Paclitaxel, an antineoplastic agent, was given to Crj: CD (SD) rats of both sexes at 38, 50, 65 and 85 mg/kg by single intravenous administration to investigate its acute toxicity. The results obtained are summarized as follows: 1. Tachypnea and decreased activity with prone position were noted for vehicle and all paclitaxel groups, and alopecia for all paclitaxel groups. 2. Deaths occurred for one out of 5 males and 2 out of 5 females at 85 mg/kg. One female died of respiratory insufficiency induced by vehicle on Day 0. One female and one male died of the systemic toxicity of paclitaxel such as hypoplasia of the bone marrow and lymphoid depletion of lymphatic organs on Days 6 and 12, respectively. 3. On Days 4 and 5, all paclitaxel groups showed decreases of reticulocyte and white blood cell counts, as well as decrease of differential count of neutrophils. These changes were generally recovered by a week after dosing. 4. Histopathological examinations revealed atrophy of the thymic medulla, hypoplasia of the bone marrow and lymphoid depletion of the spleen for a few males at 85 mg/kg, and hypospermatogenesis and tubular atrophy of the testes for all paclitaxel groups. Based on these results, 85 mg/kg of paclitaxel was lethal to rats, and hematopoietic, lymphoid and male reproductive systems were primarily affected under this condition.

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Paclitaxel, an antineoplastic agent, was intravenously given to Crj: CD (SD) rats of both sexes at 0 (saline), 0 (vehicle), 1.0 (low dose), 3.3 (intermediate dose) and l0.0 (high dose) mg/kg at five-day interval over one-month period (6 times in total) to investigate its repeated dose toxicity and the reversibility of toxic effects. The results obtained are summarized as follows: 1. Decreased activity with prone position was observed for high dose and vehicle groups, and alopecia was seen for many high dose rats. Body weight gain and food intake were suppressed for high and intermediate dose groups. No deaths occurred. 2. Red blood cell count, hemoglobin, hematocrit, white blood cell count, relative neutrophil count, platelet count and reticulocyte count were decreased for high dose groups. Red blood cell count was also decreased for intermediate dose groups. 3. Thymic atrophy, splenic hematopoiesis, bone marrow hypoplasia, testicular atrophy with suppression of spermatogenesis and tubular atrophy, and epididymal atrophy were observed for high dose rats. 4. Above-described changes excluding the findings on the testis and epididymis for high dose rats were shown to be generally reversible. Based on these results, the no-toxic effect dose of paclitaxel was estimated to be 1.0 mg/kg in rats under this study condition.

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Paclitaxel, an antineoplastic agent, was intravenously given to Crj: CD (SD) rats of both sexes at 0 (saline), 0 (vehicle), 0.3 (low dose), 1.0 (intermediate dose) and 3.3 (high dose) mg/kg at seven-day interval over a six-month period (total of 27 doses) to investigate its repeated dose toxicity. The results obtained are summarized as follows: 1. No deaths occurred in this study. Vehicle-related salivation was seen for some high dose and vehicle control rats. Soiling of the perigenital region was observed for some high dose females. 2. Red blood cell count, hemoglobin, hematocrit and white blood cell count were decreased for high dose rats. Reticulocyte count was increased and relative neutrophil count was decreased for high dose males. 3. Relative erythroid and myeloid cell count were decreased for high dose rats in bone marrow smear examinations. 4. Bone marrow hypoplasia and splenic hemosiderosis were observed for high dose rats, and thymic atrophy and lymphoid depletion were seen for some high dose males. Based on the these results, the no-toxic effect dose of paclitaxel was estimated to be 1.0 mg/kg in rats under this study condition.

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Paclitaxel, an antineoplastic agent, was administered intravenously to Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg for 63 days prior to mating and during the mating period in males, and for 14 days prior to mating and during the mating period as well as day 0 to day 7 of gestation in females. Results were as follows: 1. Body weight gains were shown a tendency to hasten in vehicle-treated male rats associated with the increased food consumption. However, the vehicle-treated group had no effect in the other parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains accompanied by the decreased food consumption in either male or female rats. 3. Adrenal and ovarian weights were decreased in 1.0 mg/kg dams at term. 4. The fertility indices in both sexes of 1.0 mg/kg were lower than the saline-treated group. However, the copulation indices in both sexes in 1.0 mg/kg rats were comparable to those of the saline-treated group. 5. Decreases in the number of corpora lutea, implantations and live fetuses or increases in the number of empty implantation sites and total embryo-fetal deaths were observed in 1.0 mg/kg dams. However, the fetal weights, crown-rump distances and tail lengths in live fetuses were not affected by paclitaxel treatment. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 0.3 mg/kg/day for parent animals and their fetuses.

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Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.15, 0.3 and 0.6 mg/kg from day 7 to day 17 of gestation. Results were as follows: 1. The ossification of hyoid bodies was retarded in F₁ fetuses by the vehicle. However, the vehicle-treated group had no effect in the other parameters that were measured in this study when compared to the saline-treated group. 2. Body weight gains and food consumption in F₀ dams were not affected by paclitaxel during the gestation and lactation periods. 3. Paclitaxel failed to affect the organ weights in F₀ dams. 4. Paclitaxel did not alter the prenatal development in F₁ fetuses. 5. External, internal and skeletal malformations were not induced by paclitaxel. Further, paclitaxel did not affect the skeletal variations and ossification processes. 6. Paclitaxel did not alter the delivery status of F₀ dams or viability and weaning indices in F₁ pups. 7. The day required for presence of hair was significantly delayed in 0.6 mg/kg F₁ pups at paclitaxel. However, the days required for pinnae detachment, incisor eruption, eye opening, testicular descent and vaginal opening were not affected by paclitaxel. 8. No effects on body weight gains or food consumption were observed in both male and female F₁ rats. 9. Paclitaxel did not alter the developmental behavior, learning ability and memory, spontaneous motor activity or emotionality in F₁ rats. 10. The reproductive performance in both male and female F₁ rats were not affected by paclitaxel. 11. Paclitaxel did not alter the organ weights in both male and female F₁ rats. 12. No influence on prenatal development was observed for F₂ fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 0.6 mg/kg/day and 0.3 mg/kg/day for dams (F₀) and their offspring (F₁), respectively.

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Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg from day 17 of gestation to postpartum day 21. Results were as follows: 1. The vehicle-treated group had no effect in any of the parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains associated with the decreased food consumption in F₀ dams during the lactation period. 3. Thymic, heart and uterine weights were reduced in 1.0 mg/kg F₀ dams at completion of the lactation period. In addition, thymic atrophy was observed for 1.0 mg/kg F₀ dams macroscopically. 4. Paclitaxel did not alter the delivery status of F₀ dams or birth, viability and weaning indices in F₁ pups. 5. The days required for presence of hair, incisor eruption and testicular descent were statistically delayed in 1.0 mg/kg F₁ rats. 6. The latency time for olfactory orientation was prolonged in 1.0 mg/kg F₁ rats on postnatal day 15. Further, the positive response rates for air righting were reduced in 1.0 mg/kg F₁ rats from postnatal day 17 to day 20. 7. 1.0 mg/kg paclitaxel caused suppression of the body weight gains in male F₁ rats from postnatal week 1 to week 12. Though body weight gains were decreased in 1.0 mg/kg female F₁ rats from postnatal week 1 to week 7, there were no significant differences between dosed animals and saline-treated animals regarding the body weight gains and food consumption during the gestation period. 8. Paclitaxel did not affect the learning ability and memory, spontaneous motor activity or emotionality in F₁ rats. 9. The reproductive performance in both male and female F₁ rats were not affected by paclitaxel. 10. Splenic weights were reduced in 1.0 mg/kg male and female F₁ rats at weaning. Furthermore, liver weights were decreased in 1.0 mg/kg male F₁ rats after mating. 11. No influence on prenatal development was observed for F₂ fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 1.0 mg/kg/day and 0.3 mg/kg/day for dams (F₀) and their offspring (F₁), respectively.

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The antigenic property of paclitaxel was examined using its protein mixtures (paclitaxel+OVA, paclitaxel+GSA, paclitaxel+RSA) in guinea pigs and mice in comparison with ovalbumin (OVA) and the protein conjugate of 4-aminoantipriyne (AAP). The following results were obtained: 1. When guinea pigs were sensitized with paclitaxel or paclitaxel+OVA emulsified with Freund's complete adjuvant, none of active systemic anaphylaxis (ASA), passive cutaneous anaphylaxis (PCA) and Schultz-Dale reaction were induced by challenge with paclitaxel or paclitaxel+GSA (guinea pig serum albumin). In the observation of active cutaneous anaphylaxis (ACA), no changes were observed in animals treated with paclitaxel alone as a sensitizing and/or a challenging antigen under the condition where slight delayed type hypersensitivity was elicited in animals sensitized with paclitaxel+OVA and challenged with paclitaxel+GSA. 2. When mice were sensitized with paclitaxel or paclitaxel+OVA adsorbed to alum, sera of these animals revealed a negative reaction in PCA using rats by challenge with paclitaxel or paclitaxel+RSA (rat serum albumin). 3. Protein bindings of paclitaxel with the above albumins were more than 40%. As shown above, paclitaxel was considered not to possess antigenic property under the experimental condition. In addition, the dose levels of paclitaxel employed in the present experiment were confirmed not to suppress the immune response to OVA.

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The vascular irritability of paclitaxel at concentrations of 0.6 and 1.2 mg/ml was examined using the rabbit ear vein by a single intravenous drip in comparison with its vehicle consisting of ethanol and Cremophor, and physiological saline. The results were as follows: 1. Slight to moderate congestion was macroscopically observed around some injection sites of the retroauricular veins infused by paclitaxel, the vehicle and saline. Its incidence and severity caused by paclitaxel was not so much different from that caused by the vehicle or saline. 2. Histopathological findings at the injection sites of the rabbits treated with paclitaxel consisted of vascular and perivascular changes, as well as alterations of the dermis and epidermis. These changes were severer than those brought by saline, and dose-dependent in their incidence and severity. Moreover, the lesions caused by paclitaxel at a concentration of 1.2 mg/ml were correspondent to those caused by the vehicle. Based on these results, the microscopic examinations suggested that the vascular irritability of paclitaxel might be attributable to administration of the vehicle.

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