NTP Study Reports
Abstract for TR-446 - 1-Trans-Delta-Tetrahydrocannabinol
TR-446
Toxicology and Carcinogenesis Studies of
1-Trans-Delta9-Tetrahydrocannabinol (CAS No. 1972-08-3) in F344 Rats and
B6C3F1 Mice (Gavage Studies)
Chemical Formula: C21H30O2 | - | 3D Structure* |
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*To view structure, download free Chemscape Chime Plug-in |
1-Trans-delta9-tetrahydrocannabinol
(THC) was nominated by the National Cancer Institute to the NTP
for study because it is the major psychoactive component of marijuana
and a widely used Schedule I substance. Male and female F344/N
rats and B6C3F1 mice received THC (97% pure) in corn oil by gavage
for 13 weeks, 13 weeks with a 9-week recovery period, or
2 years. Genetic toxicology studies were conducted in Salmonella
typhimurium, cultured Chinese hamster ovary cells, and mouse
peripheral blood cells.
13-WEEK STUDY IN RATS
Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. Six male and six female rats receiving 500 mg/kg died before the end of the study. The final mean body weights and weight gains of all dosed groups of males and females, except 5 mg/kg females, were significantly lower than those of the controls. Feed consumption by dosed groups was similar to that by controls. Clinical findings observed during the study included lethargy, sensitivity to touch, convulsions, tremors, and aggressiveness. There were no clinical pathology differences considered to be directly related to the administration of THC. The absolute and relative uterus weights of 50, 150, and 500 mg/kg females were significantly lower than those of the controls. Treatment-related multifocal atrophy was observed in the testes of 150 and 500 mg/kg males; uterine and ovarian hypoplasia observed in 150 and 500 mg/kg females was also considered to be related to THC administration. Based on final mean body weights and mortality observed in the 13-week study, doses selected for the 2-year rat study were 12.5, 25, and 50 mg/kg.
13-WEEK STUDY IN MICE
Groups of 10 male and 10 female
mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight
in corn oil by gavage, 5 days per week for 13 weeks. There were
no treatment-related deaths. The final mean body weight and
weight gain of 500 mg/kg males were significantly lower than those
of the controls. Clinical findings included lethargy and aggressiveness,
and both male and female mice in all dosed groups were easily
startled. There were no absolute or relative organ weight differences,
clinical pathology differences, or microscopic changes observed
that were considered to be related to the administration of THC.
Due to the minimal THC-related effects observed in the 13-week
study, doses selected for the 2-year mouse study were 125,
250, and 500 mg/kg.
13-WEEK WITH 9-WEEK RECOVERY STUDY IN RATS
Groups of 10 male and 10 female
rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight
in corn oil by gavage, 5 days per week for 13 weeks, and then
were allowed to recover during a 9-week treatment-free
period. Five male and eight female 500 mg/kg rats, five male and
two female 150 mg/kg rats, and three male and two female 50 mg/kg
rats died before the end of the study. During the 13-week
dosing period, mean body weight gains of all dosed groups of rats
were lower than those of the controls but returned to normal during
the recovery period. Final mean body weights of all dosed groups
were similar to those of the controls. Clinical findings observed
during the recovery period included sensitivity to touch, convulsions,
and aggressiveness. The absolute right testis weight of 500 mg/kg
males was significantly lower than that of the controls. Treatment-related
multifocal atrophy of the testis was observed in 150 and 500 mg/kg
males. There were no treatment-related lesions observed in
females administered THC.
13-WEEK WITH 9-WEEK RECOVERY STUDY IN MICE
Groups of 10 male and 10 female
mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight
in corn oil by gavage, 5 days per week for 13 weeks, and then
were allowed to recover during a 9-week treatment-free period.
The final mean body weights of all dosed groups were similar to
those of the controls. Clinical findings observed during the study
included lethargy and aggressiveness, and both male and female
mice in all dosed groups were easily startled. The absolute and
relative uterus weights of 150 and 500 mg/kg female mice were
significantly lower than those of the controls, as was the absolute
uterus weight of 50 mg/kg females.
2-YEAR STUDY IN RATS
Groups of 62 vehicle control male
rats, 60 low-dose male rats, 70 mid- and high-dose
male rats, and 60 female rats were administered 0, 12.5, 25, or
50 mg THC/kg body weight in corn oil by gavage for 104 to 105
weeks. Nine or ten animals from each group were evaluated at 15
months.
Survival, Body Weights, and Clinical Findings
Survival of all dosed groups was
generally significantly greater than that of the controls. Mean
body weights of dosed groups of males and females were lower than
those of the controls throughout the study. Convulsions and seizures
were observed in all dosed groups of male and female rats, usually
following dosing or handling.
Hematology and Clinical Chemistry
At the 15-month interim evaluation,
total leukocyte and lymphocyte counts in all dosed groups of females
were greater than those of the controls, and platelet counts in
these groups were lower than that of the controls. Levels of follicle
stimulating and luteinizing hormones in all dosed groups of males
were significantly greater than those of the controls, as was
the serum corticosterone level of 25 mg/kg females.
Pathology Findings
No increased incidences of neoplasms
were considered related to administration of THC. The incidences
of mammary gland fibroadenoma and uterine stromal polyps were
decreased in dosed groups of females, as were the incidences of
pituitary gland adenomas, interstitial cell adenomas of the testis,
and pancreatic adenomas in dosed males.
2-YEAR STUDY IN MICE
Groups of 62 vehicle control male
mice, 60 low-dose male mice, 61 mid-dose male mice,
and 60 high-dose male mice and 60 female mice were administered
0, 125, 250, or 500 mg THC/kg body weight in corn oil by gavage
for 104 to 105 weeks (males) or 105 to 106 weeks (females).
Survival, Body Weights, and Clinical Findings
Survival of 500 mg/kg males was
significantly less than that of the controls; survival of all
other groups of males and of all dosed groups of females was similar
to that of the controls. Mean body weights of all dosed groups
were markedly lower than those of the controls throughout the
study. Clinical findings in dosed groups included hyperactivity,
convulsions, and seizures which occurred following dosing or handling.
Hematology
At the 15-month interim evaluation,
total leukocyte and lymphocyte counts in all dosed groups of males
were significantly lower than those of the controls.
Pathology Findings
Increased incidences of thyroid
gland follicular cell adenoma occurred in 125 mg/kg males and
females, but the increase was not dose-related. Increased
incidences of thyroid gland follicular cell hyperplasia occurred
in all dosed groups of males and females. Increased incidences
of forestomach hyperplasia and ulcers occurred in all groups of
males administered THC. Incidences of hepatocellular adenoma and
of hepatocellular adenoma or carcinoma (combined) occurred with
a significant negative trend in male and female mice, as did incidences
of eosinophilic foci and fatty change in the liver.
GENETIC TOXICOLOGY
THC was not mutagenic in Salmonella
typhimurium strains TA97, TA98, TA100, or TA1535 with or without
rat and hamster liver S9 fractions. In cultured Chinese hamster
ovary cells, THC induced sister chromatid exchanges at the highest
dose tested in the presence of S9; at this dose level, cell cycle
delay indicative of toxicity was observed. THC did not induce
chromosomal aberrations in cultured Chinese hamster ovary cells
with or without S9 metabolic activation enzymes. In vivo, no
increase in the frequency of micronucleated erythrocytes was observed
in the peripheral blood of male or female mice administered THC
by gavage for 13 weeks.
CONCLUSIONS
Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 1-trans-delta9-tetrahydrocannabinol in male or female F344/N rats administered 12.5, 25, or 50 mg/kg. There was equivocal evidence of carcinogenic activity of THC in male and female B6C3F1 mice based on the increased incidences of thyroid gland follicular cell adenomas in 125 mg/kg groups.
Increased incidences of thyroid gland follicular cell hyperplasia occurred in male and female mice, and increased incidences of hyperplasia and ulcers of the forestomach were observed in male mice.
The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in dosed groups of female rats, as were the incidences of pancreatic adenomas, pituitary gland adenomas, and interstitial cell adenomas of the testis in dosed male rats and liver neoplasms in dosed mice. These decreases were likely related to lower body weights in dosed animals.
Synonyms: 3-Pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6h-dibenzo(b,d)pyran-1-ol; delta1-tetrahydrocannabinol; (-)-delta1-3,4-trans- tetrahydrocannabinol; delta9-tetrahydrocannabinon; THC; delta1-THC; delta9-THC
Report Date: November 1996
Pathology Tables, Survival and Growth Curves from NTP 2-year Studies
Target Organs & Incidences from 2-year Studies
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