:[ ][ ][*]
　With metabolic activation:[ ][ ][*]

3-2. Non-bacterial in vitro test (chromosomal aberration test) 2)

Purity:99.58 %
Type of cell used:Chinese hamster CHL/IU cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemical
(Chemical Substances Control Law of Japan) and
OECD Test Guideline 473
　Solvent:1 % Sodium carboxymethylcellulose solution
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Benzo[a]pyrene
　Doses:-S9 mix(6 hr short-term treatment); 0, 78.1, 156, 313, 625 μg/mL
+S9 mix(6 hr short-term treatment); 0, 625, 1250, 2500, 5000 μg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Structural chromosomal aberrations were induced at 313 and 625 μg/mL after 6 hr short term treatment without S9 mix (10.0 and 13.5 %, respectively). Polyploidy was not induced in any treatment group.

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
　Without metabolic activation:[*][ ][ ][ ][ ][*]
　With metabolic activation:[ ][ ][*][ ][ ][*]

1)The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides(An-pyo Center), 582-2 Arahama, Shioshinden, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393
2)The tests were performed by the Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874