p-tert-Butyltoluene

ρ-tert-ブチルトルエン

[CAS No. 98-51-1]

4-tert-Butyltoluene/1-Methyl-4-tert-butylbenzene

4-tert-ブチルトルエン/1-メチル-4-tert-ブチルベンゼン

Molecular formula: C₁₁H₁₆　Molecular weight: 148.24

ABSTRACT

Neither deaths nor moribund animals were noted in either sex in any group. No changes attributable to the compound administration were noted in general signs or body weights. Food consumption was initially lowered in higher dose groups (15 and 50 mg/kg/day) of both males and females, but subsequently recovered to the similar or even higher levels to those of other groups. Higher water consumption was evident in the males at 15 and 50 mg/kg throughout the administration period and in females at 50 mg/kg. At the end of administration the hematological examination revealed shortening of APTT in the males at 5 mg/kg and higher doses. In the blood chemical analysis, plasma total protein and albumin decreased slightly but significantly at 15 and 50 mg/kg in males and females. AST, urea nitrogen, and inorganic phosphorus were noted to be higher in the males at 5 mg/kg and above. Total bilirubin, urea nitrogen, and inorganic phosphorus were noted to be higher in the males at 5, 15 and 50 mg/kg/day. These changes in hematology and blood chemistry recovered after 10 days of chemical withdrawal. On necropsy at the termination of 28-day administration a dose-related increase in liver weights was noted in males and females of 15 and 50 mg/kg day groups. Weights of testis and epididymis were decreased in 50 mg/kg but not in 15 mg/kg/day group. Histopathological examination revealed hypertrophy of periportal hepatocytes in the males and females at 50 mg/kg and atrophy of seminiferous tubules and hyperplasia of Leydig cells and decrease in sperm in the epididymides. On the termination of recovery period, atrophy of seminiferous tubules in the testes and decrease in sperm in the epididymides were also noted in the males given 50 mg/kg.

The NOELs for 28-day repeated dose toxicity of p-tert-butyltoluene are considered to be 1.5 mg/kg/day in males and 5 mg/kg/day in females.

p-tert-Butyltoluene was studied for oral toxicity in rats of both sexes in an OECD preliminary reproduction toxicity screening test at doses of 0, 1.5, 5, 15, and 50 mg/kg/day.

One male animal given 50 mg/kg and one female animal given 15 mg/kg and 6 females receiving 50 mg/kg died. Hypothermia, decrease in locomotor activity, soiled fur, and reddish urine were noted in these animals. Lower body weights were noted at 15 and 50 mg/kg along with transiently lowered food consumption at 50 mg/kg. On necropsy, atrophy of the testes and epididymides was noted at 15 and 50 mg/kg. Sperm examination revealed lower values for the motility, path velocity, straight line velocity, curilinear velocity, viability, survival, number of sperm, and number of sperm/g of the left caudae epididymidis and higher values for abnormal sperm were noted at 15 and 50 mg/kg. The histopathological examination demonstrated, atrophy of seminiferous tubules of the testes, hyperplasia of Leydig cells, and decrease in sperm in the epididymides at 15 and 50 mg/kg.

The NOELs for repeated dose toxicity are considered to be 5 mg/kg/day for males and 1.5 mg/kg/day for females from this study.

No changes attributable to the compound administration were noted in the frequency of estrus, copulation index, or numbers of days before copulation. The fertility index was lowered at 15 and 50 mg/kg. No changes attributable to the compound administration were noted in the numbers of corpora lutea, or implantation sites, or the implantation rate or gestation index.

The NOELs for reproductive performance are considered to be at 5 mg/kg/day for both sexes.

Number of pups and viability on Day 4 of lactation were decreased in the group given 15 mg/kg/day. The number of stillbirths was higher at 15 mg/kg. No external abnormalities attributable to the compound administration were noted. Pup body weights were lower or tended to be lower in both sexes at 5 and 15 mg/kg on Days 0 and 4 of lactation.

The NOEL for pups is considered to be at 1.5 mg/kg/day.

SUMMARIZED DATA FROM THE STUDIES

1. Repeated Dose Oral Toxicity ¹⁾

Purity	:	95.93 %
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 (gavage)
Dosage	:	0 (vehicle), 1.5, 5, 15, 50 mg/kg
Number of animals/group	:	Males, 12; females, 12
Vehicle	:	Corn oil
Administration period	:	Males and females, 28 days
Terminal killing	:	Males and females, day 29 or 43
GLP	:	Yes

　Test results:

Neither dead nor moribund animals were noted in either sex in any group. No changes attributable to the compound administration were noted in terms of general signs or body weights. Lower food consumption was noted in the 15 mg/kg males and in both sexes given 50 mg/kg. Higher water intake was noted in the males at 15 mg/kg and in both sexes at 50 mg/kg. On urinalysis, a higher urinary volume was noted in the males at 15 mg/kg. Higher values for urinary volume and a tendency for pH lowering were noted in both sexes at 50 mg/kg. Urinary specific gravity and protein were lower or tended to be lower in the males at 50 mg/kg. In the hematological examination, shortened APTT and lower values for fibrinogen concentration were noted in the males at 5 mg/kg. At 15 mg/kg, shortened APTT and lower values for fibrinogen concentration were apparent in the males, and lowering of the fibrinogen concentration was also noted in the females. At 50 mg/kg, lower values for APTT and fibrinogen concentration were noted in the males, and lower values for the fibrinogen concentration and prolonged PT were evident in the females. Blood chemical analysis, revealed lower values for total protein and triglyceride and higher values for AST, urea nitrogen, and inorganic phosphorus in the males at 5 mg/kg. At 15 mg/kg, lower values for total protein, albumin concentration, and triglycerides and higher values for AST, A/G, total bilirubin, urea nitrogen, and inorganic phosphorus were noted in the males, and lower values for total protein, albumin concentration, total cholesterol, triglyceride, and Ca and a higher value for γ-GTP were noted in the females. At 50 mg/kg, lower values for total protein, albumin concentration, total cholesterol, triglyceride, and Na and higher values for AST, A/G, total bilirubin, urea nitrogen, creatinine, and inorganic phosphorus were noted in the males, and lower values for total protein, albumin concentration, triglyceride, K, and Ca, a tendency for total cholesterol to be lower, and higher values of γ-GTP and total bilirubin were noted in the females. On organ weight measurement, at 15 mg/kg, increase of relative liver weights was noted in the males, and higher values for absolute and relative liver weights were apparent for the females. At 50 mg/kg, decrease in absolute testis and epididymis weights and relative testis weights and increase in absolute and relative liver weights were noted in the males, with lower absolute ovary weights and higher absolute liver weights and relative liver, kidney, and adrenal weights evident in the females. In the histopathological examination, the following findings were noted in the males at 50 mg/kg: for the liver, hypertrophy of periportal hepatocytes; for the testes, atrophy of seminiferous tubules and hyperplasia of Leydig cells; and for the epididymides, decrease in sperm. Hypertrophy of periportal hepatocytes in the liver was also noted in the females at 50 mg/kg. At the termination of recovery period, atrophy of seminiferous tubules in the testes and decrease in sperm in the epididymides were still evident in the males which had received 50 mg/kg.

The NOELs for repeated dose toxicity are considered to be at 1.5 mg/kg/day for males and at 5 mg/kg/day for females.

2. Preliminary Reproduction Toxicity ¹⁾

Purity	:	96.44 %
Test Species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 421
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 1.5, 5, 15, 50 mg/kg
Number of animals/group		Males, 12; females, 12
Administration period	:	Males, 50-52 days Females, from 14 days before mating to day 3 of lactation
Terminal killing	:	Males, day 51-53 Females, day 4 of lactation
GLP	:	Yes

　Test results:

<Repeated dose toxicity>

Regarding the males, one animal died given 50 mg/kg. Hypothermia, decrease in locomotor activity, soiled fur, and reddish urine were noted at 50 mg/kg. Lower body weights were noted at 15 and 50 mg/kg. Transient lowering of food consumption was noted at 50 mg/kg. At necropsy, atrophy of the testes and epididymides was noted at 15 and 50 mg/kg. Organ weight measurement revealed the absolute testis and epididymis weights to be or tend to be lower at 15 mg/kg. The absolute and relative testis and epididymis weights were lowered at 50 mg/kg. On sperm examination, decreased values for the motility ratio, path velocity, straight line velocity, curilinear velocity, viability, survivability, number of sperm, and number of sperm/g of the left caudae epididymidis and elevation of the proportion of abnormal sperm were noted at 15 and 50 mg/kg, and a higher value for beat cross frequency was noted at 15 mg/kg. On histopathological examination, atrophy of seminiferous tubules of the testes, hyperplasia of Leydig cells, and decrease in sperm in the epididymides were noted at 15 and 50 mg/kg.

Regarding the females, one animal at 15 mg/kg and 6 animals at 50 mg/kg died. Hypothermia and decrease in locomotor activity were noted at 15 mg/kg, and hypothermia, adoption of a prone position, decrease in locomotor activity, a staggering gait, piloerection, soiled fur, lacrimation, bradypnea, diarrhea, and muscle relaxation were noted at 50 mg/kg. Body weights were lower or tended to be lower at 5 and 15 mg/kg during the pregnancy and lactation periods and were lower at 50 mg/kg before mating. Lowering of food consumption was noted at 5 mg/kg during the lactation period.

The NOELs for repeated dose toxicity are considered to be 5 mg/kg/day for males and 1.5 mg/kg/day for females.

<Reproductive and developmental toxicity>

Regarding reproductive/developmental toxicity, effects on sperm motility, sperm viability, sperm morphology, and the number of sperms were noted at 15 and 50 mg/kg, as described above. On histopathological examination, changes were noted in the testes and epididymides at 15 and 50 mg/kg, as described above. No changes attributable to compound administration were noted in the numbers of estrous cases, copulation index, or number of days before copulation. The fertility index was lowered at 15 and 50 mg/kg. No changes attributable to compound administration were noted at 1.5, 5, or 15 mg/kg in terms of the numbers of corpora lutea, or implantation sites, or the implantation rate. No changes attributable to compound administration were noted at 1.5, 5, or 15 mg/kg regarding the gestation index.

The NOELs for reproductive performance are considered to be at 5 mg/kg/day for both sexes.

Values for the following parameters were lowered or tended to be lower in pups of the 15 mg/kg group: number of pups, number of pups on Day 0 of lactation, the delivery index, birth index, live birth index, number of pups on Day 4 of lactation, and the viability index on Day 4 of lactation. The number of stillbirths tended to be higher at 15 mg/kg. The number of pups on Day 0 of lactation was zero at 50 mg/kg, since no females conceived. No external abnormalities attributable to the compound administration were noted. Pup body weights were lowered or tended to be lower in both sexes at 5 and 15 mg/kg on Days 0 and 4 of lactation.

The NOEL for pups is considered to be at 1.5 mg/kg/day.

1)	The tests were performed by Nihon Bioresearch Inc., 6-104 Majima, Fukuju-cho, Hashima, Gifu, 501-6251, Japan. Tel +81-58-392-6222 Fax +81-58-392-1284