Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OTS 798.4700 (Reproduction and Fertility Effects)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: 1,2-dichloropropane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: drinking water
Details on mating procedure:
Premating Exposure Period
male: 10 - 14 wk
female: 10 - 14 wk
Duration of treatment / exposure:
41 wk (f0 adults)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.024%, 0.10%, 0.24%
Basis:

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
0.024 other: %
Sex:
male/female
Basis for effect level:
reproductive performance
Key result
Dose descriptor:
NOEL
Effect level:
0.24 other: %
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: Generation: reproduction (migrated information)

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
0.1 other: %
Sex:
male/female
Basis for effect level:
other: Decreased water consumption and lowered body weight, and increased hepatocellular granularity were present in parental animals from the 0.24% groups of both generations.

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
0.1 other: %
Sex:
male/female
Basis for effect level:
other: Decreased water consumption and lowered body weight, and increased hepatocellular granularity were present in parental animals from the 0.24% groups of both generations.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Analysis of dosing solutions and received dose Mean exposure concentrations (determined on 3-4 occasions and presented as percent nominal with SD in parentheses) for the low, mid and high dose groups were as follows:

f0 males: 88.8 (6.1), 98.2 (7.3), 100.0 (8.2)

f0 females: 90.3 (6.9), 100.4 (4.3), 102.4 (8.4)

f1 males: 100.7 (29.0), 96.0 (0.9), 95.3 (2.2)

f1 females: 94.6 (21.8), 97.7 (2.6), 96.1 (3.1)

GENERAL

Endpoint

0.024% PDC

0.1% PDC

0.24% PDC

F0

F1

F0

F1

F0

F1

Male Bwts

 

 

 

Female Bwts (pre-breed)

 

 

 

 

Water Consumption (M + F)

Gestation Bwt

 

 

 

Gestation Bwt Gain

 

Slight ↓

Slight ↓

Gestation Water Consumption

 

 

Gestation Feed Consumption

 

Slight ↓

 

Slight ↓

 

Lactation Bwt

 

 

 

Lactation Bwt Gains

 

Slight ↓

 

 

Lactation Water Consumption

 

Lactation Feed Consumption

 

 

 

 

 

F1

F2

F1

F2

F1

F2

Litter Size

 

 

 

 

 

Postnatal Survival

 

 

 

 

Neonatal Bwt

 

 

 

 

PARENTAL GENERATIONS

Received dose Based upon mean body weight and water consumption data, males of both generations from the low, mid and high dose groups received approx. 20 - 30, 70 - 130 and 130 - 250 mg/kg bwt/d. Equivalent female groups received 30 - 40, 110 - 140 and 190 - 270 mg/kg bwt/d. Female water consumption increased during lactation, with received doses of approx 60, 200 450-500 mg/kg bwt/d.

Group

Phase

Received dose (mg/kg bwt/day)

Treatment level

0.024%

0.10%

0.24%

f0 males

pre-mating

28

91

161

 

post-mating

18

65

131

f0 females

pre-mating

33

108

189

 

gestation

38

121

217

 

lactation*

58

196

507

 

 

 

 

 

f1 males

pre-mating

33

128

250

 

post-mating

19

69

137

f1 females

pre-mating

41

140

269

 

gestation

38

126

239

 

lactation*

56

200

450

* Note: greater exposure reflects increased water consumption during lactation

In life observations

No treatment-related clinical signs were observed.

Food consumption

There were relatively minor and sporadic effects on food intake. f0 females from the high and low dose groups consumed 10% and 6% less than the controls, while f1 males from the high dose group showed an overall 8% reduction in food consumption (pre-mating and mating phases). Food intake data for the other groups were generally unremarkable.

Water consumption

A dose-related decrease in water consumption was apparent in animals from both the f0 and f1 generations, presumably reflecting reduced palatability in the mid and high dose groups. Overall, water consumption in high dose males and pregnant females was 50-60% of control, and 70% of control in lactating females. Water intake in mid dose males and mid dose pregnant females was 70 - 80% of control, and 75 - 85% of control consumption in mid dose lactating females. Results for the low dose animals were 90 - 104% of control. NOTE: Water consumption typically increases from around gestation day 13 in order to compensate for increased plasma and extracellular fluid volumes during the late stages of pregnancy. This was not the case in this study, due to the unacceptable palatability of the drinking water. This would be expected to have an adverse influence on fetal development. It is also pertinent that water consumption in untreated (control) females increased in this study during lactation, whereas major reductions were apparent in treated animals during lactation. This would be expected to have impacted post-natal survival of the pups.

Parental body weight

Body weights for the high dose animals were significantly (alpha = 0.05) lower than control in f0 and f1 generations of both sexes. In terms of affecting reproductive outcomes, effects in females appeared particularly important. Thus body weights for high dose f0 and f1 females were 5% and 11% lower than control during the pre-mating period, with a 10 - 12% decrement present during gestation and an approx. 15% reduction during lactation. Gestation body weight gains were decreased by approx. 20% in f0 and f1 females given 0.24% PDC, and by 7-13% in females given 0.1% PDC. Less consistent body weight decrements were noted in the mid dose animals, with negligible effects in the low dose generations.

Reproductive indices

There were no significant or obvious treatment-related differences in male or female reproductive performance, as assessed from mating- and conception indices, fertility or gestational period. Sporadic differences seen for some female parameters were not dose-related (ie present in low and/or mid but not high dose animals) or were within the range of historic control data. All females produced viable litters.

Hematology

Sporadic hematological changes noted in this study were not dose related and inconsistently expressed in males and females of the same generation and in same sex animals of different generations. Overall these effects appeared incidental and unrelated to treatment with PDC.

Necropsy observations

Increased relative kidney weight values in high dose animals (both sexes) appeared secondary to a lower terminal body weight. No gross pathological changes were noted in any of the parental animals.

Histology

Treatment-related histologic changes were limited to increased hepatocellular granularity (adaptive change) in males and females of both generations at all dose levels. Although no statistical analyses are reported, the incidence in high dose females (17% and 10% for f0 and f1, resectively) and high dose f1 males (13%) appears greater than control (0 - 2% for all sex/generation groups). The response in f1 high dose males (5% incidence) and mid and low dose animals of the other generations were less pronounced (2 - 8% incidence) and/or not dose related. All other tissues, including reproductive organs from both sexes, were unremarkable.

LITTER DATA

There were no significant treatment-related external observations or difference in sex ratio in either generation. The number of pups born alive was similar in the control and test groups from both phases of the study, however postnatal survival in high dose f1 litters was significantly lower than control while that of the high dose f2 litters was 10% lower than controls on PND 14 and 21; these effects appeared treatment-related. Bodyweights for high dose f0 neonates were significantly decreased, with day 21 values approx. 15% lower than control. Bodyweights of f1 litters were less severely affected (4 - 7% reduction), and attained significance only on lactation day 21.

WEANLING DATA

An increased hemoglobin concentration in high dose f1 males and an increased mean relative kidney weight in high dose f1 females appeared related to a lowered water intake and body weight, respectively. All other hematological and gross necropsy observations were comparable to control in both the f1 and the f2 generations.

Applicant's summary and conclusion

Conclusions:
Propylene dichloride was not a reproductive toxin when tested over 2 generations in SD rats exposed to 0.024%, 0.1% and 0.24% in drinking water.
Decreased water consumption (presumably reflecting unacceptable palatability of the test solution) and lowered body weight, and increased hepatocellular granularity (adaptive change), were present in parental animals from the 0.24% groups of both generations. Neonatal growth and survival were decreased in the 0.24% treatment groups, probably in response to decreased maternal water intake and lower growth. There was no effect on reproductive performance, live births or litter size in any of the test groups. Thus the NOAEL for adults and neonatal effects was 0.1% PDC
while the reproductive NOEL was 0.24% PDC, the limit of solubility.