Clearly negative Slightly negative Equivocal Slightly positive Clearly positive Total
Study 1, Rat (Scott, 1995) 25.00% 1 0.00% 0 25.00% 1 50.00% 2 0.00% 0 4
Study 2, Rat (Kelly, 1998) 100.00% 4 0.00% 0 0.00% 0 0.00% 0 0.00% 0 4
Study 3, Mouse (Redmond, 1995) 100.00% 4 0.00% 0 0.00% 0 0.00% 0 0.00% 0 4
Study 4, Mouse (Kelly, 1997) 75.00% 3 0.00% 0 25.00% 1 0.00% 0 0.00% 0 4
Study 5, Rat (NTP, 1985) 0.00% 0 0.00% 0 100.00% 3 0.00% 0 0.00% 0 3
Study 6, Mouse (NTP, 1985) 0.00% 0 0.00% 0 100.00% 3 0.00% 0 0.00% 0 3

Answer Explanations 4

Clearly negativeSlightly negativeEquivocalSlightly positiveClearly positive
Study 1, Rat (Scott, 1995)00010
Study 2, Rat (Kelly, 1998)10000
Study 3, Mouse (Redmond, 1995)10000
Study 4, Mouse (Kelly, 1997)10000
Study 5, Rat (NTP, 1985)00100
Study 6, Mouse (NTP, 1985)00100
Study 1 in F344 rats observed hepatocellular adenomas in male and female mice in the highest dose. It was positive, but only in the highest dose (25 mg/kg/day, microencapsulated 1,3-D). In this study, the material was given to rats in the diet, and when compared to Study 2, in which the material was given to rats by gavage, with clearly negative results, we can conclude that these studies are not consistent. Studies 2, 3 and 4 are clearly negative. Study 5 and Study 6 were INADEQUATE because of the presence of epichlorohydrin, but showed some evidence of carcinogenicity (SLIGHTLY POSITIVE) : The dosing regimen (two dose levels by gavage three times/week) was not well designed to study chronic toxicity and does not meet test guidelines. Tumors were found, but stomach squamous papillomas and carcinomas are local effects after gavage with 1,3-D containing epichlorohydrin, and other tumor findings are not consistent; moreover, many control mice died during the study due to myocarditis.
Clearly negativeSlightly negativeEquivocalSlightly positiveClearly positive
Study 1, Rat (Scott, 1995)10000
Study 2, Rat (Kelly, 1998)10000
Study 3, Mouse (Redmond, 1995)10000
Study 4, Mouse (Kelly, 1997)10000
Study 5, Rat (NTP, 1985)00100
Study 6, Mouse (NTP, 1985)00100
As indicated above the non-NTP studies were negative and the NTP studeis cannot be evaluated because of the contamination with epichlorohydrin.
Expert 11
Clearly negativeSlightly negativeEquivocalSlightly positiveClearly positive
Study 1, Rat (Scott, 1995)00100
Study 2, Rat (Kelly, 1998)10000
Study 3, Mouse (Redmond, 1995)10000
Study 4, Mouse (Kelly, 1997)10000
Study 5, Rat (NTP, 1985)
Study 6, Mouse (NTP, 1985)
Scott (1995): Increase in liver tumors (combined adenoma/carcinoma) in both male and female rats, indication of dose-response in males. However, most of the tumors were adenomas (only 1 carcinoma) and incidences are within or sligthly higher as compared to historical controls in the performing lab. Is it known if the material tested was identical to that in both the Kelly and the Redmond study regarding the unaccounted impurities ? In addition, there was dosing above MTD due to body weight gain reductions > 10 % in high dose males, but little indications of liver toxicity. Kelly (1998): no increase in tumor incidences seen, same for Redmond 1995 Kelly (1997): My conclusion is negative, would be even better supported if historical controls for the lesion in the performing lab would be available. Both NTP studies show an increase in tumor responses, but the interpretaion of the data is problematic as indicated above due to study design and conduct and testing of a material with significant impurities.
Clearly negativeSlightly negativeEquivocalSlightly positiveClearly positive
Study 1, Rat (Scott, 1995)00010
Study 2, Rat (Kelly, 1998)10000
Study 3, Mouse (Redmond, 1995)10000
Study 4, Mouse (Kelly, 1997)00100
Study 5, Rat (NTP, 1985)00100
Study 6, Mouse (NTP, 1985)00100
There were no clearly positive bioassays. Study 1 presented the strongest evidence of a tumorigenic effect,, with the statistically significant increase in hepatocellular adenoma incidence in high-dose males. Although this increase may be real, it was not accompanied by an increase in malignant hepatocellular tumors. The remaining studies were considered equivocal because of the presence of a carcinogenic contaminant or because of questionable histological nomenclature.
1 vote 1 0 votes
Expert 6
04/17/2019 17:11

Study one indeed provoked different answers, but with a tendence to consider it positive for hepatocellular adenomas in high dose male and female animals and in mid dose males.

2 votes 2 0 votes
Expert 11
04/18/2019 02:29

Agree based on tumor incidences and some indication of dose response. I have difficulties interpreting the response in Scott et al. considering toxicokinetics since Cmax was much lower as compared to Kelly at the same dose level. Either the observation is an artefact, the rat strain in Kelly is much more sensitive, or the two formulations have different compositions ? Any other suggestion ?

1 vote 1 0 votes
Expert 6
04/19/2019 07:18

to user 47751 - That is my question too. Is the composition of Telone II (given in the diet to F344 rats) different from the composition of DD-92 (oral-gavage to Sprague Dawle rats)? In many other situations, when comparing gavage x dietary studies, the dietary studies produce less cancer. In this case it is the opposite.
Either the composition is different (information not given) or there is a different rat strain susceptibility.
In addition, the hepatocellular adenomas percentage was significantly higher only in the highest dose.
In fact, I agree with the comment on page 36 of the white paper: "The fact that lower or comparable systemic exposures led to more severe toxicity (tumors vs. nontumors) further supports that the tumorigenicity only observed in rats via dietary exposure is not consistent.".

0
Expert 6
04/20/2019 08:11

JUST FOR CLARIFICATION:
• Clear evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a dose-related
(i) increase of malignant neoplasms, (ii) increase of a combination of malignant and benign neoplasms, or (iii) marked increase of benign
neoplasms if there is an indication from this or other studies of the ability of such tumors to progress to malignancy.
• Some evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a chemical-related increased incidence of neoplasms (malignant, benign, or combined) in which the strength of the response is less than that required for clear evidence.
• Equivocal evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a marginal increase of neoplasms
that may be chemical related.
• No evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing no chemical-related increases in malignant or benign neoplasms.
• Inadequate study of carcinogenic activity is demonstrated by studies that, because of major qualitative or quantitative limitations, cannot be interpreted as valid for showing either the presence or absence of carcinogenic activity.

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