SRC TR-10-056 

HPV1 TEST RULE – DATA ADEQUACY ASSESSMENT 

Methanesulfinic acid, hydroxy-, monosodium salt, CAS No. 149-44-0 

Repeated-Dose with Reproductive/Developmental Toxicity Screen 

Prepared by: 

Teresa Manyin, Chris Janson, and Joan D. Garey 

Environmental Science Center 

SRC, Inc. 

7502 Round Pond Road 

North Syracuse, NY 13212 

Contract No. EP-W-09-027 

Task FG007.0.009.004 

Submitted to: 

OPPT/RAD/HPVCB (7403M) 

U.S. Environmental Protection Agency 

1200 Pennsylvania Avenue 

Washington, D.C. 20460 

Elizabeth Margosches, Project Officer 

Meena Sonawane, Work Assignment Manager 

David Brooks, Alternate Work Assignment Manager 

March 5, 2010 
HPV1 Test Rule – Data Adequacy Assessment 

Methanesulfinic acid, hydroxy-, monosodium salt, CAS No. 149-44-0 

Repeated Dose with Reproductive/Developmental Toxicity Screen 

March 2010 

Submitted to: 

High Production Volume Chemicals Branch 

Risk Assessment Division 

Office of Pollution Prevention and Toxics 

Environmental Protection Agency 

WAM: Meena Sonawane 

Alternate WAM: David Brooks 

1200 Pennsylvania Avenue, NW 

Washington, DC 20460-0001 

Prepared By: 

SRC, Inc. 

Environmental Science Center 

2451 Crystal Drive, Suite 804 

Arlington, VA 22202 
Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/Develop Tox CAS No. 149-44-0

PREPARATION OF THE DATA ADEQUACY ASSESSMENT

This document contains the review of a toxicity study conducted in response to the first 

HPV TSCA Section 4 Test Rule (71 FR 13708, March 16, 2006). Using the applicable test 

guideline and professional judgment as guides, the study was reviewed for adequacy and 

evaluated for compliance with the test guideline. (The applicable test guideline is not always the 

test guideline required by the test rule, because some test sponsors requested and received 

approval from EPA to use a different guideline.) The study was summarized according to a 

standard format, assessed for adequacy, and assigned a Klimisch reliability code. If the study 

was determined to be inadequate, a basis for that conclusion is supplied. For studies already 

assigned Klimisch codes, an explanation is provided if the reviewer’s assessment of data 

adequacy differed from the pre-assigned Klimisch code. 

A detailed evaluation of the test report and study conduct is provided at the end of the 

summary document in a section entitled “Review of TSCA Section 4 Final Study Report”. Any 

deviations from the applicable test guideline are described. The study is also evaluated for 

compliance with Standard Operating Procedures, Good Laboratory Practice Standards, and 

Quality Assurance procedures, as well as the use of appropriate controls and test substances. 

Any deficiencies in the descriptions of the study method, test system, animals studied, physical 

conditions, dosage information, individual animal data, calculations, and statistical analyses are 

described, and internal inconsistencies within the study report are identified. An overall 

assessment is provided for each of the following: study conduct, data reliability, and data utility. 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

REPEATED-DOSE/REPRODUCTIVE/DEVELOPMENTAL TOXICITY 

Title: A combined 28-day repeated dose toxicity study with the reproduction/developmental 

toxicity screening test of methane sulfinic acid, hydroxy-, monosodium salt in rats by oral 

gavage

The study is: Adequate Not Adequate 

TEST SUBSTANCE 

 

Identity: Methanesulfinic acid, hydroxy-, monosodium salt, aka sodium hydroxymethane 

sulfinate (SFS), CAS No. 149-44-0 

Remarks: 88.4% purity by weight (76.9% sodium hydroxymethane sulfinate, 11.5% water); 

100.3% if calculated as dihydrate; impurities and stabilizers include 1.9% alkalinity (as sodium 

carbonate), 4.4% sodium hydroxymethanesulfonate, 1.9% sodium sulfite, 2.4% sodium sulfate, 

0.2% iron (as Fe), and 0.2% zinc (as Zn); Batch Number 07041205 from Brüggemann; 

commercial substance; white powder of a crystalline substance consisting of colorless crystals; 

MW = 118.08 

METHOD

Method/guideline followed: OECD 422 and EPA, 40 CFR 799.9365 

Test type: Combined 28-day repeated-dose toxicity study with reproductive/developmental 

toxicity screening test 

GLP compliant?: Yes

Year study performed: 2007 

Test species: Male and virgin female Wistar (Crl:WI(Han); outbred, SPF-Quality) rats; supplier: 

Charles River, Deutschland, Sulzfeld, Germany; age at initiation: approximately 10 weeks old; 

mean initial body weights: males: 292 g, females: 190 g 

Number of animals/sex/dose: 10/sex/dose 

Route of administration: Oral gavage 

Vehicle: Water (Elix, Millipore S.A.S., Molsheim, France) 

Exposure duration: Males were exposed for 30 days (during 2 weeks prior to mating, during 

mating [up to 14 days], and to termination). Females were exposed for 42 - 53 days (during 2 

weeks prior to mating, during mating and gestation, and up to Day 4 of lactation). 

Doses/concentrations tested: 0, 100, 300, and 1000 mg/kg-bw/day

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

Statistical methods used: Normally distributed data were analyzed using the Dunnett test, based 

on a pooled variance estimate. The Steel test was applied if data were not normally distributed. 

The Fisher Exact test was applied to frequency data. The following were calculated for each 

group: percentage mating, fertility index, conception rate, gestation index, duration of gestation, 

percentage of live males at first litter check, percentage of live females at first litter check, 

percentage of postnatal loss from Days 0-4 post partum, and viability index. All tests were twosided, with p < 0.05 accepted as the lowest level of significance. 

Test method/conditions remarks: 

Animals were acclimated at least 5 days prior to start of treatment. They were housed in rooms 

maintained at 19.0-23.5 °C, with a relative humidity of 26-95% and a 12-hour light/ 12 hour dark 

cycle. There were 15 air changes per hour. Prior to mating, animals were housed in groups of 5 

animals/sex/cage in Macrolon cages (MIV type, height 18 cm). Females were caged with males 

on a one-to-one basis during mating. After mating, males were housed in their home cage, with 

a maximum of 5 animals/sex/cage. Females were individually housed after mating and were 

kept with their offspring until termination. 

Cages were generally supplied with sterilized sawdust as bedding material and paper as cageenrichment. During overnight activity monitoring, animals were housed individually with 

sterilized sawdust bedding material without paper cage-enrichment. Animals were allowed free 

access to tap water and pelleted rodent diet (SMR/M-Z from SSNIFF Spezialdiaten GmbH, 

Soest, Germany). Analyses of bedding, paper, diet and water did not reveal any findings that 

were considered to affect study integrity. 

Test material: Formulations (w/w) were prepared daily, within 4 hours of dosing, and were 

homogenized to a visually acceptable level. No adjustment was made for specific gravity, 

vehicle and/or formulation. The pH of the solutions was determined weekly. The pH of a 10% 

solution was approximately 10. Sampling and chemical analysis of formulations were performed 

on one day during the treatment period; duplicate samples from each group were analyzed for 

accuracy. Duplicate samples of dosing solutions taken from the bottom, middle and top for the 

low- and high- dose groups were analyzed for homogeneity and stability at 0 hours after 

preparation. Duplicate samples of these solutions (taken from the middle) were also analyzed for 

stability at 5 hours after preparation. The analytical method used was based on the results of a 

separate project for the development and validation of the analytical method (NOTOX Project 

485209). 

The pHs of the formulations were between 8.31-8.68 (control), 10.12-10.17 (low dose), 10.10-

10.17 (mid dose) and 9.94-10.02 (high dose). The accuracy of the formulations was 102-109% 

(low dose), 98-103% (mid dose) and 87-105% (high dose). Based on the results, it was 

concluded that the formulations were prepared correctly. The low- and high-dose formulations 

were homogeneous (≤ 10% coefficient of variation). Formulations at the entire range were 

stable for at least 5 hours when stored at room temperature. 

A health examination was performed prior to treatment to ensure that the animals were in a good 

state of health. A total of 40 animals/sex were randomized into four groups of 10/sex according 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

to body weight, with all animals within 20% of the sex mean. They were identified by earmark 

and tattoo. 

Groups of animals were given 0 (water vehicle), 100, 300 or 1000 mg/kg-bw test material (at 5 

mL/kg-bw) by oral gavage, once daily, 7 days/week up to the day of scheduled termination. A 

limit dose of 1000 mg/kg-bw/day was selected as the high dose level based on data obtained in a 

preliminary range-finding study. Actual dose volumes were calculated according to the latest 

body weight. Following 14 days of exposure, males and females were co-housed (1:1). Sibling 

mating was avoided. Detection of mating was confirmed by presence of sperm in the vaginal 

lavage or by the appearance of an intravaginal copulatory plug. This day was designated as Day 

0 postcoitum. Once mating had occurred, the males and females were separated. A maximum of 

14 days was allowed for mating. There were at least 8 pregnant females per dose level. Females 

were allowed to litter normally. Day 1 of lactation was defined as the day when a litter was 

found completed. Females that were littering were left undisturbed. On Day 1 of lactation, all 

pups were individually identified by a tattoo. Examination of maternal care revealed no 

deficiencies. 

Parental animals were observed for mortality and viability at least twice daily. At least once 

daily, detailed clinical exams were conducted for all animals. This was also performed outside 

the home cage once before treatment and at weekly intervals. These observations were not 

performed when the animals were mating or housed individually. The time of onset, degree and 

duration was recorded. Cage debris of pregnant females was examined for evidence of abortion 

or premature birth. No signs of abortion, premature birth or difficult or prolonged parturition 

were recorded. 

Functional observations (hearing ability, pupillary reflex, static righting reflex and grip strength 

and a motor activity test) were recorded for the first five mated males/group and the first five 

females/group with live offspring. During the motor activity test, males were caged individually 

and females were caged with their offspring. The males were tested during week 4 of treatment 

and the assigned females were tested during lactation (all before blood sampling). 

Males and females were weighed on the first day of exposure and weekly thereafter. Mated 

females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 of gestation, and during lactation on 

Days 1 and 4. Food consumption was recorded weekly (with the exception that it was not 

recorded during breeding). Food consumption of mated females was measured on Days 0, 4, 7, 

11, 14, 17 and 20 post-coitum and after delivery on Days 1 and 4 postpartum. Water 

consumption was not quantified, but was monitored subjectively. Identities of animals paired, 

mating date, confirmation of pregnancy, and delivery day were recorded. 

After an overnight fast, blood was collected from the retro-orbital sinuses of the first five mated 

males/group and the first five females/group with live offspring, under isoflurane anesthesia. 

Standard hematological (white blood cells, differential leukocyte count, red blood cells, 

reticulocytes, red blood cell distribution width, hemoglobin, hematocrit, mean corpuscular 

volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, 

prothrombin time, and activated partial thromboplastin time) and clinical biochemistry 

parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, 

chloride, calcium, and inorganic phosphate) were performed after appropriate blood processing. 

On lactation Day 5 (or shortly thereafter), parental females were anesthetized with isoflurane and 

exsanguinated. Animals were subjected to a gross examination, organ weights (adrenal glands, 

brain, heart, kidneys, liver, spleen, and thymus) of the first 5 females with live offspring per 

group were collected and terminal body weights were recorded. Tissues (adrenal glands, aorta, 

brain, cecum, cervix, clitoral gland, colon, duodenum, eyes with optic nerve and Harderian 

gland, mammary gland area, femur, heart, ileum, jejunum, kidneys, larynx, exorbital lacrimal 

gland, liver, lung, mandibular and mesenteric lymph nodes, nasopharynx, esophagus, ovaries, 

pancreas, Peyer's patches, pituitary gland, preputial gland, rectum, mandibular and sublingual 

salivary glands, sciatic nerve, skeletal muscle, skin, spinal cord, spleen, sternum with bone 

marrow, stomach, thymus, thyroid with parathyroid, tongue, trachea, and urinary bladder) and 

gross lesions of these animals were preserved for possible future histopathological examination. 

The cervix, clitoral gland, ovaries, preputial gland, uterus, vagina and all gross lesions from 

remaining animals also were preserved. Slides of preserved organs and tissues of selected 

control and high dose animals and gross lesions of all animals were prepared and examined by a 

pathologist. The numbers of former implantation sites and corpora lutea were counted and 

recorded. 

On post-mating Days 24-26, females that had not delivered were anesthetized and exsanguinated. 

No organs were collected for weighing. Animals were subjected to a gross examination and 

tissues described above for parental females (and any gross lesions) were preserved. The 

reproductive organs of all females that failed to conceive were examined by a pathologist. 

Additionally, nongravid uteri were stained using the Salewski technique to identify former 

implantation sites. 

After completion of the mating period, parental males were anesthetized with isoflurane and 

exsanguinated and grossly examined. Organ weights (adrenal glands, brain, heart, kidneys, liver, 

spleen, and thymus) of the first 5 mated males per group were collected and terminal body 

weights were recorded. Weights of epididymides and testes of all males were also recorded. 

The same tissues preserved for selected females (see above) were preserved for the first 5 mated 

males per group (with the exception of female reproductive organs and the addition of the 

epididymides, prostate gland, seminal vesicles, testes, and coagulation gland). The coagulation 

gland, epididymides, preputial gland, prostate gland, seminal vesicles, testes and all gross lesions 

from remaining animals also were preserved. Slides of preserved organs and tissues of selected 

control and high-dose animals and gross lesions of all animals were prepared and examined by a 

pathologist. Of the selected 5 males/group of the control and high-dose group, additional slides 

of the testes were prepared to examine staging of spermatogenesis. The reproductive organs of 

all males that failed to sire were examined by a pathologist. 

The numbers of live and dead pups at the first litter check (Day 1 of lactation) and daily 

thereafter were determined. Detailed clinical observations of pups were made at least once daily. 

Live pups were weighed during lactation Days 1 and 4. Sex of all pups was determined on Days 

1 and 4 of lactation (by measuring the anogenital distance). 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

Pups were killed by decapitation on Day 5 of lactation (or shortly thereafter). All offspring were 

sexed and externally examined. Stomachs were examined for the presence of milk. Descriptions 

of all external abnormalities were recorded. If possible, defects or causes of death were 

evaluated. Any abnormal pup, organ or tissue was preserved for possible future examination. 

RESULTS

Endpoint value(s): The parental LOAEL was 1000 mg/kg-bw/day, based on reductions in mean 

body weight, body weight gain, and food consumption, as well as increases in the number of 

reticulocytes (males only) and the level of alanine aminotransferase (males only). The parental 

NOAEL was 300 mg/kg-bw/day. The reproductive and developmental NOAEL was 1000 

mg/kg-bw/day, based on no adverse effects observed at the highest dose tested. 

Results remarks: 

Formulation analysis showed that the formulations were prepared accurately, were homogeneous 

(i.e., coefficient of variation ≤ 10%) and were stable for at least 5 hours at room temperature. 

The accuracy of formulation (determined by chemical analysis) for the low-, mid-, and high-dose 

groups were 102-109%, 98-103%, and 87-105%, respectively. 

Parental animals (effects by dose level): 

1000 mg/kg-bw/day: None of the animals died and functional observations were not affected. 

One female showed hunched posture and piloerection from Day 20 post-coitum until Day 3 of 

lactation. Piloerection was noted in another female on Day 4 of lactation. Slight salivation noted 

incidentally in both sexes was attributed to the taste of the formulation and was not considered 

toxicologically relevant. Lower mean body weights were recorded for males and females at 

1000 mg/kg-bw during the complete treatment period (not always statistically significant). Body 

weight gains of males were also lower than the control throughout the treatment period. For 

females, body weight gain was decreased on Day 8 during the pre-mating period and on Day 1 of 

mating. Food consumption before or after allowance for body weight was reduced in males and 

females during the whole observation period (not always statistically significant). A slightly 

higher white blood cell count was noted in males (not statistically significant) and females. 

Relative numbers of reticulocytes were increased in males (3.6 ± 0.8% in treated vs. 2.3 ± 0.1 % 

in control). Increased mean corpuscular volume and decreased mean corpuscular hemoglobin 

concentration in females were not considered to be related to treatment as they were either within 

the range of normal or showed no dose-response relationship. Increased alanine 

aminotransferase was found in males (59.2 ± 20.4 U/I in treated vs. 38.0 ± 3.6 U/I in control). 

One male had increased activity of aspartate aminotransferase. Increased total bilirubin and 

decreased sodium in males were not considered to be related to treatment due to the lack of a 

dose-response relationship. One male showed exophthalmus of the eye, which was considered to 

be caused by blood sampling. Increases in organ/body weight ratios for the liver (2.57 ± 0.14% 

in treated vs. 2.33 ± 0.12% in control), spleen (0.225 ± 0.032 in treated vs. 0.162 ± 0.033 in 

control), testes (1.16 ± 0.15% in treated vs. 0.94 ± 0.16% in control) and epididymides (0.388 ± 

0.071 % in treated vs. 0.301 ± 0.050 in control) of males and liver (3.64 ± 0.22% in treated vs. 

3.04 ± 0.33% in control), spleen (0.287 ± 0.023% in treated vs. 0.225 ± 0.0303% in control), 

kidneys (0.83 ± 0.05% in treated vs. 0 .73 ± 0.06% in control) and adrenals (0.043 ± 0.004% in 

treated vs. 0.034 ± 0.004% in control) of females were observed. There were no corresponding 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

histological changes. An increase in the organ/body weight ratio of the brain in males (0.66 ± 

0.05% in treated vs. 0.60 ± 0 .01 % in control) was considered to be due to the relatively low 

terminal body weight (300 ± 14 g in treated vs. 336 ± 19 g in control). Absolute brain weight 

(but not relative) was slightly decreased in females (1.77 ± 0.05 g in treated vs. 1.87 ± 0.05 in 

control). Reproductive and breeding parameters were not affected by treatment at any dose 

tested. No treatment-related findings were observed for mating performance, fertility parameters 

(fertility index, conception rate, and gestation index), and duration of gestation. 

300 mg/kg-bw/day: None of the animals died and functional observations were not affected. 

Females had slightly lower mean absolute body weights on Day 8 of premating (189 ± 6.6 g in 

treated vs. 197 ± 7.2 g in control). As this had recovered on Day 1 of mating (198 ± 11.8 g in 

treated vs. 203 ± 8.2 g in control), it was not considered to be toxicologically relevant. Increased 

basophils in males, increased mean corpuscular volume and mean corpuscular hemoglobin in 

females, decreased total bilirubin in males, and decreased albumin in females were not 

considered to be related to treatment as they were either within the range of normal or showed no 

dose-response relationship. No other abnormal findings were noted. 

100 mg/kg-bw/day: None of the animals died and functional observations were not affected. 

Females had slightly lower mean absolute body weights on Day 8 of premating (189 ± 6.6 g in 

treated vs. 197 ± 7.2 g in control). As this had recovered on Day 1 of mating (196 ± 6.3 g in 

treated vs. 203 ± 8.2 g in control), it was not considered to be toxicologically relevant. Increased 

basophils in males and decreased total bilirubin in males were not considered to be related to 

treatment as they were either within the range of normal or showed no dose-response 

relationship. No other abnormal findings were noted. 

Control: One female showed exophthalmus of the eye, which was considered to be caused by 

blood sampling. 

Offspring: 

The numbers of dead and living pups at first litter check were not affected by exposure to the test 

substance. Postnatal loss and viability index were similar for the control and treated groups. 

Development of pups was not affected by treatment with up to 1000 mg/kg-bw/day. Mean pup 

body weights were similar for the control and treated groups (means ranged from 5.6-5.8 g and 

5.3-5.6 g in males and females on Day 1, and 8.3-8.8 and 8.0-8.6 g in males and females on Day 

4, with none of the low values in the listed ranges being in high-dose animals). None of the 

clinical or macroscopic findings (scabs at the neck, dark red discoloration of tail apex, blue spot 

on neck, wound at the head) were considered to be related to treatment as they were considered 

to be within normal biological variation. 

Summary Table: 

Parameter Control 100 mg/kg 300 mg/kg 1000 mg/kg 

Percentage Mating 100 100 100 100 

Fertility Index 80 100 90 100 

Gestation Index 100 100 100 100 

Mean Precoital Time* 2.5 2.9 1.4 1.7 

Duration of 

Gestation (days) 21.1 ± 0.4 21.1 ± 0.3 21.0 ± 0.0 21.1 ± 0.3 

Dead Pups at 

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Draft HPV1 Test Rule – Data Adequacy – Repeated-Dose/Repro/DevelopTox CAS No. 149-44-0

First Litter Check 0 0 0 0 

Postnatal Loss (%) 0.0 2.6 2.9 1.0 

Litters Affected 0 3 2 1 

Viability Index 100.0 97.4 97.1 99.0 

*units not listed, but presumed to be days 

CONCLUSIONS

Treatment with methane sulfinic acid, hydroxy-, monosodium salt by oral gavage in male and 

female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg-bw/day revealed parental 

toxicity at 1000 mg/kg-bw/day. No reproduction, breeding, and developmental toxicity was 

observed for treatment up to 1000 mg/kg-bw/day. Based on these findings, the parental NOAEL 

was established at 300 mg/kg-bw/day. The definitive reproduction, breeding, and developmental 

NOAEL was established as being 1000 mg/kg-bw/day. 

STUDY RELIABILITY

[1] = Reliable without restriction. 

REFERENCE

Beekhuijzen, M.E.W. 2008. A combined 28-day repeated dose toxicity study with the 

reproduction/developmental toxicity screening test of methane sulfinic acid, hydroxy-, 

monosodium salt in rats by oral gavage. NOTOX B.V. Project No. 485218 (and 485615), dated 

12 June 2008 

8 
Review of TSCA Section 4 Final Study Report 

CITB Project Manager: Catherine Roman 

Chemical Name: Methanesulfinic acid, hydroxy-, monosodium salt 

CAS Registry Number: 149-44-0 

Report Title: A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity 

screening test of methane sulfinic acid, hydroxy-, monosodium salt in rats by oral gavage 

Test Sponsor: The SFS Consortium, consisting of BrüggemannChemical US, Inc. and Royce Associates 

Testing Lab: NOTOX B.V., Hambakenwetering 7, 5231 DD 's-Hertogenbosch, The Netherlands 

Test Standard: 40 CFR 799.9365 

Date Study Received by EPA: June 2008 Date Study Due to EPA: May 17, 2007 

Special Instructions (e.g., regarding approved protocol modifications, etc.): 

 

Part I. Test Report and Study Conduct

Enter one of the following codes into each of the checkboxes 1 through 13: Agree [A], Disagree [D], Not 

Applicable [NA], or Cannot Determine [C], and add comment, below, as needed

[D] 1. The final study report indicates evidence of gross, unauthorized or undocumented deviation from 

 the EPA test standard requirements, including “shall,” “must,” or “will” violations. List 

 significant test standard deviations and “shall,” “must,” or “will” violations in comments below. 

[D] 2. The final study report indicates evidence of deviations from the “should” statements in the study protocol 

that may have a bearing on the study conclusions. List these in comments below. 

[D] 3. Approved modifications of test standard or testing protocol (CITB PM describe or attach) were not followed 

or are inadequately documented. 

[D] 4. There is evidence that laboratory Standard Operating Procedures (SOPs) were inadequately followed. 

[D] 5. The Statement of Quality Assurance (QA) inspections, their dates, and findings were missing or not signed. 

There is evidence that QA procedures may be inadequate. 

[D] 6. There is evidence that Good Laboratory Practice Standards (GLPS) were inadequately followed. 

[D] 7. The test, control, or reference substances are different from that specified in the section 4 test rule or 

Enforceable Consent Agreement (ECA). 

[D] 8. Animal identification is inadequate or unclear; use of unhealthy animals or other factors (e.g., deviations 

from temperature, lighting, dosing) are apparent. 

[D] 9. The final study report inadequately describes the study method. 

[D] 10. The final study report inadequately describes the test system. 

[D] 11. The final study report inadequately describes the dosage information. 
[D] 12. The final study report does not accurately reflect the individual animal data (or that of other discrete 

observations pertinent to the type of study conducted), or individual data were not provided. 

[D] 13. The final study report inadequately describes the calculations, interpolations, data transformations, 

statistical analyses, or modeling parameters used. 

Part II. Conclusions

Place a check mark beside the summary statement(s) that apply to this review and add comments below as 

appropriate

Part A. To be filled out by Reviewer

 

Study Conduct 1. The study was well-conducted. [X] 

 2. The study was generally well-conducted, with some minor [ ] 

 deficiencies (list in notes below). 

 3. The study conduct was significantly deficient or questionable, (give [ ] 

 reasons in notes below). 

Data Reliability 4. The study results are precise and accurate. [X] 

 5. Appropriate methods were used to determine [X] 

 statistical significance. 

 6. If repeated, the test results would be expected to be the [X] 

 same. 

Data Utility 7. The data are useful for risk assessment for the endpoint tested. [X] 

 8. The data are useful for some other purpose (e.g., dose-setting). [ ] 

 9. The data are not useful for any purpose (describe in notes below). [ ] 

Reviewer Comments (continue on separate page, if needed): 

Reviewer Name/Title/Branch/Division/Office: Teresa Manyin/SRC, Inc. 

Reviewer Signature: David Brooks/HPVCB/RAD/OPPTS 

Part B. To be filled out by CITB PM

Tiered Testing Decision 1. The tiered testing trigger was met, additional testing is indicated. [ ] 

(when applicable) 2. The trigger for additional (tiered) testing was not met. [ ] 

 

Study Acceptability 3. The study is acceptable. [ ] 

 4. The study may not be acceptable [ ] 

 (provide rationale in memo to CITB chief).