1,2-Benzenedicarboxylic acid, di-C11-14-branched alkyl esters, C13-rich

Endpoint summary

Description of key information

The target organ for oral sub-acute and sub-chronic DIDP toxicity in animals (rodent and dog) appears to be the liver (increased liver weights and significant changes in liver peroxisomal enzyme activities in rodents). It is clear that NOAELs derived from rat studies are related to peroxisome proliferation-mediated liver effects, which are considered to be species specific. Humans are less sensitive than rats.  The overall NOAEL for systemic effects following oral exposure in rats was 150 mg/kg/d. 
In a six-week dermal study with DINP, there was no evidence of systemic toxicity. Mild irritation was observed at the application sites of animals treated with DINP, although there was no difference in the severity of histopathological skin changes apparent between test and control animals. The systemic NOEL was considered to be 2.5 ml/kg/day (estimated to be 2500 mg/kg/day) and the local NOAEL was considered to be 0.5 mg/kg/day (estimated to be 500 mg/kg/day). 
In a two week inhalation study with DIDP, no systemic toxicity was observed, but local irritant effects were observed at the concentration tested, thus a NOAEL of 0.5 mg/l (500 mg/m3) can be assumed. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

150 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

500 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

500 mg/kg bw/day

Additional information

The High Molecular Weight Phthalate Ester (HMWPE) Category consists of phthalate esters with an alkyl carbon backbone with 7 carbon (C7) atoms or greater. The category is formed on the principle that substances of similar structure have similar toxicological properties. The data available on high molecular weight phthalates demonstrate that members of this category have similar biological activities and toxicological properties; verifying the use of read-across data as an appropriate approach to characterize endpoints. DTDP (C13) is a high molecular weight phthalate ester. Where data maybe lacking for DTDP, DINP (C9) and DIDP (C10), which are also high molecular weight phthalate esters, are used as read-across substances to provide toxicological information.  

Oral:

Di-isodecyl phthalate was fed to groups of five male and five female F344 rats at dietary levels of 0, 0.3, 1.2, or 2.5% for 21 days. A further group of five rats of each sex, fed 1.2% DEHP, served as a study control. Male rats given 1.2 or 2.5% showed decreased body weights as compared to control; this was seen in the females but to a lesser extent. Food intakes were reduced initially in both sexes given 1.2 or 2.5%, the effect persisting throughout treament in males given 2.5%. Absolute and relative liver weights and relative kidney weights were increased in both sexes given 1.2 or 2.5% test substance in the feed. In males given 2.5%, relative testis weights were significantly greater and no lesions were seen histologically. There was a reduction in hepatocyte cytoplasmic basophilia in rats fed 1.2 or 2.5% and in the latter group this was associated with an increase in eosinophilia. Lower periportal lipid levels were seen but this was not dose related. Serum tyiglycerides and cholesterol levels were reduced in males given 1.2 or 2.5% test substance, but no dose relationship was apparent. Both sexes given 2.5% in feed showed a marked but variable increase in peroxisome numbers and size, the females showing a greater response. Cyanide-insensitive palmitoyl-CoA oxidation was significantly increased in all treated animals except those given 0.3% in feed. There was a significant increase in the 11- and 12- hydroxylation of lauric acid in all treated males, but in the females the only significant increase was in the 12- hydroxylase level in those given 2.5% of the test substance. Therefore, the NOAEL = 0.3% (280 mg/kg/day) and LOAEL = 1.2% (1100 mg/kg/day).

 

In a Hazelton Laboratories, 1968 study, DIDP was administered to four groups of 10 male and 10 female rats in dietary levels of 0.05%, 0.3% and 1% (approximately 25, 150 and 500 mg/kg/d, respectively) for 90 days. A group of untreated rats served as control. No compound-related effects were observed at any dietary levels with regard to physical appearance, behavior or survival. Growth of the test rats was not significantly affected. Body weight gains for the two highest levels in males were lower than controls (but not significantly different) and the two test groups were comparable through the ninth week. Overall, weight gains at 13 weeks for the male test groups showed a dose-related, although slight, decrease. Body weight gains for the high dose females were only slightly lower than the controls. Food consumption values were comparable to the controls. The clinical laboratory values for the test groups showed no significant compound-related differences from control values. Observations at necropsy revealed the livers of the high dose group animals, particularly the males, to be markedly larger than those of the control rats. Statistical analysis revealed the liver weights and liver/body weight ratios for the high dose group males and females to be significantly higher than those for the corresponding controls. No other consistent gross changes were noted in the liver. Histologically, the liver showed no compound-induced alterations. The kidney/body weight ratios but not the absolute weights in the high and intermediate dose group males were significantly higher than those for the corresponding controls. Histologically, the kidneys showed no compound-induced alterations. It can be concluded from this study that the NOAEL is 0.3% (about 150 mg/kg/d) based on the fact that the highest dose leads to liver effects. Relative (but not absolute) kidney weights were affected at this intermediate dose, probably due to a lower body weight.

 

In a subchronic toxicity study, DIDP was administered in the diet to three beagle dogs/sex/dose at dose levels of 500, 3000, or 10,000 ppm for 13 weeks. Actual average doses were approximately 13, 70, and 263 mg/kg/day for males and 14, 72, and 280 mg/kg/day for females. Absolute and relative liver weights for the 10,000 ppm males were 25 and 37% higher, respectively, and for females were 51 and 44% higher, respectively, than the corresponding control weights. In the 10,000 ppm treatment groups, the livers from 1 of 2 males and 3 of 3 females showed swollen, vacuolated hepatocytes, and the livers from 1 of 2 males and 1 of 3 females showed minimal to slight pericholangitis and slight bile duct proliferation (the liver from the 3rd male was not examined). No dogs died during the study. No treatment-related differences in clinical appearance, body weights, body weight changes, food consumption, ophthalmology, hematology, clinical blood chemistry or urinalysis parameters or gross pathology were observed between dogs in the treated and control groups. The LOEL for this study is 10,000 ppm (~265 mg/kg bw/day), based on increased absolute and relative liver weights and the presence of swollen vacuolated hepatocytes from the high dose male and female dogs. The NOEL is 3,000 ppm (~75 mg/kg bw/day).

 

The dose-response relationship for induction of hepatic peroxisome proliferation by DEHP and DIDP was assessed in 42-day-old male Fischer 344 rats for 28-days. Groups of 5 rats were fed with 1% DEHP (control) and 0.02-0.05-0.1-0.3 and 1% (approximately 25-57-116- 353- 1,287 mg/kg/d) DIDP diet. The sample of DIDP used was made up of equal part by weight of Hexaplas (ICI), Jayflex DIDP (Exxon) and Palatinol Z (BASF). Food consumption and body weight were checked twice weekly, hepatic peroxisome proliferation was assessed by measurement of cyanide-insensitive palmitoyl-CoA oxidation activity. Testicular atrophy was also checked (organ weight and histological changes). This study was performed according to GLP procedures. Over the course of the study, body weight of animals fed DIDP, at all levels in the diet was not significantly different compared to controls. The two phthalates esters produced dose-related liver enlargement. At 0.1% and higher, there was a statistically significant increase in relative liver weight (3.3158 g/100 g bodyweight vs. 3.0488 g/100 g bodyweight in controls). At 0.3% and higher, this statistically significant increase was also noticed for absolute liver weight (6.6812 g vs. 5.5830g in controls). Biochemical examination of the livers revealed no effect on the whole homogenate of protein content, but an induction of the enzymes of the peroxisomal fatty acid beta-oxidation cycle. In this way palmitoyl-CoA oxidation activity was statistically dose-related increase from 0.1% expressed as μmol/min/liver weight/100g bodyweight (4.52 vs. 3.71 in controls), and from 0.3% expressed either as nmol/min/mg protein or as μmol/min/g liver (respectively 11.82 vs. 5.60 and 2.67 vs. 1.22). These slight increases at 0.1% (increase of relative liver weight and of palmitoyl-CoA activity) could be considered as the trend for peroxisome proliferation effects, clearly confirmed at 0.3% (increase of absolute liver weights and increased enzyme activity whatever the units of expression). NOELs for food consumption and enzyme activity were reported to be 51.7 mg/kg/d for DEHP. No testicular atrophy was reported at the highest dose tested: 1,093 mg/kg/d for DEHP and 1,287 mg/kg/d for DIDP.

 

Dermal:

In a six week dermal toxicity study, groups of four New Zealand White rabbits received 24-hour daily applications of DINP at 0.5 or 2.5 ml/kg, five times a week, to the closely clipped intact (two animals per group) or abraded (two animals per group) abdominal skin, wrapped with gauze adhesive tape and fitted with neck collars. Control animals (three males and one female) received mineral oil at 2.5 ml/Kg. Clinical signs were recorded daily, hematology and urinalysis undertaken initially and terminally, and histopathology was performed on the liver, kidneys and skin. There was no evidence of systemic toxicity. Mild irritation was observed at the application sites of animals treated with DINP, although there was no difference in the severity of histopathological skin changes apparent between test and control animals. The systemic NOEL was considered to be 2.5 ml/kg/day (estimated to be 2500 mg/kg/day) and the local NOAEL was considered to be 0.5 mg/kg/day (estimated to be 500 mg/kg/day).

 

Inhalation:

In a 2-week study (General Motors Research Laboratories, 1981) designed to evaluate the fate of DIDP (see Section 5.1), toxicity was assessed. DIDP was administered to 8 male rats (6 for control) by inhalation (aerosol) at analytical concentration of 505±7 mg/m3(MMAD: 0.98 μm) 6 hours a day, 5 times per week. Rats were observed daily for body weight gain, appearance and gross behavior. Animals were sacrificed at the end of the observation period (3 weeks) and tissue samples taken for histopathology. There were no marked outward signs of toxicity during exposure. The rate of body weight gain was not different between control and exposed animals. Effects in the lungs were: moderate increase in the width of alveolar septa with slight interstitial mixed inflammatory reactions, alveolar macrophages and type II pneumocytes were increased in number, peribronchial lymphoid tissue appeared slightly more prominent. In liver, spleen and kidneys, no obvious histologic alterations were noted except for a slight hepatic fatty metamorphosis. No systemic toxicity, but local irritant effects were observed at the concentration tested, thus a NOAEL of 0.5 mg/l (500 mg/m3) can be assumed.

 

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

No classification as a repeated dose toxin is indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.