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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
150 mg/kg bw/day
Additional information

Fertility -- 2-Generation Reproductive Toxicity Study

Groups of 27 male and 27 female rats were treated with CS-1246 seven days/week via oral gavage at dose levels of 0, 5, 25, or 150 mg/kg body weight/day for approximately 10 weeks prior to breeding, through breeding (two weeks), gestation (three weeks) and lactation (three weeks) for each of two generations (Carney, E.W.et al, 2008). In-life parameters included clinical observations, feed consumption, body weights, estrous cyclicity, reproductive performance, pup survival, pup body weights, and puberty onset. In addition, post-mortem evaluations included gross pathology, histopathology, organ weights, oocyte quantitation and sperm count, motility and morphology in adults, and gross pathology and organ weights in weanlings.

A treatment-related decrease in lactation body weight gains over the entire lactation period (lactation days 0-21) was evident in P1 and P2 females given 150 mg/kg/day. Evidence of stomach irritation was seen in the majority of animals given 150 mg/kg/day and consisted of gross pathological observations of non-glandular mucosal thickening, along with histopathological evidence of hyperplasia of the limiting ridge epithelium, subacute to chronic inflammation of the glandular mucosa and submucosa, and hyperplasia, hypertrophy, and increased mitotic figures in the glandular mucosa. Erosions in the glandular mucosa were also present in some P1 females and some P2 males. Similar effects, albeit of lesser severity and incidence, were seen in animals given 25 mg/kg/day. P1 males given 150 mg/kg/day had increased absolute and relative liver weights accompanied by histological findings of slightly altered tinctorial properties (increased eosinophilia) of centrilobular hepatocytes. P1 and P2 males given 150 mg/kg/day had slight-treatment-related increases in absolute and relative thyroid gland weights, without associated histopathologic change. There were no other signs of parental toxicity at these or lower dose levels. There were no effects on any parameter of reproductive performance or offspring survival at any dose level tested. 

In conclusion, based on the stomach irritation the no-observed-effect level (NOEL) was 5 mg/kg/day. The NOEL for systemic toxicity, (hepatic and thyroid effects seen in the 150 mg/kg treated males), was 50 mg/kg/day. There were no evidence of reproductive toxicity at any dose levels and based on the highest dose used the NOEL for reproductive toxicity was 150 mg/kg/day.  

 

References

Carney, E.W., Zablotny, C. L., Stebbins, K. E., Thomas, J. (2008)BIOBANCS-1246: Two Generation Oral Gavage Reproduction Study CRL-CD(SD) Rats The Dow Chemical Company Report No:DR-0365-7827-008.GLP, Unpublished

 


Short description of key information:
A well conducted 2-generation reproductive toxicity study showed no evidence that treatment with the substance, at maternally toxic doses, has any adverse effects on fertility or reproduction. Two developmental toxicity studies conducted in the rat and rabbit failed to find any evidence for the substance being a selective developmental toxicant even at doses causing maternal toxicity.

Effects on developmental toxicity

Description of key information
In conclusion because exposure to CS-1246 produced only small delays in ossification, a common variant with smaller fetuses, it is not considered to be a selective developmental toxicant. A NOAEL of 250 mg/kg/bw/day was established in the rat teratology study.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
250 mg/kg bw/day
Additional information

Developmental -- Rat Teratology

Pregnant female rats were dosed daily, (doses 0, 50, 250 or 650 mg/kg/day), from gestation days 6-15 with aqueous solutions of CS-1246 (Tornesi, B. and Brooks, K.J. 2007). Animals were observed twice daily for signs of toxicity and body weights were recorded on gestation days 0, 6, 9, 12, 16, and 20.

 

Each surviving female was sacrificed on gestation day 20 and examined for gross abnormalities. The number of corpora lutea on each ovary was counted. The uterus was opened and the total number and location of all fetuses, early and late resorptions, and total number of implantation sites were recorded. The individual uterine distribution of implantation sites was documented. Uteri with no macroscopic evidence of nidation were excised, opened, and placed in ammonium sulfide solution for detection of early implantation loss.

 

Each fetus was weighed, sexed, and subjected to a detailed external examination. Approximately half of the fetuses underwent a soft tissue examination, and the other half a skeletal examination. External, visceral, and skeletal findings were recorded as developmental variations or malformations.

Survival of the dams was 100% in all dose groups. Mean maternal body weights were depressed in animals dosed with 650 mg/kg/day; no adverse effect on maternal body weights was seen at dose levels of 50 and 250 mg/kg/day. There were no treatment-related necropsy findings noted at any dose level.

 

Eighteen fetuses (in four litters) in the 650 mg/kg/day group had malformations. Most of the malformations were abdominal wall defects and/or cleft palate, and were clustered mainly in 2 litters. The mean fetal weight was slightly decreased in the 650 mg/kg/day group when compared to controls, (although still within the historical control range). The decrease was attributable mainly to the size of the fetuses in the two litters with most of the malformed fetuses. An increase in the percentage of fetuses in the high dose group with delayed ossification of sternebrae 5 and 6 was considered biologically-relevant and related to treatment. No fetal anomalies were noted in the 50 and 250 mg/kg/day groups with the incidence of fetal and developmental variations comparable to those seen in the concurrent control group and historical control data. No other signs of embryotoxicity or fetotoxicity were apparent at any dose level.

Based on the weight loss measured in the high dose animals the NOEL for maternal toxicity was identified as 250 mg/kg/day. As thedelay in ossification of sternebrae 5 and 6seen in the high dose (650 mg/kg/day) group was considered to be related to treatment the NOEL for non-specific developmental delay was identified as 250 mg/kg/day. The other effects seen in the high dose group, i.e. cleft palate and abdominal wall defects, were not considered to be indicative of developmental toxicity but rather a cluster effect. Reasons for this include:

·   15 of the 18 malformed fetuses were clustered in two litters (4 of the 4 malformed in the first litter and 11 of the 13 in the second) indicating a litter clustering effect rather than a selective development effect.

·    The developmental study in the rabbit showed no evidence of any fetal toxicity

·    The 2-generation study in the rat, (although using lower doses than the rat teratology study), showed no evidence of cleft palate or abdominal wall defects; the latter which would have been captured by decreased postnatal survival or increased pups born dead neither of which were seen in the study.

·    A reproductive and developmental (OECD 422) study with 2-amino-2-ethyl-1,3-propandiol (AEDP) which is the major metabolite of CS-1246 showed no evidence of either reproductive or teratogenic effects at doses up to 1,000 mg/kg/day (Ishidaet al) 

 In conclusion because exposure to CS-1246 produced only small delays in ossification, a common variant with smaller fetuses, it is not considered to be a selective developmental toxicant.

 

Developmental -- Rabbit Teratology

Groups of twenty-six time-mated female New Zealand White rabbits were administered CS-1246 by gavage at targeted dose levels of 0, 15, 50, or 150 mg/kg/day on gestation days (GD) 7-27 (Nemec, M.D., 1989). In-life parameters evaluated for all groups included: clinical observations, body weight, body weight gain, and feed consumption. On GD 28, all surviving rabbits were euthanized and examined for gross pathologic alterations and changes in liver, kidney, and gravid uterine weight. The number of corpora lutea, uterine implantations, resorptions, and live/dead fetuses were determined. All fetuses were weighed, sexed, and examined for external and visceral alterations. Also, the heads were examined for craniofacial alterations by serial sectioning for approximately one half of the fetuses in each litter, while skeletal examinations were evaluated on all fetuses.

Oral administration of CS-1246 at 150 mg/kg/day was associated with maternal effects characterized by weight loss and reduced food consumption presumably as a result of stomach irritation. There were no maternal effects at lower doses. There were no treatment-related developmental effects at any dose level. 

Based on these findings, the maternal no-observed-effect-level (NOEL) was considered to be 50 mg/kg/day, while the NOEL for developmental effects was 150 mg/kg/day.

References:

Nemec, M.D. (1989) A Teratology Study in Rats with AMINE CS-1246. 

WIL Research Laboratories, Inc. The Dow Chemical Company Report No: DR-0365-7725-011. GLP, Unpublished

Tornesi, B. and Brooks, K.J. (2007) CS-1246: Oral Gavage Developmental Toxicity Study in NewWhite Rabbits. The Dow Chemical Company Report No: DR-0365-7827-006. GLP, Unpublished

Justification for classification or non-classification

Based the available data regarding effects on fertility and developmental toxicity, classification is not warranted according to EU Directive 67/548/EEC and CLP Regulation (EC) No. 1272/2008.