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EC number: 201-224-3
CAS number: 79-77-6
Result: no influence on gestational parameters, no adverse signs of developmental toxicity, no indications of teratogenic effects
TEST SUBSTANCE ANALYSES
The stability of the test substance suspensions over a period of 4 days (at 4°C) and the correct concentration of the test substance in the test preparation was demonstrated (always above 90% and below 110% of nominal concentrations).
MATERNAL TOXIC EFFECTS BY DOSE LEVEL
- Mortality and day of death: There were no substance-related or spontaneous mortalities in any of the groups.
- Clinical examinations: Each test group including the controls contained a sufficient number of females with implantation sites at necropsy (20 or more).
Clinical symptoms: All high dose and the majority (22 out of 25) of the mid dose animals showed transient salivation immediately after treatment on one or several days of the treatment period; however, the observed salivation persisted in the respective females only for a few minutes after the actual gavaging had taken place. After cessation of treatment on day 19 p.c., salivation did not occur any longer. The observed temporary salivation of the animals was considered to be substance-induced. It is very likely, that this finding was induced by bad taste of the test substance or local affection of the upper digestive tract. Salivation itself is not assessed as an adverse or toxic effect.
Additionally, 21 high dose dams showed dark-yellow discolored urine on gestation days 12 - 20 p.c. which is probably related to a chemical reaction of the test substance or its metabolites with the bedding or with components of the air and does not represent a toxicologically relevant finding. Comparable urine findings have been observed in a 4-week range finding study in Wistar rats with dietary administration of the test substance, Project No.: 30S0449/02045 (BASF AG, 2003).
No indications for disturbances of the general behavior, however, occurred in the control and low dose dams.
- Food consumption: The mean food consumption of the high dose dams was statistically significantly reduced (9% below the concurrent control value) at initiation of treatment (days 6 - 8 p.c.). On the following days of the treatment period, however, food consumption of the high dose rats reached or even exceeded control values. The food consumption of the females of low and mid dose dams was unaffected and did not show any statistically significant or biologically relevant differences in comparison to the controls.
The transient reductions in food consumption at 400 mg/kg bw were accompanied by corresponding impairments in body weight gain of these dams at initiation of dosing.
- Body weight data: The mean body weights of the low, mid and high dose rats were substantially similar to the concurrent control values.
A statistically significant impairment in mean body weight gain (about 29% below the concurrent control value) occurred in high dose group on treatment days 8 - 10 p.c.; on the other treatment days (i.e. days 6 - 8 and 10 - 19 p.c.) weight gains of the 400 mg/kg bw females were sometimes below and sometimes above those of the corresponding controls without attaining statistical significance. As the food consumption of these rats was also transiently diminished and the corrected body weight gain was also slightly decreased this was considered to be a substance-related sign of maternal toxicity.
Body weight gains of the dams at 25 and 100 mg/kg bw/day) were similar to those of the concurrent controls.
- Corrected body weight gain (net maternal body weight change): The corrected body weight gains (terminal body weight on day 20 p.c. minus weight of the unopened uterus minus body weight on day 6 p.c.) of the dams of the low and mid dose groups revealed no differences of any biological relevance to the corresponding control group. The net weight change of the 400 mg/kg bw rats, however, was about 17% below the concurrent control value (not statistically significant). As food consumption and body weight gain of this group was also temporarily diminished, the effects on net body weight gain at the top dose are considered to be substance-related, borderline signs of maternal toxicity.
EXAMINATION OF THE DAMS AT TERMINATION
- Uterus weight: The mean gravid uterus weights of the animals of all test groups were not influenced by the administration of the test substance.
- Liver weight: Absolute and relative mean liver weights were statistically significantly increased at the mid and high dose groups and were about 9 or 29% (absolute) and 8 or 29% (relative) above control values. These weight increases, which are considered to be substance-induced, are indicative of hepatic changes primarily caused by microsomal enzyme induction. Absolute and relative liver weights of the low dose dams, however, were similar to the control values and did not show any toxicologically significant changes.
- Necropsy findings: There occurred no substance-related observations at necropsy in any of the dams of all test groups. Only very few spontaneous findings were recorded for single low and mid dose rats (one hydrometra in low dose female which consequently did not become pregnant, hemorrhagic thymus in one mid dose female). No association to the test compound was assumed for these findings due to their scattered occurrence without any relation to dosing.
- Reproduction data of dams: The conception rate reached 96% in the controls, 92% in the low and the high dose groups, and 100% in the mid dose. There were no substance-related and/or biologically relevant differences between the test groups in the conception rate, in the mean number of corpora lutea and implantation sites, the pre- and the postimplantation losses, and the number of resorptions and viable fetuses (see table below). The pre- and the postimplantation loss values in the 25 and 100 mg/kg groups, however, were above the upper ranges of the historical control values and the mean number of live fetuses/low dose dam was statistically significantly below the concurrent and the historical control value. These differences appeared without any dose-response relationship and thus are not considered to reflect any substance-induced effect. They can well be explained by the fact that one low dose dam and two mid dose dams resorbed all of their implants and thus had no viable fetuses (the same was also observed for one control dam). Moreover, one low dose, which had 7 implantation sites, resorbed 6 implants and had only one live fetus at terminal sacrifice. If these 5 rats are excluded from the calculation of the means, pre- and postimplantation loss values as well as the mean number of live fetuses/dam fit well into the historical control ranges with one unimportant exception (preimplantation loss value at 25 mg/kg bw/day).
Table: Pre- and postimplantation loss (PRI and POI) values and mean number of live fetuses per dam
Dose Control Low Mid High Historical
dose control range
PRI 6.0 14.4 12.7 4.7 8.7 (3.5-12.2)
Corrected 4.8 12.9* 8.7 4.7
POI 9.9 14.8 15.2 6.2 6.7 (3.7-11.3)
Corrected 6.0 7.3 7.9 6.2
Live fetuses 8.7 7.4* 8.2 8.6 8.8 (7.9-9.8)
Corrected 8.7 7.7 8.2 8.6
Corrected: exclusion of 5 dams, * P < = 0.05
EXAMINATION OF FETUSES
- Sex distribution of fetuses: The sex distribution of the fetuses in all test groups was comparable with that of the control fetuses.
- Weight of placentae: The mean placental weights in the substance-treated groups did not show any differences with toxicological relevance. The statistically significant increase of the mean placental weight of the high dose male fetuses (0.45g versus 0.41g in the control group; p <= 0.05) is not considered to demonstrate an adverse finding and the respective value was fully within the historical control range (0.32g-0.58g).
- Weight of fetuses: The mean fetal body weights in all test groups were not influenced by the test substance administration and were very similar to or even identical with concurrent control values.
- Fetal external, soft tissue and skeletal observations:
The scattered occurrence of the few observed external, soft tissue and skeletal malformations in single fetuses of the controls, the low and mid dose group without a consistent pattern, without any dose-response relationship and/or at incidences, which are similar to historical control rates did not suggest any substance-induced origin of these findings. Most of the observed malformations were limited to one multiply malformed mid dose fetus. The external examination of this fetus revealed gastroschisis, anal atresia, malrotated left hindlimb, and a thread-like tail. During its skeletal evaluation additional malformations like severely malformed sternum and absent vertebrae were recorded. The other malformations that occurred were anasarca (in one control fetus), situs inversus (in one low dose fetus), and cleft sternum (in another control fetus).
If all different types of malformations are summarized, in total 2 of the 200 examined control fetuses [= 1.0%] in 2 out of 23 litters [= 8.7%], one of the 163 examined low dose fetuses [= 0.6%] in one out of 22 litters [= 4.5%], one of the 189 examined mid dose fetuses [= 0.5%] in one out of 23 litters [= 4.3%] and none of the 197 examined high dose fetuses (from 23 litters) showed malformations. The mean percentages of affected fetuses/litter with total malformations amounted to 0.8, 0.5, 0.6, and 0.0% at 0; 25; 100 or 400 mg/kg bw/day respectively. These low, non dose-related incidences did not suggest any relationship to the test substance.
External variations did not occur in any of the fetuses in this study. Soft tissue variations, exclusively in the form of dilated renal pelvis and/or ureters, and a broad range of skeletal variations occurred in all test groups including the controls. All fetal and litter incidences for these variations and the corresponding mean percentages of affected fetuses/litter did not show a clear relation to dosing, were not considered to be of any toxicological relevance and/or could be found at a comparable frequency in the historical control data. This statement included the statistically significantly increased occurrence of three variations (i.e. supraoccipital holes, bipartite ossification of thoracic centrum [with dumbbell-shaped cartilage of centrum] and supernumerary 14th rib [without cartilage]) at the mid dose group.
If all variations were summarized, in total 105 of the 200 examined control fetuses [= 53%] in all 23 litters [= 100%], 88 of the 163 examined low dose fetuses [= 54%] in all 22 litters [= 100%], 99 of the 189 examined mid dose fetuses [= 52%] in all 23 litters [= 100%] and 97 of the 197 examined high dose fetuses [= 49%] in all 23 litters [= 100%] showed variations. The mean percentages of affected fetuses/litter with total variations amounted to 52.8, 56.2, 52.9, and 50.8% at 0; 25, 100 or 400 mg/kg bw/day respectively. These incidences did not suggest a treatment-relationship, but reflect the usual biological variation inherent in the strain of rats used for this experiment.
A spontaneous origin was also assumed for the few unclassified cartilage observations which were recorded for several fetuses of all test groups. Distribution and type of these findings do not suggest any relation to treatment as the mean percentages of affected fetuses/litter with these findings amounted to 17.0, 18.5, 15.4, and 13.6% at 0; 25; 100 or 400 mg/kg bw/day, respectively.
The following substance-related findings were obtained:
Test group 3 (400 mg/kg body weight/day):
• transient salivation in all rats immediately after gavaging on days 6
- 19 p.c.
• discolored urine in a total of 21 out of 25 dams (days 12 - 20 p.c.)
• statistically significantly reduced food consumption on days 6 - 8
p.c. (about 9% below controls)
• statistically significant impairments in absolute body weight gain on
days 8 -10 p.c.(about 29% below controls)
• lower corrected body weight gain (about 17% below controls) without
attaining statistical significance
• statistically significantly increased absolute and relative liver
weights (about 29% above controls)
• no substance-related effects on gestational parameters or fetuses
Test group 2 (100 mg/kg body weight/day):
• transient salivation in 22 out of 25 rats immediately after gavaging
between treatment days 10 - 19 p.c.
• statistically significantly increased absolute and relative liver
weights (about 8 or 9% above controls)
Test group 1 (25 mg/kg body weight/day):
• no substance-related adverse effects on dams, gestational parameters
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