Butanedioic acid, sulfo-, monoesters with lanolin alcs., disodium salts

Toxicity to reproduction

Administrative data

Endpoint:

three-generation reproductive toxicity

Type of information:

other: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data have been obtained from a publication of a study on a substance with structural similarity. The test was performed under GLP.

Data source

Reference

Reference Type:

publication

Title:

Three generation reproduction study with dioctyl sodium sulfosuccinate in rats.

Author:

MacKenzie K, Henwood S, Foster G, Akin F, Davis R, Debaecke P et al.

Year:

1990

Bibliographic source:

Fundam. Appl.Toxicol. 15(1):53-62, 1990

Materials and methods

Principles of method if other than guideline:

Three-generation study by feeding administration on diet.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dioctyl Sodium Sulfosuccinate (DSS)

IUPAC Name:

Dioctyl Sodium Sulfosuccinate (DSS)

Test animals

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7 weeks, no littermates
- Diet: basal (ground Purina Certified Rodent Chow N.5002)
- Acclimation period: 4 weeks

Administration / exposure

Route of administration:

oral: feed

Vehicle:

acetone

Details on exposure:

DIET PREPARATION
Test diets (ground Purina Certified Rodent Chow No. 5002) containing dioctyl sodium sulfosuccinate (DSS) dissolved in acetone were mixed weekly.

EXPOSURE BY DIET
F0: female rats) were fed the basal diet or a test for 10 and 2 weeks, respectively.
F1: groups of 30 male and 30 female F1 animals were fed the same dose levels for at least 10 weeks postweaning, and the breeding program was repeated to produce F2 animals
F2: feeding procedure was repeated with F2 animals to produce F3 offspring.

Details on mating procedure:

Three-generation study:
Female rats fed (F0) were mated to produce an F1 litter.
Sibling and half-sibling mating were avoided.
F2 animals were produced;
F3 offspring were produced.

Details on analytical verification of doses or concentrations:

Samples of test diets were assayed periodically for DSS to verify homogeneity and stability of DSS after storage.

Duration of treatment / exposure:

2 -1 0 weeks

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.1 % DSS
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.5 %DSS
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1 %DSS
Basis:
nominal in diet

No. of animals per sex per dose:

P: groups of 30 male and 30 female
F1: groups of 30 male and 30 female

Examinations

Parental animals: Observations and examinations:

BODY WEIGHT: recorded weekly for males and before mating, Days 0, 7, 14 and 20 of gestation and Days 0, 7, 14 and 21 of lactation for females.
FOOD CONSUMPTION: was recorded on males and females weekly before mating, and twice weekly during gestation and lactation (females only).

Litter observations:

Individual pup weights and the number of pups born live or found dead were recorded on lactation Day 0.
Intact dead pups were examined and preserved.
The number and sex of pups and individual pup weights were recorded on lactation Day 4.
Pups were culled from litters to achieve a maximum of 10 (5 of each sex if possible)/ litter.
Pups were weighed and examined externally on Days 7, 14 and 21 of lactation.

Postmortem examinations (parental animals):

All F0, F1 and F2 animals were observed twice daily during the study and subjected to gross necropsy upon study termination.

Postmortem examinations (offspring):

Twenty weanlings/sex/group from the F3 litter were necropsied.

Organs grossly examined at necropsy were colon, duodenum, epididymides, ileum, jejunum, kidneys, liver, mammary gland (with skin), ovaries, prostate, seminal vesicles, stomach, testes, uterus and vagina.

Statistics:

Statistical Analyses:
Body weight, food consumption, reproductive indices, precoital interval, length of gestation, pup viability and body weight, sex ratios and litter size (alive and dead by sex) were analysed using a oneway ANOVA.
When necessary, data were transformed to achieve homogeneity. Dunnett's t-test was used to compare means of groups analysed by ANOVA. Data that could not be transformed to homogeneity were analysed nonparametrically, using a Kruskal-Wallis test.
The Nemenyi, Nemenyi-Kruskal-Wallis or Wilcoxon-Mann-Whitney two sample rank test were used compare non parametric means.
Reproductive indices and the total number of live and dead pups were analyzed by the Cochran-Armitage test for trend and the Fisher-Irwin exact test for heterogeneity.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not examined

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

BODY WEIGHT AND FOOD CONSUPTION:
F0, F1 and F2 males treated with 1.0% DSS was significantly less than controls at week 4, weeks 2, 4, 8, and 10, and weeks 2 and 10, respectively.
There was no consistent effect of any dose on food consumption in females.
Body weights of F1 males and females treated with 1.0% (131 and 114 g, respectively) were lower than controls(149 and 127 g, respectively) and final weights of F1 (447 g) and F2 (467 g) males and females(255 and 269 g, respectively) treated with 1.0% and F2 males treated with 0.5% (492 g)were lower than their respective controls (510 and 531 g for F1 and F2males, and 281 and 285 g for F1 and F2 females, respectively).
Mean birth weight of male (6.1 g) and female (5.8 g) pups born to animals treated with 1.0% were significantly lower than control (6.7 and 6.4, respectively).
REPRODUCTIVE INDICES:
There was no effect of treatment on the total number of pups (ranged from 326 for F3 treated with 0.1% to 416 for F1 control) or litters [ranged from 25 for F3 treated with 0.1% to 30 for four other groups (F1 control, 0.1 and 1.0% F1 and 1.0% F2)], litter size (ranged from 5.9 for F1 males treated with 1.0% to 7.2 for female F2 control) or sex ratio (ranged from 47.2 for F2/1.0% to 51.5 for F2/0.5%).
Perinatal pup survival across the three generations was 99% for controls and ranged from 96% (for F3 generation of animals treated with 1.0%; significantly different from control of 99%) to 100% for the treated groups.
The pup survivability ranged from 95-100% for controls, from 98-100% for low- and mid-dose groups and from 91-99% for the high dose group (no effect of treatment). There were no treatment related mortality and antemortem or microscopic observations in any animals examined (F0, F1 and F2 adults and F3
weanlings).

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

0.1 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings:

not examined

Details on results (F1)

WEIGHT AND FOOD CONSUPTION:
all three generations of male and female pups born to animals treated with 0.5% (43, 43 and 49 g for F1, F2 and F3 males and 41, 42 and 46 g for females) or 1.0% (36, 36 and 38 g for F1, F2 and F3 males and 34, 35 and 37 g for females weighed significantly less than controls on Day 21 (47, 49 and 54 g for F1, F2 and F3 males and 45, 46 and 51 g for females, respectively).
No milk was found in the abdomens on lactation day 4 in 3 control F2 pups, 7 F2 pups in the 0.1% dose group, 18 F2 pups and 1 F3 pup in the 0.5% dose group, and 10 F2 pups and 17 F3 pups in the 1.0% dose groups.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

0.1 other: %

Sex:

male/female

Basis for effect level:

other: NOAEL listed is for effect on lactation and pup weight on Day 21.

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEC

Generation:

F2

Effect level:

0.1 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL listed is for effect on lactation and pup weight on Day 21.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

DSS at 0.5 and 1.0% affected lactation. Reduced body weights in animals receiving 0.5 or 1.0% did not interfere with growth and development or normal reproductive performance.
NOAECs for P, F1 and F2 generation, based on the effect on lactation and pup weight on Day 21 were 0.1 % of DSS dose in diet.

Executive summary:

Diet containing 0.1, 0.5 or 1.0 Dioctyl Sodium Sulfosuccinate (DSS) dissolved in acetone was administered to a groups of 30 male and 30 female rats for 10 and 2 weeks. These animals (F0)were then mated to produce an F1 litter.

Groups of 30 male and 30 female F1 animals were fed the same dose levels for at least 10 weeks postweaning, and the breeding program was repeated to produce F2 animals.

The same feeding and mating procedure was repeated with F2 animals to produce F3 offspring. The study was terminated upon weaning of the F3 generation.

Individual pup weights and the number of pups born live or found dead were recorded on lactation Day 0.

The number and sex of pups and individual pup weights were recorded on lactation Day 4.

Pups were weighed and examined externally on Days 7, 14 and 21 of lactation.

Twenty weanlings/sex/group from the F3 litter were necropsied.

Weanlings not selected for mating or necropsy were examined externally.

All F0, F1 and F2 animals were observed twice daily during the study and subjected to gross necropsy upon study termination. Organs grossly examined at necropsy were colon, duodenum, epididymides, ileum, jejunum, kidneys, liver, mammary gland (with skin), ovaries, prostate, seminal vesicles, stomach, testes, uterus and vagina.

Body weights were recorded weekly for males and before mating, Days 0, 7, 14 and 20 of gestation and Days 0, 7, 14 and 21 of lactation for females. Food consumption of males and females was recorded weekly before mating, and twice weekly during gestation and lactation (females only).

Statistical Analyses were done.

RESULTS:

Food consumption of F0, F1 and F2 males treated with 1.0% DSS was significantly less than controls at week 4, weeks 2, 4, 8, and 10, and weeks 2 and 10, respectively.

There was no consistent effect of any dose on food consumption in females.

Body weights of F1 males and females treated with 1.0% (131 and 114 g, respectively) were lower than controls (149 and 127 g, respectively) and final weights of F1 (447 g) and F2 (467 g) males and females (255 and 269 g, respectively) treated with 1.0% and F2 males treated with 0.5% (492 g)were lower than their respective controls (510 and 531 g for F1 and F2males, and 281 and 285 g for F1 and F2 females, respectively). Mean birth weight of male (6.1 g) and female (5.8 g) pups born to animals treated with 1.0% were significantly lower than control (6.7 and 6.4, respectively).

All three generations of male and female pups born to animals treated with 0.5% (43, 43 and 49 g for F1, F2 and F3 males and 41, 42 and 46 g for females) or 1.0% (36, 36 and 38 g for F1, F2 and F3 males and 34, 35 and 37 g for females weighed significantly less than controls on Day 21 (47, 49 and 54 g for F1, F2 and F3 males and 45, 46 and 51 g for females, respectively). No milk was found in the abdomens on lactation day 4 in control F2 pups, 7 F2 pups in the 0.1% dose group, 18 F2 pups and 1 F3 pup in the 0.5% dose group, and 10 F2 pups and 17 F3 pups in the 1.0% dose groups.

Reproductive indices: There was no effect of treatment on the total number of pups (ranged from 326 for F3 treated with

0.1% to 416 for F1 control) or litters [ranged from 25 for F3 treated with 0.1% to 30 for four other groups (F1 control,

0.1 and 1.0% F1 and 1.0% F2)], litter size (ranged from 5.9 for F1 males treated with 1.0% to 7.2 for female F2 control)

or sex ratio (ranged from 47.2 for F2/1.0% to 51.5 for F2/0.5%).

Perinatal pup survival across the three generations was 99% for controls and ranged from 96% (for F3 generation of animals treated with 1.0%; significantly different from control of 99%) to 100% for the treated groups.

The pup survivability ranged from 95-100% for controls, from 98-100% for low- and mid-dose groups and from 91-99% for the high dose group (no effect of treatment). There were no treatment related mortality and antemortem or microscopic observations in any animals examined (F0, F1 and F2 adults and F3 weanlings).

The NOAEL for effect on lactation and pup weight on Day 21 were defined at 0.1 % of DSS on diet.

DSS at 0.5 and 1.0% affected lactation. Reduced body weights in animals receiving 0.5 or 1.0% did not interfere with growth and development or normal reproductive performance.