Thiophene was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 25, 100 and 400 mg/kg/day.
With regard to repeat dose toxicity, males receiving 100 mg/kg or more showed leaning after each daily administration, and suppression of food consumption and body weight gain were observed in the 400 mg/kg group. At necropsy after treatment day 42, hypertrophy of hepatocytes, infiltration of macrophages in the central zones, and increase in relative liver weights were observed in the groups given 100 mg/kg or more. In the 400 mg/kg group, necrosis of hepatocytes and homogenous or vesicular cytoplasmic change of hepatocytes in the central zones were observed. In addition, thiophene at 400 mg/kg slightly affected the cerebellum, because pyknosis/necrosis of granular cells in the cerebellum was observed in this group. Decreases in of glucose and ALP and increase in inorganic phosphorus were observed in the 100 mg/kg or more groups.
In the females, leaning was observed after the administration of 100 mg/kg or more, and suppression of body weight gain and food consumption was noted during the early administration period in the 400 mg/kg group. At necropsy, hepatic changes were observed in the groups treated with 100 mg/kg or more, and increase in relative liver weight was apparent in the 400 mg/kg group. In addition, necrosis of cerebellar granular cells was observed in the groups given 100 mg/kg or more. In the 400 mg/kg group, dilatation and edema of ventricles were observed. Relative kidney weights were increased, and vacuolar degeneration of the tubular epithelium was observed in the groups given 100 mg/kg or more.
With regard to the reproductive/developmental toxicity, there were no adverse effects on copulation, ovulation and fertility in any thiophene-treated group. However, abnormal parturition associated with the administration of this compound was found in each group. Most of the dams with changes in the cerebellum in the groups treated with 100 mg/kg or more exhibited abnormal lactation. No adverse effects on pup viability on postnatal day 0 or the sex ratio were detected in any thiophene-treated group. In the 400 mg/kg group, pup weights at birth and on postnatal day 4, and viability on postnatal day 4 were decreased. No morphological abnormalities associated with the administration of thiophene were found in any pup.
In conclusion, the NOEL for toxicity of thiophene administered repeatedly under the condition of the present study was suggested to be 25 mg/kg/day for parental animals, and those for reproductive toxicity in males and females were 400 mg/kg/day and 25 mg/kg/day, respectively.
Thiophene was not mutagenic to Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA, with or without an exogeneous metabolic activation system.
Thiophene did not induce structural chromosomal aberrations and polyploidy in CHL/IU cells up to the limit concentration of 10 mM, in the absence or presence of an exogenous metabolic activation system.
| Purity | : | 98.0 wt% |
| Test species/strain | : | Rat/Crj:CD (Sprague-Dawley) |
| Test method | : | OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test |
| Route | : | Oral (Gavage) |
| Doses | : | 25, 100, 400 mg/kg/day |
| Number of animals/group | : | Males, 13; Females, 13 |
| Vehicle | : | Corn oil |
| Administration period | : | Males, 42 days, Females, from 14 days prior to mating to Day 3 of lactation |
| Terminal killing | : | Males, day 43, Females, day 4 of lactation |
| GLP | : | Yes |
Test results:
At the autopsy after treatment day 42, hypertrophy of hepatocytes, infiltration of the macrophages into the central zoned and increased relative liver weights were observed in the groups given 100 mg/kg or more. In the 400 mg/kg group, necrosis of hepatocytes in the central zone, homogenous or vesicular cytoplasmic change of hepatocytes in the central zone were observed as well as increases in the concentrations of plasma bilirubin and total cholesterol and activities of various enzymes (e.g., transaminase) related to hepatic disorders. Thus, hepatic toxicity was noted in the groups given 100 mg/kg or more. In addition, thiophene at the dose level of 400 mg/kg slightly affected the cerebellum, because pyknosis/necrosis of granular cells in the cerebellum was observed in one male in this group. Decreases in the serum concentration of glucose and the activity of ALP and increase in the concentration of inorganic phosphorus were observed in the groups given 100 mg/kg or more. Increased relative kidney weights in the groups given 100 mg/kg or more, and slight increase in eosinophilic bodies in the 400 mg/kg group were also noted. In addition, decreased spleen weights were observed in the 400 mg/kg group, although no abnormalities in this organ were noted in the histopathological, hematological, and blood chemical examinations. No adverse changes were found in other organs in any group, and thiophene at the dose level of 25 mg/kg showed no toxicity in males.
The NOEL for repeat dose toxicity in parent animals of both sexes was suggested to be 25 mg/kg/day.
The NOELs for reproductive/developmental toxicity in males and females are considered to be, respectively, 400 mg/kg/day and 25 mg/kg/day.
| Purity | : | 98 % |
| Test species/strains | : | Salmonella typhimurium TA100, TA1535, TA98, TA1537,
Escherichia coli WP2 uvrA |
| Test methods | : | Guidelines for Screening Mutagenicity Testing of
Chemicals (Japan) and OECD (471 and 472) |
| Procedures | : | Plate incorporation method |
| Solvent | : | DMSO |
| Positive controls | : | -S9 mix, 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, WP2, TA98), Sodium azide (BRTA1535)and 9-Aminoacridine (TA1537),
+S9 mix, 2-Aminoanthracene (five strains) |
| Doses | : | 0, 78.1, 156, 313, 625, 1250, and 2500 μg/plate (TA1537), 0, 156 - 5000 μg/plate (TA100, TA1535, TA98) , 0, 313 - 5000 μg/plate (WP2) on -S9 mix and +S9 mix. |
| S9 | : | Rat liver, induced with phenobarbital and 5,6-benzoflavons |
| Plates/test | : | 3 |
| Number of replicates | : | 2 |
| GLP | : | Yes |
Test results:
Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
| + | ? | - | |
| Without metabolic activation: | [ ] | [ ] | [*] |
| With metabolic activation: | [ ] | [ ] | [*] |
Escherichia coli WP2 uvrA
| + | ? | - | |
| Without metabolic activation: | [ ] | [ ] | [*] |
| With metabolic activation: | [ ] | [ ] | [*] |
| Purity | : | 98% |
| Type of cell used | : | Chinese hamster lung (CHL/IU) cells |
| Test method | : | Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) |
| Solvent | : | Dimethylsulfoxide |
| Positive controls | : | -S9 mix, Mitomycin C
+S9 mix, Cyclophosphamide |
| Doses | : | -S9 mix (continuous treatment): 0, 0.21, 0.42, 0.84 mg/ml
-S9 mix (short-term treatment): 0, 0.21, 0.42, 0.84 mg/ml +S9 mix (short-term treatment): 0, 0.21, 0.42, 0.84 mg/ml |
| S-9 | : | Rat liver, induced with phenobarbital and 5,6-benzoflavone |
| Plates/test | : | 2 |
| GLP | : | Yes |
| clastogenicity | polyploidy | |||||
| + | ? | - | + | ? | - | |
| Without metabolic activation: | [ ] | [ ] | [*] | [ ] | [ ] | [*] |
| With metabolic activation: | [ ] | [ ] | [*] | [ ] | [ ] | [*] |
| 1) | The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627 |