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Diss Factsheets

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study with acceptable restrictions Not full study report published, but main information is given in sufficient details.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
Deviations:
no
Principles of method if other than guideline:
Study contents reported here were chosen to determine whether exposure to D911P impairs reproductive performance in the rat, including sensitive periods of development.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters
EC Number:
271-085-1
EC Name:
1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters
Cas Number:
68515-43-5
IUPAC Name:
dioctyl phthalate
Details on test material:
- Name of test material (as cited in study report): 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters, D911P
The alkyl moieties have a carbon distribution of 97% in the range C9 to C11 (typically 13–23% C9, 37–47% C10, 33–43% C11), and are highly linear (minimum 80%), with predominantly mono-2-methyl branching in the remainder.
- Source: BP Chemicals (Hull)
- Analytical purity: 99.2% (m/m)
- Batch: PLA/S20517/97

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (Margate, Kent, UK)
- Age at study initiation: (P) 6 wks; (F1) x wks
- Weight at study initiation: (P) Males: 145 to 228 g; Females: 115 to 198 g;
- Housing: Animals were housed in cages in groups of four of the same sex, except during mating when males and females were pair-housed, and during gestation and weaning when females were housed individually.
- Diet (ad libitum): LAD 2 SQC, Special Diet Services, Witham, UK
- Water: ad libitum
- Acclimation period: 13 days

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required dietary concentrations of both substances were achieved by direct dilution of a premix with untreated diet. All formulations were prepared on a weekly basis.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to 3 weeks
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy
- After 21 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged individually.

Treatment of the F0 generation continued for 10 weeks before pairing. For the females, the duration and regularity of the oestrus cycle was established by daily vaginal smears, commencing 10 days before pairing. At pairing, one male and one female were housed together, taking care not to pair
siblings, for up to 3 weeks. Cages were examined each morning for evidence of copulation plugs and vaginal smears were collected for assessment of spermatozoa and stage of oestrus. Males that failed to mate were replaced with another of proven fertility in order to maximise the
number of litters. The day on which evidence of mating was found was designated Gestation Day (GD) 0, and females were then removed to individual cages. From GD 20, females were checked three times daily for evidence of onset, progress, and completion of parturition. All animals were
allowed to litter naturally (F0 offspring), and rear their own offspring until Day 21 of lactation. Dams were examined daily for evidence of normal maternal behaviour.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Tests indicated that the method of preparation produced a homogenous distribution of test substance, which was stable under the conditions used. Samples of diet were analysed for each group at weeks 1, 8 (control and 1.0% only), 11, 14, 18, 28, and 31. All formulations were within 8.5% of the nominal concentrations.
Duration of treatment / exposure:
Continuously over two generations.
Treatment of the F0 generation continued for 10 weeks before pairing.
Frequency of treatment:
ad libitum feeding
Details on study schedule:
- Selection of parents from F1 generation when pups were 25 days of age.
Animals of F1 generation were mated in the 10th week postweaning.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 0.1, 0.5 and 1.0/2.0%
Basis:
nominal in diet
Highest dose was reduced to 1.0 % after week 7
Remarks:
Doses / Concentrations:
0,120,600 and 2400 mg/kg bw/d
Basis:
actual ingested
F0 males and females in the first week of treatment
Remarks:
Doses / Concentrations:
0, 61, 312, 684 and 0, 77, 388, 792 mg/kg bw/d
Basis:
actual ingested
in males and females after the 7th week
Remarks:
Doses / Concentrations:
0, 56, 280, 619 and 0, 63, 328, 696 mg/kg bw/d
Basis:
actual ingested
in males and females by 10th week
Remarks:
Doses / Concentrations:
0, 163, 867, 1760 mg/kg bw/d
Basis:
actual ingested
in females during lactation
No. of animals per sex per dose:
28
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale:
Based on information for similar substances, a pilot study was conducted by using dietary inclusion levels of 0.1%, 0.5%, and 1.0%. There were no
apparent treatment-related effects on either the F0 or F1 generation in this study (not reported here). Therefore, dietary inclusion levels for the main study were set at 0.1%, 0.5% and 2.0% D911P. Because of marked reaction to treatment among the F0 males, the highest treatment level was reduced to 1.0% D911P after the sixth week of treatment.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily for clinical signs of treatment, and any animals found in distress were humanely sacrificed.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on a weekly basis, except for mated females, which were weighed on Days 0, 6, 13,
and 20 after mating, and Days 1, 4, 7, 14, and 21 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Food consumption was monitored on a cage basis each week, except for mated females for whom food consumption was monitored on an individual basis on Days 0 through 5, 6 though 12, and 13 through 20 of gestation, and Days 1 through 6, 7 through 13, and 14 through 21 of lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Oestrous cyclicity (parental animals):
For the females, the duration and regularity of the oestrus cycle was established by daily vaginal smears, commencing 10 days before pairing.
Sperm parameters (parental animals):
An unmeasured sample of epididymal fluid was exuded by gentle squeezing, and the sperm allowed to diffuse into medium [M199 containing 0.5% bovine serum albumin (BSA)] at 37°C. A sample was taken for motility analysis of at least 200 sperm with the Hamilton Thorne IVOS Computer
Assisted Sperm Analyser (CASA). A sample of epididymal fluid (5 ml) was diluted with medium (995 ml), and an aliquot (50 ml) was set aside for
assessment of sperm morphology. The remainder was homogenised and stained with IDENT before counting by CASA, analysing 10 fields per animal. The aliquot taken for morphologic assessment was added to 4% neutral buffered formaldehyde (950 ml), applied to a microscope slide and stained with 1% nigrosin/eosin before assessment by light microscopy of at least 200 sperm. The frozen testis was thawed and then homogenised in SMT (0.9% saline, 0.01% merthiolate, 0.05% Triton X-100; 25 ml). An aliquot was stained with IDENT and counted as described previously.
Litter observations:
PARAMETERS EXAMINED
F0 offspring were examined approximately 24 h after birth (Postnatal Day [PND] 1) and the following were recorded for each litter: number of pups (live and dead), body weights of live offspring, sex ratio, and observations on individual pups. Litters of nine or more offspring were culled by random selection to eight, where possible four males and four females, on PND 4. At PND 25 males and females (one male and one female from each litter where possible) were randomly selected to produce the next (F1) generation.

The selected F1 females were examined for vaginal opening from Postnatal D (PND) 28, and the selected males were examined for preputial separation from PND 38. Examinations were made on a daily basis, and body weight was recorded on the day that vaginal opening or preputial separation was completed.
Postmortem examinations (parental animals):
Parental males were killed when the majority of litters had reached 2 weeks of age. Immediately after sacrifice, one epididymis (normally the left) was removed, weighed, and samples of fluid obtained from the cauda were diluted for assessment of sperm count, motility, and morphology. The
whole left testis was taken and frozen (220°C) before determination of homogenisation-resistant spermatid count.
Females were killed after their litters had been weaned. All animals were subject to complete gross necropsy, and any abnormal tissues were retained for further examination.
The following organs were also routinely removed: adrenal glands, brain, epididymides, kidneys, liver, caudal mammary gland, ovaries, oviduct, pituitary, prostate, seminal vesicles and coagulation gland, spleen, right testis, thymus, uterus and cervix, and vagina. Uteri were examined for the number of implantation sites [13]. Organs were stored in 4% neutral buffered formaldehyde, except the right testis, which was fixed in Bouin’s fluid for 24 h, before transfer into 70% industrial methylated spirit. In addition, liver sections from selected F1 male adults were frozen before analysis of cyanide-insensitive palmitoyl CoA oxidase activity.
HISTOPATHOLOGY
All organs from the control and high dose were examined microscopically, as well as those from the low and intermediate treatment groups that were found abnormal under macroscopic evaluation.

Postmortem examinations (offspring):
F0 offspring not selected for continuation, and all F1 offspring, were killed at PND 25 and examined macroscopically for abnormalities. Any abnormal tissues were retained for further examination. The following organs were also routinely removed: brain, epididymides, liver, ovaries, oviduct, prostate, seminal vesicles and coagulation gland, spleen, testes, thymus, uterus and cervix, and vagina. Offspring culled on PND 4 were not subjected to formal necropsy, unless grossly abnormal. All adults and weaned animals were killed by CO2 asphyxiation.
Offspring culled on PND 4, and any killed humanely before PND 10 were killed with pentobarbitone sodium, administered by intraperitoneal injection.
HISTOPATHOLOGY
All organs from the control and high dose were examined microscopically, as well as those from the low and intermediate treatment groups that were found abnormal under macroscopic evaluation.
Statistics:
For organ and body weight data, homogeneity of variance was assessed with Bartlett’s test. Where this was statistically significant, pair-wise comparison was performed with the Behrens–Fisher test, otherwise Dunnett’s test was used. Intergroup differences in macroscopic pathology and histopathology were assessed with Fisher’s exact test. Food-consumption and litter data were analysed with parametric tests (analysis of variance followed by Williams’ test) or nonparametric tests (Kru´skal–Wallis followed by Shirley’s test) as appropriate. For litter data, the litter was generally taken as being the unit for analysis. Because most distributions were non-normal, nonparametric analyses were routinely used.
Reproductive indices:
Pre-coital interval, gestation length, number of live litters, implantation sites, litter size
Offspring viability indices:
- Live birth index (live offspring on PND 1 compared to total litter size on PND 1)
- Viability index (live offspring on PND 4 compared to live offspring on PND 1)
- Lactation index (live offspring on day of examination [PND7 and PND21] compared to offspring on PND 4 after culling)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
significantly (p < 0.01) reduced growth in males of highest dose group
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
significantly (p < 0.01) reduced growth in males of highest dose group
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
clear hepatotoxicity at the highest dose
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: reduced food intake in males of the highest dose group

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
slightly reduced gestation length in highest dose group

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No data shown

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Significantly reduced growth in F0 males within the first week of treatment, which accompanied reductions in food consumption and conversion efficiency. Male body weights in the highest dose groups were 75% to 80% of the concurrent control values after 6 weeks of exposure. The severity of this reaction was considered incompatible with the objectives of the study. Consequently, the highest level was reduced to 1.0% in the diet, for both males and females from week 7. From this point on, food conversion efficiency was the same in all groups, and body weight gain of males in the high exposure group was similar to control values. However, food consumption remained depressed in comparison to control, and body weights were consistently lower by about 20% to 25% in males until the time of mating. At the time mating commenced, mean body weights were 100%, 96%, and 76% of control in the 0.1%, 0.5%, and 1.0% D911P dose groups, respectively.
Females of both generations were less susceptible than the males. In the F0 generation, body weights of animals in the highest dose groups were only significantly affected by treatment with D911P, but were still within 10% of control values.
Overall, body weight gain by D911P exposed animals up to the time of mating was 86% of that in the control group.
Food consumption in female animals was similar for all treatment groups of both generations through gestation and lactation (not shown).

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
There were no apparent treatment-related effects on the regularity or duration of the oestrus cycle in all females of F0 and F1 generation

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Testicular spermatid count was significantly higher than control in all D911P-treatment groups of the F0 generation (p < 0.05). In the F1 generation no significant differences between treatment groups and controls occurred. Additionally, epididymal sperm counts and sperm quality were unaffected in F0 and F1 generation in all treatment groups. Therefore the increased testicular spermatid counts cannot be clearly attributed to treatment.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no apparent treatment-related effects on time to mating, fecundity or mating success in either generation.
Gestation length was slightly reduced in the highest dose group of F0 and F1 generations. The distribution of gestation lengths for animals exposed to 1.0% was significantly changed toward shorter duration compared to the control group. The nature of the shift in gestation length induced by D911P was to reduce the modal value by 0.5 days. Parturition, litter size, and offspring body weights were unaffected by treatment. There were no effects of treatment with D911P upon the number of implantation sites, litter size, or pup survival in either generation. Pup growth was largely unaffected, except for slightly reduced body weights of offspring in the highest dosage groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Statistically significant changes in organ weights in both generations were generally limited to animals in the highest exposure group.
The weight of the seminal vesicles and prostate was reduced (p < 0.01) in highest dose group males. The weights of the testes were unaffected in all treatment groups. Animals exposed to D911P did not show significantly reduced ovary weight, but the weight of the uterus and cervix was reduced (p < 0.01) in the F0 generation. When organ weights were expressed in relation to body weight, most of the differences between the high-dose and other groups were no longer apparent. In the case of testes, epididymides (except F1 animals), and kidneys in males there was a significant increase in relative organ weight compared to control. However, uterus and cervix weight in the high dose group remained significantly depressed.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Macroscopic findings were largely limited to the livers of males in the high-dose groups. Livers were small, although lobes were swollen, pale, and showed areas of macroscopic change, whereas some had irregular surfaces. Surface changes in colour and texture were noted in a number of animals. There were low incidences of similar effects in males (swelling) and females (enlargement) of the intermediate- and high-dose groups.

HISTOPATHOLOGY (PARENTAL ANIMALS)
The range of microscopic findings in the high-dose males was indicative of periacinar hepatotoxicity, with consequential increased cell turnover and regenerative hyperplasia.
Bile duct proliferation and congestion probably resulted from the altered architecture of the liver. Again, similar effects were noted at lower incidence in males of the intermediate dosage group, and very restricted effects (periacinar vacuolation and necrosis or hypertrophy) were noted in females. In addition, there was a significant increase in the activity of palmitoyl coenzyme A oxidase activity, a marker of peroxisomal proliferation, in the livers of F1 males in both the intermediate- and high-dose groups.
No other organs, including the reproductive organs, showed any macroscopic or histologic changes considered to be related to treatment.

OTHER INFORMATION:
The NOEL for liver in parental and F1 animals based on microscopic examination was found to be 60 mg/kg bw/d (0.1% in diet).

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
reproductive health parameters and general systemic toxicity
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Remarks:
equivalent to 0.5% in diet
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Remarks:
reproductive health parameters and general systemic toxicity
Effect level:
620 mg/kg bw/day
Based on:
test mat.
Remarks:
equivalent to 1.0% in diet
Sex:
male/female
Basis for effect level:
other: reduced parental body weight gain (F0 and F1 males), and reduced reproductive organ weights (males and females of F0 and F1)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced body weights of F1 male and female offspring in the highest exposure group during the last 2 weeks of lactation, reduced body weight gains in F1 males of the highest dose group
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
in F0 and F1 males and females of highest dose group
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
changes in livers of the highest dose group
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
clear hepatotoxicity at the highest dose

Details on results (F1)

VIABILITY (OFFSPRING)
No significant differences were found in live birth index, viability index and lactation index between treatment and control groups of F0 and F1 generations

CLINICAL SIGNS (OFFSPRING)
No effects

BODY WEIGHT (OFFSPRING)
After formal allocation of offspring to the F1 generation (approx. 28 days of age), body weights in all F1 males were comparable for the first 2 or 3 weeks of treatment after weaning. However, from about the fifth week, males in the highest dose group exhibited reduced body weight gain compared to controls. As in the case of the F0 generation, this response accompanied slight reductions in food consumption and conversion. The deviation from control values of body weights in the highest dose groups increased from 4 to 6 weeks, reaching a nadir of about 90% by week 6.
Females of both generations were less susceptible than the males. In the F0 generation, body weights of animals in the highest dose groups were only significantly affected by treatment, but were still within 10% of control values.
Females of the F1 generation were unaffected by treatment, and food consumption and conversion efficiency were similar for all groups of animals.
Mean pup weights of F1 male and female offspring (F2) were reduced in the highest exposure group during the last 2 weeks of lactation.

SEXUAL MATURATION (OFFSPRING)
The age of onset of sexual maturation—defined as the day at which preputial separation and vaginal opening were completed—in females was similar in all groups. Preputial separation in males appeared to be delayed by ~1 day in the highest dose group, but this apparent difference was not statistically significant (p < 0.05) and the values were within the range of laboratory historical controls.

ORGAN WEIGHTS (OFFSPRING)
Statistically significant changes in organ weights in both generations were generally limited to animals in the highest exposure group.
The weight of the seminal vesicles and prostate was reduced (p < 0.01) in highest dose group males. The weights of the testes were unaffected in all treatment groups. Animals exposed to D911P did not show significantly reduced ovary weight, but the weight of the uterus and cervix was reduced (p < 0.01) in the F0 generation. When organ weights were expressed in relation to body weight, most of the differences between the high-dose and other groups were no longer apparent. In the case of testes, epididymides (except F1 animals), and kidneys in males there was a significant increase in relative organ weight compared to control. However, uterus and cervix weight in the high dose group remained significantly depressed.

GROSS PATHOLOGY (OFFSPRING)
Macroscopic findings were largely limited to the livers of males in the high-dose groups. Livers were small, although lobes were swollen, pale, and showed areas of macroscopic change, whereas some had irregular surfaces. Surface changes in colour and texture were noted in a number of animals. There were low incidences of similar effects in males (swelling) and females (enlargement) of the intermediate- and high-dose groups.
There were no macroscopic changes in offspring killed before weaning or at 25 days of age that were attributed to treatment (not shown);

HISTOPATHOLOGY (OFFSPRING)
The range of microscopic findings in the high-dose males was indicative of periacinar hepatotoxicity, with consequential increased cell turnover and regenerative hyperplasia.
Bile duct proliferation and congestion probably resulted from the altered architecture of the liver. Again, similar effects were noted at lower incidence in males of the intermediate dosage group, and very restricted effects (periacinar vacuolation and necrosis or hypertrophy) were noted in females. In addition, there was a significant increase in the activity of palmitoyl coenzyme A oxidase activity, a marker of peroxisomal proliferation, in the livers of F1 males in both the intermediate- and high-dose groups.
No other organs, including the reproductive organs, showed any macroscopic or histologic changes considered to be related to treatment.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Remarks:
reproductive health parameters and general systemic toxicity
Generation:
F1
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Remarks:
equivalent to 0.5% in diet
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Remarks:
reproductive health parameters and general systemic toxicity
Generation:
F1
Effect level:
620 mg/kg bw/day
Based on:
test mat.
Remarks:
equivalent to 1.0% in diet
Sex:
male/female
Basis for effect level:
other: reduced parental body weight gain (F0 and F1 males), transient depression of offspring (F2) body weight gain (males and females) and reduced reproductive organ weights (males and females of F0 and F1)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Completion of preputial separation (PS) and vaginal opening (VO) in animals of the F1 generation exposed to D911P in the diet

 

Dietary Concentration (%)

D911P

 

0

0.1

0.5

1.0

Historical Controla

Males

 Age at PS (d)

 

44.8±2.3

(41-50)

 

44.6±2.5

(41-50)

 

44.6±2.7

(41-50)

 

46.1±2.8

(43-52)

 

43.7-47.3b

41-57c

 Bodyweight at PS (g)

235±22

229±27

228±23

237±26

 

Females

 Age at VO (d)

 

34.7±2.0

(30-38)

 

35.3±2.3

(32-41)

 

34.9±3.3

(30-42)

 

35.0±2.2

(31-41)

 

33.0-35.7b

29-40d

 Bodyweight at VO (g)

128±16

123±17

119±18

122±16

 

alaboratory historical control ranges for CD rats

bgroup mean values, n = 7

cindividual animal values, n = 197

dindividual animal values, n = 198

Testicular and epididymal sperm counts and sperm quality in F0 and F1 rats exposed to D911P in the diet

 

Dietary D911P Concentration (%)

F0Generation

F1Generation

0

0.1

0.5

2.0/1.0a

0

0.1

0.5

1.0

Number of animals

27

28

28

28

28

27

28

27

Testis spermatid count (106/g)

108±33

139±49*

134±41*

136±51*

122±43

123±45

114±37

115±50

Epididymis sperm evaluation

 Sperm count (107/mL)

 Motile (%)

 Progressively motile (%)

 Normal morphology (%)

 

 

219±47

76±8

40±9

 

96±3

 

 

227±71

 75±10

40±10

 

95±4

 

 

223±58

73±11

38±9

 

95±3

 

 

206±61

73±15

39±10

 

93±11

 

 

215±60

77±8

38±7

 

91±9

 

 

200±55

77±8

38±8

 

92±7

 

 

199±36

77±6

40±7

 

89±11

 

 

201±50

75±8

37±7

 

89±12

 

a2.0% from week 1 through to week 3, 1.0% thereafter

Applicant's summary and conclusion