Styrene-acrylonitrile trimer (SAN Trimer) is a mixture of isomers formed by the condensation of two moles of acrylonitrile and one mole of styrene and has a molecular weight of 210. The mixture is composed of two structural forms: 4-cyano-1,2,3,4-tetrahydro-a-methyl-1-naphthaleneacetonitrile (THNA, CAS No. 57964-39-3) and 4-cyano-1,2,3,4-tetrahydro-1-naphthalenepropionitrile (THNP, CAS No. 57964-40-6).
SAN Trimer is a by-product of the production of acrylonitrile styrene plastics and is created in specific manufacturing processes for polymers of acrylonitrile and styrene. In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress.
Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats.
Rare neoplasms were present in the central nervous system of male and female rats. In the original evaluation, the 800 and 1,600 ppm groups of male rats each had one astrocytoma and one granular cell tumor in the brain. Also in the brain, one 400 ppm female had a granular cell tumor and one control, one 400 ppm, and one 800 ppm female had a mixed cell glioma. In the spinal cord, one astrocytoma was noted in a 1,600 ppm male in the original evaluation. In the expanded review of the spinal cord, one granular cell tumor was found in a 400 ppm male and one meningioma was found in an 800 ppm female.
There were statistically significant increases in the incidence of spinal nerve root degeneration in 1,600 ppm males and the incidences of sciatic nerve degeneration in 800 and 1,600 ppm females. More importantly, there were increases in the severities of both nerve lesions in males and in the severity of spinal nerve root degeneration in females.
The incidences of bone marrow hyperplasia were significantly increased in 1,600 ppm males and females and 800 ppm females. Incidences of bone marrow granulomatous inflammation were increased in 1,600 ppm males and 800 and 1,600 ppm females, and the increase in the 800 ppm females was significant. Because this lesion is very rare and did not occur in control animals, it should be considered biologically significant. In the liver, the incidence of eosinophilic focus was significantly increased in 1,600 ppm males and the incidences of mixed cell focus were significantly increased in 400 and 1,600 ppm males. Incidences of mixed cell focus were increased in the liver of all exposed groups of females, and the increase was significant in the 1,600 ppm group. The incidence of transitional epithelial hyperplasia of the urinary bladder in 1,600 ppm females was significantly greater than that in the controls.
There were significant decreases in the incidences of pituitary gland pars distalis adenoma in 1,600 ppm males and females, and the incidences in both sexes occurred with negative trends. The incidences of mammary gland fibroadenoma occurred in females with a negative trend, and the incidences in 800 and 1,600 ppm females were significantly less than that in the control group. The incidences of mononuclear cell leukemia in all exposed groups of males and females were significantly less than those in the controls.
In vivo, however, results of a comet assay indicated significantly increased levels of DNA damage in brain cells of male and female juvenile rats following administration of SAN Trimer (Batch 3) by oral gavage. Dose-related increases in DNA damage in liver cells of these rats were also observed, but the increases were smaller than those observed in brain cells and were judged to be equivocal in both males and females. Indications of DNA damage following exposure to SAN Trimer were also seen in leukocytes of male and female rats. Increases in male rats were significant, but in females, observed levels of DNA damage did not correlate with dose. Therefore, the results were judged to be positive in males and equivocal in females. In addition to the positive comet assay results, significant increases in the frequencies of micronucleated reticulocytes were observed in peripheral blood of male and female juvenile rats dosed with SAN Trimer.
Exposure to SAN Trimer resulted in increased incidences and/or severities of peripheral nerve degeneration in male and female F344/N rats, increased incidences of nonneoplastic lesions of the bone marrow and liver in male and female F344/N rats, and of nonneoplastic urinary bladder lesions in female F344/N rats.
The incidences of pituitary gland adenoma and mononuclear cell leukemia in male and female F344/N rats and mammary gland fibroadenoma in female F344/N rats were decreased.
|Concentrations in feed||0, 400, 800, or 1,600 ppm||0, 400, 800, or 1,600 ppm|
|Body weights||1,600 ppm group more than 10% less than the control group after week 1||800 and 1,600 ppm groups were more than 10% less than the control group after weeks 41 and 13, respectively|
|Survival rates||36/50, 39/50, 39/50, 44/50||41/50, 38/50, 37/50, 46/50|
|Nonneoplastic effects||Spinal nerve roots: nerve fiber degeneration (34/47, 37/48, 37/50, 43/50)|
Sciatic nerve: nerve fiber degeneration (37/50, 40/50, 41/50, 43/50)
Bone marrow: hyperplasia (24/50, 24/50, 24/50, 37/50); granulomatous inflammation (0/50, 0/50, 0/50, 3/50)
Liver: eosinophilic focus (17/50, 19/50, 22/50, 33/50); mixed cell focus (6/50, 19/50, 12/50, 20/50)
|Sciatic nerve: nerve fiber degeneration (28/49, 35/49, 43/49, 40/50)|
Bone marrow: hyperplasia (16/50, 25/50, 25/50, 38/50); granulomatous inflammation (0/50, 0/50, 6/50, 2/50)
Liver: mixed cell focus (4/50, 8/50, 7/50, 13/50)
Urinary bladder: transitional epithelium hyperplasia (1/50, 0/50, 0/50, 12/50)
|Decreased incidences||Pituitary gland (pars distalis): adenoma (16/50, 10/50, 13/50, 4/50)|
Mononuclear cell leukemia: (15/50, 7/50, 5/50, 3/50)
|Pituitary gland (pars distalis): adenoma (22/50, 12/50, 19/50, 9/50)|
Mammary gland: fibroadenoma (36/50, 31/50, 26/50, 20/50)
Mononuclear cell leukemia: (13/50, 2/50, 3/50, 2/50)
|Level of evidence of carcinogenic activity||No evidence||No evidence|
|Bacterial gene mutations:||Negative in Salmonella typhimurium strains TA98 and TA100 and in Escherichia coli strain WP2 uvrA/pKM101 with and without S9|
|DNA damage in juvenile rats||Positive in brain cells (males and females) and in leukocytes (males); equivocal in liver (males and females) and in leukocytes (females)|
Rat peripheral blood in vivo:
|Positive in males and females|
Date: July 2012